Methods for sustained lowering of blood pressure using manp

Abstract

This disclosure provides methods and compositions for lowering blood pressure in a patient in need thereof. This disclosure also provides methods and compositions for sustained lowering of blood pressure in a patient in need thereof. The methods provided therein may be used in combination with one or more antihypertensive drugs or diuretics.

Description

[0001] Attorney Docket No. P35514WO00 / 1105770.00037 METHODS FOR SUSTAINED LOWERING OF BLOOD PRESSURE USING MANP CROSS-REFERENCE TO RELATED APPLICATION AND INCORPORATION OF SEQUENCE LISTING This application claims the benefit of U.S. Provisional Application No.63 / 559,046, filed February 28, 2024, and U.S. Provisional Application No.63 / 757,547, filed February 12, 2025, which is incorporated by reference herein in its entirety. A sequence listing contained in the file named “P35514WO00_SL26.xml” which is 2,249 bytes (measured in operating system MS- Windows®), created on February 15, 2025, containing a total number of 1 SEQ ID NO is filed electronically herewith and incorporated by reference in its entirety. BACKGROUND OF THE INVENTION Hypertension, also known as high blood pressure (BP), is a long-term medical condition in which BP in the arteries is persistently elevated. While it usually does not cause symptoms, it is a major risk factor for stroke, coronary artery disease, heart failure, atrial fibrillation, peripheral arterial disease, vision loss, chronic kidney disease, and dementia. Difficult-to-control / Resistant Hypertension (DTC / RH) is a condition where blood pressure remains elevated despite optimal use of three antihypertensive medications of different classes, including a diuretic. Such patients are more likely to have a secondary cause and to suffer end-organ damage. DTC / RH remains challenging to treat and with no approved drugs or devices. Atrial natriuretic peptide (ANP) plays a key role in BP homeostasis. Specifically, ANP exerts a number of cardiorenal and metabolic actions through the particulate guanylyl cyclase Areceptor (GC-A) and its second messenger 3 ,5 -cyclic guanosine monophosphate (cGMP). Inhumans, higher levels of circulating ANP is associated with lower BP and protection from hypertension. African Americans are known to have lower levels of natriuretic peptides than white and Hispanic individuals. See e.g., Gupta D et al., “Racial differences in natriuretic peptide levels: the Dallas Heart Study,” JACC Heart Fail., 3(7):513-519 (2016). Although ANP has been regarded as a promising agent for treating hypertension, its rapid enzymatic degradation and the need for continuous intravenous infusion have limited its clinical development. MANP is a novel atrial natriuretic peptide (ANP) analogue engineered to overcome the therapeutic limitations of native ANP. A previous first-in-human study on the effects of MANP was performed in patients with essential hypertension subjects who were off medications. See Chen HH et al., “First-in-Human Study of MANP: A Novel ANP (Atrial Natriuretic Peptide) Analog in Human Hypertension,” Attorney Docket No. P35514WO00 / 1105770.00037 Hypertension, 78(6):1859-1867 (2021). The safety and efficacy of MANP in resistant hypertension is not known. It is also not known how baseline natriuretic peptide levels influence responses to MANP. SUMMARY The subject matter of the present disclosure is based in part on the surprising discovery that MANP administered to patients with resistant hypertension can lower blood pressure in a sustained manner, and without being bound to theory, may have greater effects in populations known to have lower levels of natriuretic peptides. In an aspect, the present disclosure provides a method for lowering blood pressure in a patient in need thereof, comprising: administering one or more doses of MANP of at least 4 μg / kg, wherein a first blood pressure of the patient, measured at a first timepoint after one of the one or more doses, is reduced by at least 5 mmHg compared to an initial blood pressure measured before receiving the first dose of MANP. In an aspect, the present disclosure provides a method for sustained lowering of blood pressure in a patient in need thereof, comprising: administering one or more doses of MANP, wherein a first blood pressure of the patient, measured at a first time interval of at least 24 hours after the one or more doses of MANP is administered, is at least 5 mmHg lower than an initial blood pressure of the patient measured before receiving the first dose of MANP. In an aspect, the present disclosure provides a method for lowering blood pressure in a subject identified as having a BMI greater than 29.9 kg / m2and hypertension, comprising: administering one or more doses of MANP, wherein a first blood pressure of the patient, measured at a first timepoint after one of the one or more doses, is reduced by at least 5 mmHg compared to an initial blood pressure measured before receiving the first dose of MANP. BRIEF DESCRIPTION OF THE DRAWINGS Aspects of the disclosure are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and are for purposes of illustrative discussion of aspects of the disclosure. In this regard, the description and the drawings, considered alone and together, make apparent to those skilled in the art how aspects of the disclosure may be practiced. FIG.1 depicts the sitting systolic blood pressure of study patients over the duration of the study. Attorney Docket No. P35514WO00 / 1105770.00037 FIG.2 depicts the change from baseline sitting systolic blood pressure of study patients over the duration of the study. FIG.3 depicts the sitting systolic blood pressure of study patients self-identified as African American over the duration of the study. FIG.4 depicts the sitting systolic blood pressure of study patients self-identified as non- African American over the duration of the study. FIG.5 depicts the change from baseline sitting systolic blood pressure of study patients self-identified as African American over the duration of the study. FIG.6 depicts the change from baseline sitting systolic blood pressure of study patients self-identified as non-African American over the duration of the study. FIG.7 depicts the sitting diastolic blood pressure of study patients over the duration of the study. FIG.8 depicts the change from baseline sitting diastolic blood pressure of study patients over the duration of the study. FIG.9 depicts the sitting diastolic blood pressure of study patients self-identified as African American over the duration of the study. FIG.10 depicts the sitting diastolic blood pressure of study patients self-identified as non- African American over the duration of the study. FIG.11 depicts the change from baseline sitting diastolic blood pressure of study patients self-identified as African American over the duration of the study. FIG.12 depicts the change from baseline sitting diastolic blood pressure of study patients self-identified as non-African American over the duration of the study. FIG.13 depicts the pre-dose systolic blood pressure of study patients. FIG.14 depicts the pre-dose systolic blood pressure of study patients self-identified as African American. FIG.15 depicts the change from baseline pre-dose systolic blood pressure of study patients. FIG.16 depicts the change from baseline pre-dose systolic blood pressure of study patients self-identified as African American. FIG.17 depicts the pre-dose diastolic blood pressure of study patients. FIG.18 depicts the pre-dose diastolic blood pressure of study patients self-identified as African American. FIG.19 depicts the change from baseline pre-dose diastolic blood pressure of study patients. Attorney Docket No. P35514WO00 / 1105770.00037 FIG.20 depicts the change from baseline pre-dose diastolic blood pressure of study patients self-identified as African American. FIG.21 depicts the mean cGMP levels of study patients. FIG.22 depicts the mean cGMP levels of study patients self-identified as African American. FIG.23 depicts the mean aldosterone levels of study patients. FIG.24 depicts the mean aldosterone levels of study patients self-identified as African American. DETAILED DESCRIPTION The present disclosure describes methods of lowering blood pressure and methods for sustained lowering of blood pressure in a patient in need thereof, comprising administering one or more doses of MANP. This description is not intended to be a detailed catalog of all the different ways in which the disclosure may be implemented, or all the features that may be added to the instant disclosure. For example, features illustrated with respect to one embodiment may be incorporated into other embodiment, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. Thus, the disclosure contemplates that in some embodiments of the disclosure, any feature or combination of features set forth herein can be excluded or omitted. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant disclosure. In other instances, well-known structures, interfaces, and processes have not been shown in detail in order not to unnecessarily obscure the invention. It is intended that no part of this specification be construed to effect a disavowal of any part of the full scope of the invention. Hence, the following descriptions are intended to illustrate some particular embodiments of the disclosure, and not to exhaustively specify all permutations, combinations and variations thereof. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used in the description of the disclosure herein is for the purpose of describing particular aspects or embodiments only and is not intended to be limiting of the disclosure. All publications, patent applications, patents and other references cited herein are incorporated by reference in their entireties for the teachings relevant to the sentence and / or paragraph in which the reference is presented. References to techniques employed herein are Attorney Docket No. P35514WO00 / 1105770.00037 intended to refer to the techniques as commonly understood in the art, including variations on those techniques or substitutions of equivalent techniques that would be apparent to one of skill in the art. Unless the context indicates otherwise, it is specifically intended that the various features of the disclosure described herein can be used in any combination. Moreover, the present disclosure also contemplates that in some embodiments of the disclosure, any feature or combination of features set forth herein can be excluded or omitted. The methods disclosed herein include and comprise one or more steps or actions for achieving the described method. The method steps and / or actions may be interchanged with one another without departing from the scope of the present disclosure. In other words, unless a specific order of steps or actions is required for proper operation of the embodiment, the order and / or use of specific steps and / or actions may be modified without departing from the scope of the present disclosure. As used in the description of the disclosure and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. As used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). The terms “about” and “approximately” as used herein when referring to a measurable value such as a length, a frequency, or a measurement value and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. As used herein, phrases such as “between X and Y” and “between about X and Y” should be interpreted to include X and Y. As used herein, phrases such as “between about X and Y” mean “between about X and about Y” and phrases such as “from about X to Y” mean “from about X to about Y.” As used herein, the term “exemplary” is used to mean serving as an example, instance, or illustration. Any embodiment or aspect described as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments or aspects, nor is it meant to preclude equivalent structures and techniques known to those of ordinary skill in the art. Rather, use of the word exemplary is intended to present concepts in a concrete fashion, and the disclosed subject matter is not limited by such examples. Attorney Docket No. P35514WO00 / 1105770.00037 Methods for Lowering Blood Pressure In an aspect, the present disclosure provides for, and includes, methods for lowering blood pressure in a patient in need thereof, comprising: administering one or more doses of MANP of at least 4 μg / kg, wherein a first blood pressure of the patient, measured at a first timepoint after one of the one or more doses, is reduced by at least 5 mmHg compared to an initial blood pressure measured before receiving the first dose of MANP. In an aspect, the present disclosure provides for, and includes, methods for sustained lowering of blood pressure in a patient in need thereof, comprising: administering one or more doses of MANP, wherein a first blood pressure of the patient, measured at a first time interval of at least 24 hours after the one or more doses of MANP is administered, is at least 5 mmHg lower than an initial blood pressure of the patient measured before receiving the first dose of MANP. Blood Pressure and Measurement As used herein, “blood pressure” refers to the pressure of circulating blood against the walls of blood vessels. In an aspect, blood pressure is the pressure in an artery. In an aspect, blood pressure is the pressure in a vein. In an aspect, blood pressure is the pressure in a brachial artery. In an aspect, blood pressure is the mean arterial pressure. In an aspect, blood pressure is a pulse pressure. In an aspect, blood pressure is measured in millimeters of mercury (mmHg). As used herein, “systolic blood pressure” refers to the maximum pressure during one heartbeat or cardiac cycle. As used here, “diastolic blood pressure” refers to the minimum pressure between two heartbeats in a cardiac cycle. In an aspect, BP is measured by methods known in the art. In an aspect, BP is measured by direct or invasive methods. In an aspect, BP is measured by insertion of a cannula into the artery. In an aspect, the cannula is connected to an electronic pressure transducer. In an aspect, BP measurement is continuous. In an aspect, BP is measured by indirect or non-invasive methods. In an aspect, BP is measured by auscultatory methods. In an aspect, BP is measured by oscillometric methods. In an aspect, BP is measured by palpation. In an aspect, BP is measured by a vascular unloading technique. In an aspect, BP is measured by tonometry. In an aspect, BP is measured by pulse decomposition analysis. In an aspect, BP is measured by the pulse wave velocity technique. In an aspect, BP is measured by a sphygmomanometer or a blood pressure gauge. In an aspect, a sphygmomanometer comprises an inflatable cuff, a measuring unit (the mercury manometer, or aneroid gauge), and a mechanism for inflation which may be a manually operated bulb and valve or a pump operated electrically. In an aspect, a sphygmomanometer comprises a Attorney Docket No. P35514WO00 / 1105770.00037 manual meter. In an aspect, a sphygmomanometer comprises a digital meter. In an aspect, BP is measured by a digital blood pressure monitor, comprising an inflatable sphygmomanometer cuff and an electronic pressure sensor. In an aspect, sitting BP is measured when the subject sits in a comfortable chair with the back supported for at least 3 minutes before reading. Both feet of the subject are flat on the ground and both legs are uncrossed. The arm of the subject is rested with the cuff in position but completely deflated, on a table at chest height. In an aspect, systolic BP and diastolic BP are measured using methods known in the art. In an aspect, the cuff of a sphygmomanometer is completely deflated for a full minute between measurements. In an aspect, the size of a cuff is selected and fitted for the patient. In an aspect, measurements are taken from both arms to determine if the pressure is significantly higher in one arm than the other, and if so, the higher reading arm would be used for readings. In an aspect, a BP measurement is the average of two measurements taken with the cuff remaining in position but completely deflated for a full minute between measurements. In an aspect, the presence or extent of hypertension may be evaluated using other methods known in the art, including, without limitation, general clinical examination to evaluate BP, heart rate, heart rhythm, arterial oxygen, and hemoglobin levels; echocardiography to measure ejection fraction, left ventricle (LV) and left atrial (LA) diameter, LV wall motion, LV filling pressure, and diastolic function by pulse and tissue Doppler; use of a Swan-Ganz catheter to measure cardiac output, pulmonary wedge capillary pressure, pulmonary arterial pressure, right ventricle pressure, right atrial pressure, and systemic and pulmonary vascular resistance; assessment of kidney function by determination of glomerular filtration rate, serum creatinine, and blood urea nitrogen; and measurement of biomarkers such as B-type natriuretic peptide (BNP), amino-terminal proBNP (NT-proBNP), troponin-T, troponin-I, C-reactive protein (CRP), and creatine kinase, serum cystatin-C, albuminuria, neutrophil gelatinase associated lipocalin (NGAL), Nacetyl-beta-D- glucosaminidase (NAG), kidney injury molecule-1 (KIM-1), angiotensin-II, renin, aldosterone, and inflammatory cytokines (e.g., interleukin (IL)-6, IL-18, etc.). Hypertension As used herein, “hypertension” refers to a medical condition where the blood pressure in the arteries is elevated. In an aspect, hypertension exists when the systolic BP is at least 140 mmHg while sitting. In an aspect, hypertension exists when the diastolic BP is at least 90 mmHg while sitting. In an aspect, hypertension in a diabetic patient exists when the systolic BP is at least 130 mmHg while sitting. In an aspect, hypertension in a diabetic patient exists when the diastolic BP is Attorney Docket No. P35514WO00 / 1105770.00037 at least 80 mmHg while sitting. In an aspect, hypertension exists when the systolic BP is at least 140 mmHg and the diastolic BP is at least 90 mmHg of a diastolic BP. In an aspect, hypertension in a diabetic patient exists when the systolic BP is at least 130 mmHg and the diastolic BP is at least 80 mmHg of a diastolic BP. As used herein, “resistant hypertension” (RH) of “difficult-to-control hypertension” (DTC) refers to blood pressure that remains above 140 mmHg systolic BP and 90 mmHg diastolic BP, in spite of the patient being prescribed three or more antihypertensive drugs simultaneously with different mechanisms of action, including a diuretic. In an aspect, a patient with resistant hypertension is prescribed three antihypertensive drugs that includes a diuretic. In an aspect, a patient with resistant hypertension is prescribed four antihypertensive drugs that includes a diuretic. In an aspect, a patient with resistant hypertension is prescribed five antihypertensive drugs that includes a diuretic. As used herein, “obese” or “obesity” refers to a body mass index (BMI) greater than 29.9 kg / m2. In an aspect, a patient identified as obese has a BMI greater than or equal to 30 kg / m2. In an aspect, a patient diagnosed as obese has a BMI of 30-40 kg / m2. In an aspect, BMI is calculated by dividing an individual’s weight in pounds (lb) by the square of the height in inches (in) and multiplying by a conversion factor of 703, rounded to one decimal place. In an aspect, BMI is calculated by dividing an individual’s weight in kilograms (kg) by the square of the height in meters (m), rounded to one decimal place. In an aspect, a patient in need of lowering blood pressure has hypertension. In an aspect, a patient in need of lowering blood pressure has resistant hypertension. In an aspect, a patient in need of lowering blood pressure has difficult-to-control hypertension. In an aspect, a patient in need of lowering blood pressure is at least 18 years old. In an aspect, a patient in need of lowering blood pressure is 18-80 years old. In an aspect, a patient in need of lowering blood pressure has a body mass index (BMI) of at least 18 kg / m2. In an aspect, a patient in need of lowering blood pressure has a BMI of 18-40 kg / m2. In an aspect, a patient in need of lowering blood pressure is obese. In an aspect, a patient in need of lowering blood pressure has a BMI greater than or equal to 29.9 kg / m2. In an aspect, a patient in need of lowering blood pressure has an estimated glomerular filtration rate (eGFR) of at least 30 mL / min / 1.73m2. In an aspect, a patient in need of lowering blood pressure has a hypertensive emergency. As used herein, a “hypertensive emergency” refers to an acute, marked elevation in blood pressure that may or may not be associated with signs of target-organ damage. Attorney Docket No. P35514WO00 / 1105770.00037 In an aspect, a patient’s estimated glomerular filtration rate (eGFR) is a measure of the patient’s kidney function. Without being bound by theory, creatinine is a breakdown product of creatine phosphate from muscle and protein metabolism, that is released at a constant rate by the body into the blood. Creatinine is removed from the blood by the kidneys through glomerular filtration, thus blood levels of creatinine may be used to calculate eGFR. In an aspect, the eGFR is calculated using the Modification of Diet in Renal Disease Study (MDRD) equation. See e.g., Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D, “A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation,” Modification of Diet in Renal Disease Study Group, Ann. Intern. Med., 130:461-70 (1999). In an aspect, the eGFR is calculated using the 4-variable Modification of Diet in Renal Disease Study equation (MDRD-4). See e.g., Levey AS, Coresh J, Greene T, et al., “Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate,” Ann. Intern. Med., 145:247-54 (2006). In an aspect, a patient in need of lowering blood pressure has an estimated glomerular filtration rate (eGFR) of at least 30 mL / min / 1.73m2. In an aspect, a patient in need of lowering blood pressure has an estimated glomerular filtration rate (eGFR) of equal to or greater than 90 mL / min / 1.73m2. In an aspect, a patient in need of lowering blood pressure has an estimated glomerular filtration rate (eGFR) of about 68-89 mL / min / 1.73m2. In an aspect, a patient in need of lowering blood pressure has an estimated glomerular filtration rate (eGFR) of about 45-59 mL / min / 1.73m2. In an aspect, a patient in need of lowering blood pressure has an estimated glomerular filtration rate (eGFR) of about 30-44 mL / min / 1.73m2. In an aspect, a patient in need of lowering blood pressure is African American. In an aspect, a patient in need of lowering blood pressure self-identifies as African American. MANP As used herein, an “MANP” is an ANP-based peptide having an amino acid sequence that includes the 28 amino acid mature human ANP sequence with an additional 12 amino acid carboxy terminus. Without being bound by theory, MANP is a pGC-A / cGMP activator that can significantly lower blood pressure and vascular resistance. International Patent Application Nos. PCT / US2017 / 060808 and PCT / US2023 / 074449 disclose analogues of MANP that can be used to treat cardiorenal and metabolic disease and are incorporated herein in their entireties. In an aspect, MANP comprises a peptide with the sequence set forth in SEQ ID NO:1 SLRRSSCFGGRMDRIGAQSGLGCNSFRYRITAREDKQGWA. In an aspect, an MANP can be a variant of the sequence set forth in SEQ ID NO: 1. In an aspect, an MANP can contain the amino Attorney Docket No. P35514WO00 / 1105770.00037 acid sequence set forth in SEQ ID NO:1, together with one or more amino acid additions, subtractions, or substitutions. In an aspect, an MANP can contain the amino acid sequence set forth in SEQ ID NO:1, together with one or more amino acid additions, subtractions, and substitutions. In an aspect, an MANP can contain the amino acid sequence set forth in SEQ ID NO:1, together with one, two, three, four, five, six, seven, eight, nine, or ten single amino acid residue additions, subtractions, or substitutions. In an aspect, an MANP can contain the amino acid sequence set forth in SEQ ID NO:1, together with one, two, three, four, five, six, seven, eight, nine, or ten single amino acid residue additions, subtractions, and substitutions. In an aspect, any amino acid residue set forth in SEQ ID NO:1 can be subtracted, and any amino acid residue (e.g., any of the 20 conventional amino acid residues or any other type of amino acid such as ornithine or citrulline) can be added to the sequence set forth in SEQ ID NO:1. In an aspect, an MANP can contain one or more chemical structures such as e-aminohexanoic acid; hydroxylated amino acids such as 3-hydroxyproline, 4- hydroxyproline, (5R)-5-hydroxy-L-lysine, allo-hydroxylysine, and 5-hydroxy-L- norvaline; and / or glycosylated amino acids such as amino acids containing monosaccharides (e.g., D-glucose, D-galactose, D-mannose, D-glucosamine, and D- galactosamine) or combinations of monosaccharides. MANPs having one or more amino acid additions, subtractions, or substitutions relative to the representative MANP sequence set forth in SEQ ID NO:1, also referred to herein as “variant” MANPs, can be generated using any suitable method. In an aspect, amino acid substitutions can be made by selecting substitutions that do not differ significantly in their effect on maintaining (a) the structure of the peptide backbone in the area of the substitution, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. For example, naturally occurring residues can be divided into groups based on side-chain properties: (1) hydrophobic amino acids (norleucine, methionine, alanine, valine, leucine, and isoleucine); (2) neutral hydrophilic amino acids (cysteine, serine, and threonine); (3) acidic amino acids (aspartic acid and glutamic acid); (4) basic amino acids (asparagine, glutamine, histidine, lysine, and arginine); (5) amino acids that influence chain orientation (glycine and proline); and (6) aromatic amino acids (tryptophan, tyrosine, and phenylalanine). Substitutions made within these groups can be considered conservative substitutions. Non-limiting examples of useful conservative substitutions can include, without limitation, substitution of valine for alanine, lysine for arginine, glutamine for asparagine, glutamic acid for aspartic acid, serine for cysteine, asparagine for glutamine, aspartic acid for glutamic acid, proline for glycine, arginine for histidine, leucine for isoleucine, isoleucine for leucine, arginine for lysine, leucine for methionine, leucine for phenylalanine, glycine for proline, Attorney Docket No. P35514WO00 / 1105770.00037 threonine for serine, serine for threonine, tyrosine for tryptophan, phenylalanine for tyrosine, and / or leucine for valine. In an aspect, an MANP can include one or more non-conservative substitutions. Non- conservative substitutions typically entail exchanging a member of one of the classes described above for a member of another class. Such production can be desirable to provide large quantities or alternative embodiments of such compounds. Whether an amino acid change results in a functional polypeptide can readily be determined by assaying the specific activity of the polypeptide variant using, for example, methods disclosed herein. In an aspect, an MANP can have a length of, for example, 35 to 45 amino acid residues (e.g., 35 to 40, 40 to 45, 35 to 37, 36 to 38, 37 to 39, 38 to 40, 39 to 41, 40 to 42, 41 to 43, 42 to 44, or 43 to 45 amino acid residues). In an aspect, an MANP may include an amino acid sequence with at least 90% (e.g., at least 90%, at least 92.5%, at least 95%, at least 97.5%, or 100%) sequence identity to the sequence set forth in SEQ ID NO:1. Percent sequence identity is calculated by determining the number of matched positions in aligned amino acid sequences, dividing the number of matched positions by the total number of aligned amino acids, and multiplying by 100. A matched position refers to a position in which identical amino acids occur at the same position in aligned amino acid sequences. In an aspect, the percent sequence identity between a particular nucleic acid or amino acid sequence and a sequence referenced by a particular sequence identification number may be determined as follows. First, a nucleic acid or amino acid sequence is compared to the sequence set forth in a particular sequence identification number using the BLAST 2 Sequences (Bl2seq) program from 25 the stand-alone version of BLASTZ containing BLASTN version 2.0.14 and BLASTP version 2.0.14. This stand-alone version of BLASTZ may be obtained online at fr.com / blast or at ncbi.nlm.nih.gov. Instructions explaining how to use the Bl2seq program may be found in the readme file accompanying BLASTZ. Bl2seq performs a comparison between two sequences using either the BLASTN or BLASTP algorithm. BLASTN is used to compare nucleic acid sequences, while BLASTP is used to compare amino acid sequences. To compare two nucleic acid sequences, the options are set as follows: -i is set to a file containing the first nucleic acid sequence to be compared (e.g., C:\seq1.txt); -j is set to a file containing the second nucleic acid sequence to be compared (e.g., C:\seq2.txt); -p is set to blastn; -o is set to any desired file name (e.g., C:\output.txt); -q is set to -1; -r is set to 2; and all other options are left at their default setting. In an aspect, the following command may be used to generate an output file containing a comparison between two sequences: C:\Bl2seq -i c:\seq1.txt -j c:\seq2.txt -p blastn -o c:\output.txt - q -1 -r 2. To compare two amino acid sequences, the options of Bl2seq are set as follows: -i is set to Attorney Docket No. P35514WO00 / 1105770.00037 a file containing the first amino acid sequence to be compared (e.g., C:\seq1.txt); -j is set to a file containing the second amino acid sequence to be compared (e.g., C:\seq2.txt); -p is set to blastp; -o is set to any desired file name (e.g., C:\output.txt); and all other options are left at their default setting. In an aspect, the following command may be used to generate an output file containing a comparison between two amino acid sequences: C:\Bl2seq -I c:\seq1.txt -j c:\seq2.txt -p blastp -o c:\output.txt. If the two compared sequences share homology, then the designated output file will present those regions of homology as aligned sequences. If the two compared sequences do not share homology, then the designated output file will not present aligned sequences. Once aligned, the number of matches is determined by counting the number of positions where an identical nucleotide or amino acid residue is presented in both sequences. The percent sequence identity is determined by dividing the number of matches either by the length of the sequence set forth in the identified sequence (e.g., SEQ ID NO:1), or by an articulated length (e.g., 20 consecutive nucleotides or amino acid residues from a sequence set forth in an identified sequence), followed by multiplying the resulting value by 100. In an aspect, an amino acid sequence that has 37 matches when aligned with the sequence set forth in SEQ ID NO:1 is 2592.5 percent identical to the sequence set forth in SEQ ID NO:1 (i.e., 37 ÷ 40 x 100 = 92.5). It is noted that the percent sequence identity value is rounded to the nearest tenth. In an aspect, 75.11, 75.12, 75.13, and 75.14 are rounded down to 75.1, while 75.15, 75.16, 75.17, 75.18, and 75.19 are rounded up to 75.2. It also is noted that the length value will always be an integer. Dosage In an aspect, the method for lowering blood pressure comprises administering one or more doses of MANP at a dose effective for lowering blood pressure. In an aspect, a dose of MANP is at least 3 μg / kg. In an aspect, a dose of MANP is at least 4 μg / kg. In an aspect, a dose of MANP is at least 4.5 μg / kg. In an aspect, a dose of MANP is at least 5 μg / kg. In an aspect, a dose of MANP is at least 5.5 μg / kg. In an aspect, a dose of MANP is at least 6 μg / kg. In an aspect, a dose of MANP is at least 6.5 μg / kg. In an aspect, a dose of MANP is at least 7 μg / kg. In an aspect, a dose of MANP is at least 7.5 μg / kg. In an aspect, a dose of MANP is at least 8 μg / kg. In an aspect, a dose of MANP is at least 8.5 μg / kg. In an aspect, a dose of MANP is at least 9 μg / kg. In an aspect, a dose of MANP is about 3 μg / kg. In an aspect, a dose of MANP is about 3.5 μg / kg. In an aspect, a dose of MANP is about 4 μg / kg. In an aspect, a dose of MANP is about 4.5 μg / kg. In an aspect, a dose of MANP is about 5 μg / kg. In an aspect, a dose of MANP is about 5.5 μg / kg. In an aspect, a dose of MANP is about 6 μg / kg. In an aspect, a dose of MANP is about 6.5 μg / kg. In an aspect, a dose of MANP is about 7 μg / kg. In an aspect, a dose of MANP is about 7.5 μg / kg. In an aspect, a Attorney Docket No. P35514WO00 / 1105770.00037 dose of MANP is about 8 μg / kg. In an aspect, a dose of MANP is about 8.5 μg / kg. In an aspect, a dose of MANP is about 9 μg / kg. In an aspect, a dose of MANP is about 3 μg / kg to about 9 μg / kg. In an aspect, a dose of MANP is about 4 μg / kg to about 8 μg / kg. In an aspect, a dose of MANP is about 4.5 μg / kg to about 7 μg / kg. In an aspect, a dose of MANP is about 4.5 μg / kg to about 6 μg / kg. In an aspect, the method for lowering blood pressure comprises administering one or more doses of MANP. In an aspect, the method for lowering blood pressure comprises administering more than one dose of MANP. In an aspect, the method for lowering blood pressure comprises administering at least two doses, at least three doses, at least four doses, at least five doses, at least six doses, at least seven doses, at least eight doses, at least nine doses, at least ten doses, at least 11 doses, at least 12 doses, at least 13 doses, at least 14 doses, at least 15 doses, at least 16 doses, at least 17 doses, at least 18 doses at least 19 doses or at least 20 doses of MANP. In an aspect, five doses of MANP are administered. In an aspect, the method for lowering blood pressure comprises administering one or more doses of MANP at fixed time intervals. In an aspect, the doses are administered at least once every 6 hours, at least once ever 12 hours, at least once ever 18 hours, at least once every 24 hours, at least once every 48 hours, at least once every 72 hours, at least once every week, at least once every two weeks, or at least once a month. In an aspect, the doses are administered once every 24 hours. Concomitant Medication In an aspect, the method for lowering blood pressure in a patient in need thereof further comprises administering one or more anti-hypertensive medication. In an aspect, the method further comprises administering one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. Without being bound by theory, diuretics help the kidneys remove salt and water through urine, lowering the amount of fluid flowing through the veins and arteries, thereby reducing blood pressure. In an aspect, the method for lowering blood pressure in a patient in need thereof further comprises administering a diuretic. In an aspect, the diuretic is chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, metolazone, bumetanide, ethacrynic acid, furosemide, torsemide, amiloride, eplerenone, spironolactone, or triamterene. In an aspect, the diuretic is selected from the group consisting of hydrochlorothiazide, spironolactone, bumetanide, chlorthalidone, furosemide, and hydralazine. Attorney Docket No. P35514WO00 / 1105770.00037 Without being bound by theory, Ca2+channel blockers block calcium from entering the cells of the heart and arteries, allowing blood vessels to relax and open, thereby lowering blood pressure. Some Ca2+channel blockers may also slow the heart rate, further lowing blood pressure. In an aspect, the method for lowering blood pressure in a patient in need thereof further comprises administering a Ca2+channel blocker. In an aspect, the Ca2+channel blocker is amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, or verapamil. In an aspect, the Ca2+channel blocker is selected from the group consisting of amlodipine besilate, verapamil, diltiazem, and nifedipine. Without being bound by theory, ACE inhibitors block the production of angiotensin 2 which narrows blood vessels, thereby lowering blood pressure. Angiotensin 2 also releases hormones that raise blood pressure. In an aspect, the method for lowering blood pressure in a patient in need thereof further comprises administering an ACE inhibitor. In an aspect, the ACE inhibitor is benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, or trandolapril. In an aspect, the ACE inhibitor is selected from the group consisting of benazepril and lisinopril. Without being bound by theory, angiotensin II receptor blockers (ARBs) stop the action of angiotensin 2. In an aspect, the method for lowering blood pressure in a patient in need thereof further comprises administering an ARB. In an aspect, the ARB is azilsartan, candesartan, irbesartan, losartan, Olmesartan, telmisartan, or valsartan. In an aspect, the ARB is selected from the group consisting of losartan and olmesartan. Without being bound by theory, alpha-blockers lower blood pressure by keeping a hormone called norepinephrine from tightening the muscles in the walls of smaller arteries and veins. As a result, the blood vessels remain open and relaxed. This improves blood flow and lowers blood pressure. In an aspect, the method for lowering blood pressure in a patient in need thereof further comprises administering an alpha-blocker. In an aspect, the alpha-blocker is doxazosin, prazosin, tamsulosin, clonidine, or terazosin. In an aspect, the alpha-blocker is selected from the group consisting of doxazosin, prazosin, tamsulosin, and clonidine. Without being bound by theory, beta-blockers block the effects of the hormone epinephrine, also known as adrenaline, and cause the heart to beat more slowly with less force, thereby lowering blood pressure. In an aspect, the method for lowering blood pressure in a patient in need thereof further comprises administering a beta-blocker. In an aspect, the beta-blocker is acebutolol, atenolol, bisoprolol, carvedilol, metoprolol, nadolol, nebivolol, or propanolol. In an aspect, the beta-blocker is selected from the group consisting of carvedilol, atenolol, bisoprolol, metoprolol, and nebivolol. Attorney Docket No. P35514WO00 / 1105770.00037 In an aspect, the method further comprises administering one or more medications selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. In an aspect, the method further comprises administering at least two medications selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. In an aspect, the method further comprises administering at least three medications selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. In an aspect, the method further comprises administering at least four medications selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. In an aspect, the method further comprises administering at least five medications selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. In an aspect, before receiving any MANP, the patient was receiving one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. In an aspect, before receiving any MANP, the patient was receiving one or more medications selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. In an aspect, before receiving any MANP, the patient was receiving at least two medications selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. In an aspect, before receiving any MANP, the patient was receiving at least three medications selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. In an aspect, before receiving any MANP, the patient was receiving at least four medications selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. In an aspect, before receiving any MANP, the patient was receiving at least five medications selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. Attorney Docket No. P35514WO00 / 1105770.00037 In an aspect, the patient was receiving one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks at least 10 weeks, at least 3 months, at least 6 months, at least 9 months, or at least 12 months before receiving any MANP. In an aspect, the patient was receiving one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker, for at least 6 weeks before receiving any MANP. In an aspect, the patient was receiving one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker, for at least 6 months before receiving any MANP. In an aspect, the patient continues receiving one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks at least 10 weeks, at least 3 months, or at least 6 months after receiving MANP. In an aspect, the patient stops receiving one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker, for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks at least 10 weeks, at least 3 months, or at least 6 months while receiving MANP. BP Monitoring In an aspect, an initial blood pressure is measured before receiving any dose of MANP. In an aspect, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten BP measurements is taken before receiving any doses of MANP. In an aspect, an initial blood pressure is measured at least 5 min, at least 10 min, at least 15 min, at least 20 min, at least 30 min, at least 35 min, at least 40 min, at least 45 min, at least 50 min, at least 55 min, at least 60 min, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at Attorney Docket No. P35514WO00 / 1105770.00037 least 11 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks before receiving any dose of MANP. In an aspect, an initial blood pressure is measured about 5 min, about 10 min, about 15 min, about 20 min, about 30 min, about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 60 min, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 3 weeks, or about 4 weeks before receiving any dose of MANP. In an aspect, a first blood pressure of the patient is measured at a first timepoint after a dose of MANP. In an aspect, a first timepoint is about 5 min, about 10 min, about 15 min, about 20 min, about 30 min, about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 60 min, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 18 hours, about 24 hours after receiving a dose of MANP. In an aspect, a first timepoint is at least 5 min, at least 10 min, at least 15 min, at least 20 min, at least 30 min, at least 35 min, at least 40 min, at least 45 min, at least 50 min, at least 55 min, at least 60 min, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 18 hours, or at least 24 hours after receiving a dose of MANP. In an aspect, a first blood pressure of the patient is measured at a first time interval after a dose of MANP. In an aspect, a first time interval is about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 2 weeks, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 3 weeks, or about 4 weeks after receiving a dose of MANP. In an aspect, a first time interval is at least 24 hours, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 2 weeks, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 3 weeks, or at least 4 weeks after receiving a dose of MANP. In an aspect, a patient’s blood pressure measured at a first timepoint after one of the one or more doses of MANP is reduced compared to an initial blood pressure measured before receiving the first dose of MANP. In an aspect, a patient’s systolic or diastolic blood pressure measured at a Attorney Docket No. P35514WO00 / 1105770.00037 first timepoint after one of the one or more doses of MANP is reduced by at least 1 mmHg, at least 2 mmHg, at least 3 mmHg, at least 4 mmHg, at least 5 mm Hg, at least 6 mmHg, at least 7 mmHg, at least 8 mmHg, at least 9 mmHg, at least 10 mmHg, at least 11 mmHg, at least 12 mmHg, at least 13 mmHg, at least 14 mmHg, at least 15 mmHg, at least 16 mmHg, at least 17 mmHg, at least 18 mmHg, at least 19 mmHg, at least 20 mmHg, at least 25 mmHg, at least 30 mmHg, at least 35 mmHg, at least 40 mmHg, at least 45 mmHg, at least 50 mmHg, at least 55 mmHg, at least 60 mmHg, at least 65 mmHg, at least 70 mmHg, at least 75 mmHg, at least 80 mmHg, at least 85 mmHg, at least 90 mmHg, at least 95 mmHg, at least 100 mmHg, at least 105 mmHg, at least 110 mmHg, at least 115 mmHg, or at least 120 mmHg. In an aspect, a patient’s systolic or diastolic blood pressure measured at a first timepoint after one of the one or more doses of MANP is reduced by about 1mmHg, about 2 mmHg, about 3 mmHg, about 4 mmHg, about 5 mm Hg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, about 15 mmHg, about 16 mmHg, about 17 mmHg, about 18 mmHg, about 19 mmHg, about 20 mmHg, about 25 mmHg, about 30 mmHg, about 35 mmHg, about 40 mmHg, about 45 mmHg, about 50 mmHg, about 55 mmHg, about 60 mmHg, about 65 mmHg, about 70 mmHg, about 75 mmHg, about 80 mmHg, about 85 mmHg, about 90 mmHg, about 95 mmHg, about 100 mmHg, about 105 mmHg, about 110 mmHg, about 115 mmHg, or about 120 mmHg. In an aspect, a patient’s blood pressure measured at a second timepoint after the first time interval is reduced compared to that measured before receiving the first dose of MANP. In an aspect, a patient’s systolic or diastolic blood pressure measured at a second timepoint after the first time interval is reduced by about 1mmHg, about 2 mmHg, about 3 mmHg, about 4 mmHg, about 5 mm Hg, about 6 mmHg, about 7 mmHg, about 8 mmHg, about 9 mmHg, about 10 mmHg, about 11 mmHg, about 12 mmHg, about 13 mmHg, about 14 mmHg, about 15 mmHg, about 16 mmHg, about 17 mmHg, about 18 mmHg, about 19 mmHg, about 20 mmHg, about 25 mmHg, about 30 mmHg, about 35 mmHg, about 40 mmHg, about 45 mmHg, about 50 mmHg, about 55 mmHg, about 60 mmHg about 65 mmHg, about 70 mmHg, about 75 mmHg, about 80 mmHg, about 85 mmHg, about 90 mmHg, about 95 mmHg, about 100 mmHg, about 105 mmHg, about 110 mmHg, about 115 mmHg, or about 120 mmHg compared to that measured before receiving the first dose of MANP. In an aspect, a patient’s systolic or diastolic blood pressure measured at a second timepoint after the first time interval is reduced by at least 1 mmHg, at least 2 mmHg, at least 3 mmHg, at least 4 mmHg, at least 5 mm Hg, at least 6 mmHg, at least 7 mmHg, at least 8 mmHg, at least 9 mmHg, at least 10 mmHg, at least 11 mmHg, at least 12 mmHg, at least 13 mmHg, at least 14 mmHg, at least 15 mmHg, at least 16 mmHg, at least 17 mmHg, at least 18 mmHg, at least 19 Attorney Docket No. P35514WO00 / 1105770.00037 mmHg, at least 20 mmHg, at least 25 mmHg, at least 30 mmHg, at least 35 mmHg, at least 40 mmHg, at least 45 mmHg, at least 50 mmHg, at least 55 mmHg, at least 60 mmHg, at least 65 mmHg, at least 70 mmHg, at least 75 mmHg, at least 80 mmHg, at least 85 mmHg, at least 90 mmHg, at least 95 mmHg, at least 100 mmHg, at least 105 mmHg, at least 110 mmHg, at least 115 mmHg, or at least 120 mmHg compared to that measured before receiving the first dose of MANP. eGFR Monitoring In an aspect, an initial eGFR is measured or calculated before receiving any dose of MANP. In an aspect, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten eGFR measurements is taken before receiving any doses of MANP. In an aspect, an initial eGFR measurement is taken at least 5 min, at least 10 min, at least 15 min, at least 20 min, at least 30 min, at least 35 min, at least 40 min, at least 45 min, at least 50 min, at least 55 min, at least 60 min, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks before receiving any dose of MANP. In an aspect, an initial eGFR measurement is taken about 5 min, about 10 min, about 15 min, about 20 min, about 30 min, about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 60 min, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 3 weeks, or about 4 weeks before receiving any dose of MANP. In an aspect, a first eGFR measurement is taken at a first timepoint after a dose of MANP. In an aspect, a first eGFR measurement is taken at about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks about 10 weeks, about 11 weeks, or about 12 weeks after receiving a dose of MANP. In an aspect, a first timepoint is at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks after receiving a dose of MANP. Attorney Docket No. P35514WO00 / 1105770.00037 In an aspect, a first eGFR measurement of the patient is taken at a first time interval after a dose of MANP. In an aspect, a first time interval is about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks about 10 weeks, about 11 weeks, or about 12 weeks after receiving a dose of MANP. In an aspect, a first time interval is at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks after receiving a dose of MANP. In an aspect, a patient’s GFR measured at a first timepoint after one of the one or more doses of MANP is compared to an initial eGFR measured before receiving the first dose of MANP. In an aspect, a patient’s eGFR measured at a first timepoint after one of the one or more doses of MANP is equal to or greater than the initial eGFR measured before receiving the first dose of MANP. In an aspect, a patient’s eGFR measured at a first timepoint after one of the one or more doses of MANP is increased by at least 1 mL / min / 1.73m2, at least 2 mL / min / 1.73m2, at least 3 mL / min / 1.73m2, at least 4 mL / min / 1.73m2, at least 5 mL / min / 1.73m2, at least 6 mL / min / 1.73m2, at least 7 mL / min / 1.73m2, at least 8 mL / min / 1.73m2, at least 9 mL / min / 1.73m2, at least 10 mL / min / 1.73m2, at least 11 mL / min / 1.73m2, at least 12 mL / min / 1.73m2, at least 13 mL / min / 1.73m2, at least 14 mL / min / 1.73m2, at least 15 mL / min / 1.73m2, at least 16 mL / min / 1.73m2, at least 17 mL / min / 1.73m2, at least 18 mL / min / 1.73m2, at least 19 mL / min / 1.73m2, at least 20 mL / min / 1.73m2, at least 25 mL / min / 1.73m2, at least 30 mL / min / 1.73m2, at least 35 mL / min / 1.73m2, at least 40 mL / min / 1.73m2, at least 40 mL / min / 1.73m2, at least 45 mL / min / 1.73m2, at least 50 mL / min / 1.73m2, at least 55 mL / min / 1.73m2, at least 60 mL / min / 1.73m2, at least 65 mL / min / 1.73m2, or at least 70 mL / min / 1.73m2compared to that measured before receiving the first dose of MANP. In an aspect, a patient’s eGFR measured at a first timepoint after one of the one or more doses of MANP is increased by about 1 mL / min / 1.73m2, about 2 mL / min / 1.73m2, about 3 mL / min / 1.73m2, about 4 mL / min / 1.73m2, about 5 mL / min / 1.73m2, about 6 mL / min / 1.73m2, about 7 mL / min / 1.73m2, about 8 mL / min / 1.73m2, about 9 mL / min / 1.73m2, about 10 mL / min / 1.73m2, about 11 mL / min / 1.73m2, about 12 mL / min / 1.73m2, about 13 mL / min / 1.73m2, about 14 mL / min / 1.73m2, about 15 mL / min / 1.73m2, about 16 mL / min / 1.73m2, about 17 mL / min / 1.73m2, about 18 mL / min / 1.73m2, about 19 mL / min / 1.73m2, about 20 mL / min / 1.73m2, about 25 mL / min / 1.73m2, about 30 mL / min / 1.73m2, about 35 mL / min / 1.73m2, about 40 mL / min / 1.73m2, about 45 mL / min / 1.73m2, Attorney Docket No. P35514WO00 / 1105770.00037 about 50 mL / min / 1.73m2, about 55 mL / min / 1.73m2, about 60 mL / min / 1.73m2about 65 mL / min / 1.73m2, or about 70 mL / min / 1.73m2compared to that measured before receiving the first dose of MANP. In an aspect, a patient’s GFR measured at a second timepoint after the first time interval is increased compared to an initial eGFR measured before receiving the first dose of MANP. In an aspect, a patient’s eGFR measured at a second timepoint after the first time interval is increased by at least 1 mL / min / 1.73m2, at least 2 mL / min / 1.73m2, at least 3 mL / min / 1.73m2, at least 4 mL / min / 1.73m2, at least 5 mL / min / 1.73m2, at least 6 mL / min / 1.73m2, at least 7 mL / min / 1.73m2, at least 8 mL / min / 1.73m2, at least 9 mL / min / 1.73m2, at least 10 mL / min / 1.73m2, at least 11 mL / min / 1.73m2, at least 12 mL / min / 1.73m2, at least 13 mL / min / 1.73m2, at least 14 mL / min / 1.73m2, at least 15 mL / min / 1.73m2, at least 16 mL / min / 1.73m2, at least 17 mL / min / 1.73m2, at least 18 mL / min / 1.73m2, at least 19 mL / min / 1.73m2, at least 20 mL / min / 1.73m2, at least 25 mL / min / 1.73m2, at least 30 mL / min / 1.73m2, at least 35 mL / min / 1.73m2, at least 40 mL / min / 1.73m2, at least 40 mL / min / 1.73m2, at least 45 mL / min / 1.73m2, at least 50 mL / min / 1.73m2, at least 55 mL / min / 1.73m2, at least 60 mL / min / 1.73m2, at least 65 mL / min / 1.73m2, or at least 70 mL / min / 1.73m2compared to that measured before receiving the first dose of MANP. In an aspect, a patient’s eGFR measured at a second timepoint after the first time interval is increased by about 1 mL / min / 1.73m2, about 2 mL / min / 1.73m2, about 3 mL / min / 1.73m2, about 4 mL / min / 1.73m2, about 5 mL / min / 1.73m2, about 6 mL / min / 1.73m2, about 7 mL / min / 1.73m2, about 8 mL / min / 1.73m2, about 9 mL / min / 1.73m2, about 10 mL / min / 1.73m2, about 11 mL / min / 1.73m2, about 12 mL / min / 1.73m2, about 13 mL / min / 1.73m2, about 14 mL / min / 1.73m2, about 15 mL / min / 1.73m2, about 16 mL / min / 1.73m2, about 17 mL / min / 1.73m2, about 18 mL / min / 1.73m2, about 19 mL / min / 1.73m2, about 20 mL / min / 1.73m2, about 25 mL / min / 1.73m2, about 30 mL / min / 1.73m2, about 35 mL / min / 1.73m2, about 40 mL / min / 1.73m2, about 45 mL / min / 1.73m2, about 50 mL / min / 1.73m2, about 55 mL / min / 1.73m2, about 60 mL / min / 1.73m2about 65 mL / min / 1.73m2, or about 70 mL / min / 1.73m2compared to that measured before receiving the first dose of MANP. cGMP Monitoring In an aspect, an initial plasma cGMP is measured or calculated before receiving any dose of MANP. In an aspect, at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or at least ten plasma cGMP measurements is taken before receiving any doses of MANP. In an aspect, an initial plasma cGMP measurement is taken at least 5 min, at least 10 min, at least 15 min, at least 20 min, at least 30 min, at least 35 min, at Attorney Docket No. P35514WO00 / 1105770.00037 least 40 min, at least 45 min, at least 50 min, at least 55 min, at least 60 min, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks before receiving any dose of MANP. In an aspect, an initial plasma cGMP measurement is taken about 5 min, about 10 min, about 15 min, about 20 min, about 30 min, about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 60 min, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 2 weeks, about 3 weeks, or about 4 weeks before receiving any dose of MANP. In an aspect, a first plasma cGMP measurement is taken at a first timepoint after a dose of MANP. In an aspect, a first plasma cGMP measurement is taken at 5 min, about 10 min, about 15 min, about 20 min, about 30 min, about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 60 min, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, or about 3 days after receiving a dose of MANP. In an aspect, a first timepoint is at least 5 min, at least 10 min, at least 15 min, at least 20 min, at least 30 min, at least 35 min, at least 40 min, at least 45 min, at least 50 min, at least 55 min, at least 60 min, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 2 days, or at least 3 days after receiving a dose of MANP. In an aspect, a first cGMP measurement of the patient is taken at a first time interval after a dose of MANP. In an aspect, a first time interval is 5 min, about 10 min, about 15 min, about 20 min, about 30 min, about 35 min, about 40 min, about 45 min, about 50 min, about 55 min, about 60 min, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 18 hours, about 24 hours, about 2 days, or about 3 days after receiving a dose of MANP. In an aspect, a first time interval is at least 5 min, at least 10 min, at least 15 min, at least 20 min, at least 30 min, at least 35 min, at least 40 min, at least 45 min, at least 50 min, at least 55 min, at least 60 min, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 18 hours, at least 24 hours, at least 2 days, at least 3 days after receiving a dose of MANP. Attorney Docket No. P35514WO00 / 1105770.00037 In an aspect, a patient’s plasma cGMP measured at a first timepoint after one of the one or more doses of MANP is compared to an initial plasma cGMP measured before receiving the first dose of MANP. In an aspect, a patient’s plasma cGMP measured at a first timepoint after one of the one or more doses of MANP is equal to or greater than the initial plasma cGMP measured before receiving the first dose of MANP. In an aspect, a patient’s plasma cGMP measured at a first timepoint after one of the one or more doses of MANP is increased by at least 1 pmol / mL, at least 2 pmol / mL, at least 3 pmol / mL, at least 4 pmol / mL, at least 5 pmol / mL, at least 6 pmol / mL, at least 7 pmol / mL, at least 8 pmol / mL, at least 9 pmol / mL, at least 10 pmol / mL, at least 11 pmol / mL, at least 12 pmol / mL, at least 13 pmol / mL, at least 14 pmol / mL, at least 15 pmol / mL, at least 16 pmol / mL, at least 17 pmol / mL, at least 18 pmol / mL, at least 19 pmol / mL, at least 20 pmol / mL, at least 25 pmol / mL, at least 30 pmol / mL, at least 35 pmol / mL, at least 40 pmol / mL, at least 40 pmol / mL, at least 45 pmol / mL, or at least 50 pmol / mL compared to that measured before receiving the first dose of MANP. In an aspect, a patient’s plasma cGMP measured at a first timepoint after one of the one or more doses of MANP is increased by about 1 pmol / mL, about 2 pmol / mL, about 3 pmol / mL, about 4 pmol / mL, about 5 pmol / mL, about 6 pmol / mL, about 7 pmol / mL, about 8 pmol / mL, about 9 pmol / mL, about 10 pmol / mL, about 11 pmol / mL, about 12 pmol / mL, about 13 pmol / mL, about 14 pmol / mL, about 15 pmol / mL, about 16 pmol / mL, about 17 pmol / mL, about 18 pmol / mL, about 19 pmol / mL, about 20 pmol / mL, about 25 pmol / mL, about 30 pmol / mL, about 35 pmol / mL, about 40 pmol / mL, about 45 pmol / mL, or about 50 pmol / mL compared to that measured before receiving the first dose of MANP. EXAMPLES EXAMPLE I - A Phase 1b, Multiple Ascending Dose Trial Examining the Effect of Subcutaneous MANP on Blood Pressure in Difficult to Control / Resistant Hypertensive Subjects The effect of MANP on blood pressure is evaluated at ascending dose levels in patients with difficult-to-control (DTC) or resistant hypertension (RH). Methodology: Five cohorts of eight hypertensive subjects on stable doses of at least three hypertensive drugs (including a diuretic) for at least 6 weeks prior to screening are selected. Subjects are evaluated for participation in the study during a 3-week Screening Period including a blood pressure (BP) Qualifying Visit, 2 to 5 days prior to randomization. Eligible subjects are admitted to the Pharmacokinetic (PK) Unit for 7 days with 5 days of treatment administration followed by two Attorney Docket No. P35514WO00 / 1105770.00037 safety follow-up visits on Days 12 and 21. The total length of participation is approximately 42 days. Approximately 45 adult male and female subjects between the ages of 18 and 80 years with DTC / RH are planned to be analyzed, with 37 patients randomized (28 to five successive cohorts and 9 to placebo). The study aims to enroll 50% African Americans (AA) and 50% Non-African Americans (NAA). Subjects are randomized in a 6:2 ratio to one of the 5 cohorts. MANP disclosed herein (SEQ ID NO: 1) is tested in 5 cohorts once daily for 5 days. Cohort 1 receives doses of 3 μg / kg MANP. Cohort 2 receives 4 μg / kg MANP. Cohort 3 receives 4.5 μg / kg MANP. Cohort 4 receives 7 μg / kg MANP. Cohort 5 receives 6 μg / kg MANP. Each dose of the study treatment (MANP or placebo) is administered as a single subcutaneous bolus injection in the morning at approximately 8 am (± 1 hour) for 5 consecutive days. Placebo is 0.9% saline solution administered as a single subcutaneous bolus injection in the morning at approximately 8 am (± 1 hour) for 5 consecutive days. The treatment assignments were double-blind for the duration of the study. Inclusion Criteria: Patients meet all of the following inclusion criteria: 1. Patient has DTC / RH, defined as hypertensive subjects with clinical systolic blood pressure systolic blood pressure (SBP) 140 mmHg or diastolic blood pressure diastolic blood pressure (DBP) 90 mmHg (or SBP 130 mmHg or DBP 80 mmHg for diabetics) derived from the average BPs from the Screening Visit and Visit 1, while on at least three standard-of-care antihypertensive medications (which must include a diuretic) for at least 6 weeks prior to Screening. Mean BPs at each visit are derived from the average of two seated BPs measured with an Indie Health Blood Pressure (BP) Monitor after the subject had been at rest in the seated position for at least three minutes and with the cuff remained in position but completely deflated for a full minute between measurements. 2. Patient has an estimated glomerular filtration rate (eGFR) calculated based on the equation from the Modification of Diet in Renal Disease Study (MDRD) MDRD eGFR 30 mL / min / 1.73m2. 3. Patient is between the ages of 18 and 80 years. 4. Patient has a body mass index (BMI) of 18–40 kg / m2. 5. Female patient of childbearing potential has had a negative serum pregnancy test result at Screening and a negative urine pregnancy test on admission to the PK Unit at Visit 2, Day -1. (i) Female patient who is not of childbearing potential is defined as: Attorney Docket No. P35514WO00 / 1105770.00037 a) Postmenopausal (defined as at least 12 months with no menses in women 45 years of age) with documented blood follicle stimulating hormone (FSH) >40mIU / mL; OR b) Has had a hysterectomy and / or bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation / occlusion at least 6 weeks prior to Screening; OR c) Has a congenital or acquired condition that prevented childbearing. (ii) Female patient of childbearing potential agrees to avoid becoming pregnant while receiving study treatment and for 14 days after the last study visit by complying with one of the following: a) practiced abstinence from heterosexual activity, OR b) uses (or had her partner use) acceptable contraception during heterosexual activity. Acceptable methods of contraception are: A. hormonal contraception (contraceptive pill or injection); and an additional barrier method of contraception such as a diaphragm, condom, sponge, or spermicide. B. vasectomy of a female subject’s male partner. C. in the absence of hormonal contraception or vasectomy of a female subject’s male partner, combination contraceptives methods (requiring use of two of the following) are used: a. non-hormonal intrauterine device (IUD); b. diaphragm with spermicide (could not be used in conjunction with cervical cap / spermicide); c. cervical cap with spermicide (nulliparous women only); d. contraceptive sponge (nulliparous women only); e. male condom or female condom (could not be used together). 6. Males willing to use a barrier birth control method (condom) for ANY sexual activity throughout the study and for an additional 14 days after the last study visit (Day 21). 7. Patient is able to communicate effectively with the study personnel. 8. Patient is willing and able to comply with the study procedures and visit schedule including follow-up visits. 9. Patient is adequately informed of the nature and risks of the study and gives written informed consent prior to receiving study medication in languages relevant to the study population. Exclusion Criteria: Attorney Docket No. P35514WO00 / 1105770.00037 Subjects who meet any of the following criteria are excluded from the study: 1. Has known hypersensitivity or allergy to MANP or its components, carperitide, other natriuretic peptides, or related compounds. 2. Has mean orthostatic BP changes derived from the average orthostatic changes from the Screening Visit and Visit 1 defined as a mean decrease in SBP of > 20 mmHg or a mean decrease in DBP of > 10 mmHg. 3. Has orthostatic symptoms (e.g., dizziness, light headedness, and / or palpitations) within two minutes of standing from the sitting position at either the Screening Visit or Visit 1. 4. Has HbA1c 8% at Screening. 5. Subject is pregnant or breastfeeding. 6. Has any disease or condition (medical or surgical) which, in the opinion of the Investigator, might compromise the hematologic, cardiovascular, pulmonary, renal, gastrointestinal, hepatic, or central nervous system; or other conditions that may interfere with the absorption, distribution, metabolism or excretion of study drug, or would place the subject at increased risk. 7. Has completed of a COVID-19 vaccination regimen within 30 days of screening. Subjects who complete a vaccination regimen more than 30 days before screening are eligible for participation. Completion of a vaccination regimen refers to the last injection of the recommended vaccination regimen. 8. Non COVID-19 vaccinated subjects who do not agree to refrain from receiving vaccination during participation in this study. 9. Has a history of unstable angina or myocardial infarction within 6 months prior to Screening. 10. Has New York Heart Association (NYHA) Grade 3 or 4 congestive heart failure (CHF), valvular heart disease, ventricular cardiac arrhythmia requiring treatment or pulmonary hypertension. 11. Has cardiac surgery, coronary angioplasty, stroke, or transient ischemic attack (TIA) within 6 months prior to Screening. 12. Has abnormal laboratory values at the Screening Visit that is considered clinically significant by the Investigator. However, subjects are excluded if a) Serum sodium of < 135 mEq / L or > 145 mEq / L; b) Serum potassium of < 3.5 mEq / L or > 5.5 mEq / L. 13. Has a positive screen for Hepatitis B (HbsAg, Hepatitis B Surface Antigen), Hepatitis C (anti HCV, Hepatitis C Antibody), or HIV (anti-HIV 1 / 2). 14. Receives an Investigational drug within a 30-day period of the Screening Visit including the COVID-19 vaccine. Attorney Docket No. P35514WO00 / 1105770.00037 15. Subject has a recent history (within 1 year of Screening) of alcohol abuse or dependence. Alcohol abuse includes heavy alcohol intake as defined by > 3 drinks per day or > 14 drinks per week or binge drinking. 16. Has consumed alcohol within 72 hours prior to dose administration or during any in- patient period. 17. Has a positive urine drug screen including ethanol, cocaine, THC, barbiturates, amphetamines, benzodiazepines, and opiates unless, in the opinion of the Investigator, a positive finding as a result of a legitimate medical prescription for a valid medical condition. Occasional intermittent use of cannabinoid products is allowed provided that no cannabinoid products are used during the 1 week prior to each visit. 18. Has a history (within the last 2 years) of illicit drug use, significant mental illness, physical dependence to any opioid, or any history of drug abuse or addiction. 19. Has a history of difficulty with donating blood or donated blood or blood products within 45 days prior to enrollment. 20. Has a clinically significant new illness in the 1 month before Screening in the opinion of the Investigator. 21. Has a history of severe allergies (e.g., anyone with a known history of anaphylaxis to medication[s] or allergens and / or asthma requiring hospitalization). 22. Has malignancy within 5 years of the Screening visit (with the exception of basal and squamous cell skin carcinoma and treated carcinoma-in-situ (CIS) of the cervix). 23. Has known prior exposure to any ANP-related peptide (MANP, nesiritide, carperitide, or other ANP-related peptides in development), whether previously FDA-approved or not. Removal of Subjects from Dosing or Assessment: Subjects who are discontinued from dosing or from the study for any of the following reasons: 1. During the Ascending Dose Phase of the trial, dose escalation is stopped if 2 subjects in the cohort develops clinically significant hypotension, defined as a decrease in sitting SBP to < 90 mmHg confirmed by repeat measurement, or accompanying lightheadedness or dizziness or visual symptoms. Once the stopping criteria are met, a decision is made by the Investigator and sponsor to enter one or more additional cohorts at the same dosage level (in the absence of serious toxicity) or at a lower dosage level, but higher doses were not to be administered. 2. The subject experiences an adverse event (AE) that in the judgement of the Investigator is related to the Investigational drug and poses a significant risk to the subject for continued participation in the study. Attorney Docket No. P35514WO00 / 1105770.00037 3. The subject becomes pregnant. 4. There is significant protocol violation or noncompliance on the part of the subject or the Investigator. 5. There is intercurrent illness that requires treatment not consistent with the protocol requirements, or intercurrent illness and the associated treatment poses a significant risk to the subject for continued participation in the study in the judgment of the Investigator. 6. The subject meets one of the exclusion criteria during the study. 7. The subject wishes to withdraw for any reason. 8. The sponsor elects to end the study, or the Investigational Site elects to end the study at their site. 9. There is any other reason that in the judgment of the Investigator poses an unacceptable risk to the subject. Concomitant Therapy: All medications and supplements (other than IP) taken by the subject from Visit 2, Day 1 through Visit 4 are considered “concomitant” medications and supplements. Medications and supplements taken prior to Visit 2, Day 1 that are no longer being taken at the time of Visit 2, Day 1 are considered “prior” medications and supplements. Clinical BPs and Orthostatic BPs: Clinical BPs are measured with an Indie Health BP Monitor at Screening, Visit 1, Day -1, pre-dose (-20 min) on Day 1 (± 15 min), and at 0.5, 1, 2, 4, 6, 12 hours (± 5 min), and 24 hours (± 15 min) post-dose on Days 1-5, Visits 3 and 4, and ET Visit. Clinical BPs are measured after the subject had been resting for at least 3 minutes and are measured prior to any blood draw that occurred at the same time point. Clinical BPs are derived from the average of two BPs measured with an Indie Health BP Monitor after the subject had been at rest in the seated position for at least three minutes and with the cuff remaining in position but completely deflated for a full minute between measurements. Orthostatic BPs are measured with an Indie Health BP Monitor. Subjects are seated for 3 min, and BP is measured. The subjects are made to stand, and a single BP measurement is taken 2 min after standing. Orthostatic BPs are measured at Screening, Visit 1, pre-dose (-20 min) on Day 1 (± 15 min), and at 0.5, 1, and 6 hours (± 5 min) post-dose on Days 1-5, Visits 3 and 4, and ET Visit. Table 1: Daily schedule of events (Screening through Safety Follow-up Visit 4) Attorney Docket No. P35514WO00 / 1105770.00037 Table 2: PK Unit Schedule of Events (Admission to PK Unit, Visit 2, Day -1) Table 3: PK Unit Schedule of Evens (Visit 2, Days 1-6) Attorney Docket No. P35514WO00 / 1105770.00037 Attorney Docket No. P35514WO00 / 1105770.00037 eGFR: Serum chemistry is measured and the amount of serum creatine is measured at Screening (baseline) and at Visit 4 on Day 21. The estimated Glomerular Filtration Rate (eGFR) and change from baseline are calculated and summarized. Cyclic Guanosine Monophosphate (cGMP): Levels of plasma cyclic guanosine monophosphate (cGMP) are determined. Samples are collected pre-dose (-20 min) (± 15 min), and at 0.25, 0.5, 1, 1.5, 3, 6, 12 hours (± 5 min), and 24 hours (± 15 min) post-dose on Day 1 and Day 5 (see Table 3). Approximately 108 mL of blood is collected for pharmacokinetic samples. The plasma samples are shipped on dry ice via overnight delivery to the analytical lab for analysis. Aldosterone: Levels of plasma aldosterone are determined. Samples are collected pre-dose (-20 min) (± 15 min), and at 1, 3, 6, 12 hours (± 5 min), and 24 hours (± 15 min) post-dose on Day 1 and Day 5, Visits 3 and 4 (see Table 3). The Buffy coat from the Day 1 pre-dose sample and Day 6 sample is retrieved and stored. The plasma samples are shipped on dry ice via overnight delivery to the analytical lab for analysis. Statistical and Analytical Plan: All measured variables and derived parameters are listed individually and tabulated by descriptive statistics. For descriptive statistics, summary tables are provided giving sample size, frequency (counts and percentages) for proportions of categorical variables by study group and sample size, arithmetic mean, standard deviation, coefficient of variation (if appropriate), median, minimum, and maximum, by study group for continuous variables. Prior and concomitant medications will be coded using the World Health Organization (WHO) Drug dictionary September 2021 version. Attorney Docket No. P35514WO00 / 1105770.00037 Clinical BPs are measured at Screening, Visit 1, Visit 2 Day -1, Visit 2 Day 1 pre-dose (-20 min) on Day 1 (± 15 min), and at 0.5, 1, 2, 4, 6, 12 hours (± 5 min), and 24 hours (± 15 min) post- dose on Days 1-5, Visits 3, and 4. Individual values are listed and summarized using descriptive statistics as appropriate (i.e., mean, median, range, and standard deviation). Individual change from baseline (Predose Visit 2, Day 1) clinical BP values are calculated and summarized descriptively. Percentage change toward ideal values for SBP, DBP, and Pulse Rate are listed and summarized descriptively by visit and timepoint and a responder rate of subjects achieving the ideal value is also be listed and summarized by visit and timepoint using frequencies and percentages. Percentage change toward ideal value is defined as the following:Post-dose value Ideal value Pre-dose value Ideal valueThis statistic is a measure of how close subjects’ post-dose value is to the ideal value, relative to how much of a drop was needed from their Pre-dose value to achieve the ideal value. If a Post-dose value is less than or equal to the Pre-dose value, then the result is: Between 0% and 100% when the Post-dose SBP value is more than the ideal value, Exactly 100% when the post-dose value equals the ideal value, and More than 100% when the post-dose value is less than the ideal value. If the Post-dose value is greater than the Pre-dose value, then the result is negative. Ideal values of SBP and DBP of 110mmHg and 70mmHg respectively, are used. For Orthostatic BP, subjects are seated for 3 mins, and BP is measured. The subjects are made to stand, and a single BP measurement is taken 2 min after standing. Orthostatic BPs are measured pre-dose (-20 min) on Day 1 (± 15 min), and at 0.5, 1, and 6 hours (± 5 min) post-dose on Days 1-5. Individual values are listed and summarized using descriptive statistics as appropriate (i.e., mean, median, range, and standard deviation). Individual change from baseline (Predose Visit 2, Day 1) values are calculated and summarized descriptively. The eGFR is calculated and summarized using descriptive statistics as appropriate (i.e., mean, median, range, and standard deviation). The eGFR change from baseline is calculated and summarized descriptively. Pharmacokinetic and pharmacodynamic analysis is conducted using model-independent methods as implemented in Phoenix WinNonlin® (version 8.0 or later) and are based on plasma concentrations of cGMP. Individual plasma concentrations of cGMP are listed for each subject and sampling time and summarized descriptively using the arithmetic mean, SD, CV (%), median, minimum, and maximum. Individual plasma concentration-time profiles of cGMP are plotted on both a linear and a semi-logarithmic scale. Mean values are also presented graphically. Attorney Docket No. P35514WO00 / 1105770.00037 Pharmacokinetic and pharmacodynamic parameters of cGMP are listed for each subject. cGMP is present in the subjects regardless of treatment. To correct for this, both the observed and change from pre-dose values are analyzed. Results – Patient Demographics A summary of subject disposition comparing MANP and placebo for all subjects is presented in Table 4. Table 4: Summary of Subject Disposition – All Subjects A summary of subject demographics and baseline characteristics for all subjects is presented in Table 5. Table 5: Summary of Subject Demographics and Baseline Characteristics – All Subjects Attorney Docket No. P35514WO00 / 1105770.00037 Results – Concomitant Medication Concomitant hypertensive medications use is summarized in Table 6. Table 6: Summary of Concomitant Antihypertensive Medication – All Subjects

[0002] Attorney Docket No. P35514WO00 / 1105770.00037 Other prominent concomitant medications use is summarized in Table 7. Table 7: Summary of Other Concomitant Medication – All Subjects Results – Change in sitting Systolic BP from baseline Attorney Docket No. P35514WO00 / 1105770.00037 For study qualification, DTC / RH subjects have clinic SBP 140 mmHg or DBP 90 mmHg (or SBP 130 mmHg or DBP 80 mmHg for diabetics) derived from the average BPs from Screening and Visit 1, while on at least three standard-of-care antihypertensive medications which must include a diuretic. The average qualifying Screening and Visit 1 SBPs per treatment group are depicted in the first two data points (from the left) in FIG.1. The placebo group has the highest screening SBPs (152.1 mmHg) that were 4.4 mmHg higher than 3 μg / kg group (146.7 mmHg), 5.1 mmHg higher than 4 μg / kg group (147.0 mmHg), 3.3 mmHg higher than 4.5 μg / kg group (148.8 mmHg), 10.3 mmHg higher than 7 μg / kg group (146.7 mmHg), and 11.4 mmHg higher than 6 μg / kg group (140.7 mmHg). These differences generally persist through Visit 1 and Day 1 when study treatment dosing commenced. While the Screening and Visit 1 SBPs are typical daytime measures, the Day - 1 SBPs are collected in the evening on the admission day approximately 12 hours before the administration of the first dose on Day 1 and cannot be reliably compared to the Screening, Visit 1 and Day 1 baseline SBPs. MANP dosing is administered in the morning (8 am ± 1-hour) on Days 1 through 5 and ends on the morning of Day 6. On each dosing day, BPs and pulse rate are collected at 0.5, 1, 2, 4, 6, 12 and 24 hours after dosing and are represented by corresponding data point on Days 1 through 5 in FIG.1. Thus, Days 1 through 5 each have 7 data points. While each dose group is small (N=6 for all, except N=4 for the 7 μg / kg group) and had variable BPs with considerable overlap, the SBPs of the 7, 4, and 4.5 μg / kg groups generally clusters in the lower ranges of SBPs while the placebo, 3, and 6 μg / kg groups generally has the higher SBPs. These changes are discussed in more detail below. The SBPs on Days 12 and 21 (on the right side of FIG.1) are collected at safety follow-up visits approximately 7 and 16 days after the last dose on MANP on the morning of Day 5. Interestingly, despite the absence of MANP over this period, these SBPs are lower than the Screening SBPs by 11.2 mmHg in the placebo group and by 4.9, 19.5, 18.5, 10, and 12.7 mmHg in the 3, 4, 4.5, 7, and 6 μg / kg groups respectively which may reflect the lingering antihypertensive effects of MANP. FIG.2 represents the average changes in sitting SBP for all treatment groups from baseline over the 5 days of therapy, commencing on the morning of Day 1 and concluding on the morning of Day 6, twenty-four hours after the last MANP dose on the morning of Day 5. For the purposes of assessing SBP effects, baseline SBP is determined as the Visit 2 Day 1 Pre-dose value, typically assessed at 8 am ± 1 hour just prior to the first dose of subcutaneous MANP or Placebo on Visit 2 Day 1. Thereafter, subsequent doses of MANP or placebo are Attorney Docket No. P35514WO00 / 1105770.00037 administered at approximate 24-hour intervals on Visit 2 Day 2, Visit 2 Day 3, Visit 2 Day 4, and Visit 2 Day 5. As is the case for Screening and Visit 1 SBPs, baseline SBPs (Table 9) differs considerably between the treatment groups with the placebo (145.9 mmHg), 3 μg / kg (148.8 mmHg), and the 7 μg / kg (148.5 mmHg) having the highest baseline SBPs, while the 4 μg / kg (138.3 mmHg), 4.5 μg / kg (134.3 mmHg), and the 6 μg / kg (129.0 mmHg) groups have lower baseline SBPs that are respectively 7.6 mmHg, 11.6 mmHg, and 16.9 mmHg less than the placebo baseline SBP. In considering the changes in SBP from baseline depicted in FIG.2, the 7 μg / kg group clearly has the greatest SBP reductions, and while there is considerable overlap among the remaining groups, the 4 μg / kg group generally generates the next largest SBP reductions. Exhibited strikingly in the 7 μg / kg group, but generally present for all groups, SBP falls after each morning dose attaining a peak reduction around 6 hours after dosing and then gradually diminishes thereafter. Table 8 tabulates the baseline SBP along with the maximum and minimum SBP changes and their associated time points for each treatment group for each of the 5 days of therapy. Aside from the placebo group which is a compilation of the placebo treated subjects from each treatment group, the order of the treatment group columns from left to right represents the sequence of ascending doses from 3 μg / kg to 7 μg / kg, and then finally, the reduction to 6 μg / kg. The placebo treatment group has large reductions in SBP which is probably a function of higher baseline BPs and the general sedentary nature associated with in-house confinement. Peak placebo SBP reductions mostly occurs 24 hours after dosing after the greatest number of sedentary hours associated with the prior night’s sleep and rest. Considering the maximum SBP reductions for the remaining treatment groups, especially on Day 1, there appears to be a dose-response relationship with increasing SBP reductions as one progresses from 3 μg / kg to 4 μg / kg, and then to 7 μg / kg. While the 4.5 μg / kg generally has lower reductions than the 4 μg / kg group, probably related to its lower baseline starting point, considering the 4 and 4.5 μg / kg groups as a single entity does not detract from the general sense of a dose- response relationship as one progresses from 3 μg / kg, through the combined 4 and 4.5 μg / kg groups to the 7 μg / kg group. The SBP reductions for the 6 μg / kg group are oddly the lowest of the treatment groups, but it must be appreciated that this group’s starting baseline is 11.4 mmHg less than the placebo baseline and that if this difference is hypothetically added to the results of the 6 μg / kg group the general sense of a dose-response relationship is maintained—especially on Day 1. Attorney Docket No. P35514WO00 / 1105770.00037 For each treatment group, peak SBP reductions (Max ) occur within the first 6 hours of dosing, while minimum SBP reductions (Min ) generally occur beyond the 12-hour timepoint or very early in the next dosing cycle before the onset of activity of the next dose. Thus, peak SBP reductions clusters around the 4-to-6-hour timepoints after dosing while minimum reductions clustered around the latter part of the 24-hour dosing cycle. Table 8: Baseline SBP along with the maximum and minimum SBP changes ( ) and theirassociated time points (hours after dosing) for each of the 5 days of therapy – All Subjects (Safety Population) Baseline is defined as Visit 2 Day 1 Pre-Dose. SBP changes ( ) = Post-Dose SBP value – Visit 2Day 1 Pre-Dose Baseline. Negative values indicate an SBP reduction; positive values an SBP increase. Thus, maximum changes (Max ) represent the largest SBP reductions (i.e., largest negative values) or the smallest positive value if all changes were positive (i.e., SBP increased). Minimum changes (Min ) represent the smallest SBP reductions (i.e., smallest negative values) or the largest positive value if all changes were positive (i.e., SBP increased). This study also attempts to evaluate the percentage change toward ideal BP with the ideal values set at 110 mmHg, 70 mmHg for SBP and DBP respectively. Attorney Docket No. P35514WO00 / 1105770.00037 If a post-dose value is less than or equal to the pre-dose value, then the percentage toward the ideal value would be between 0% and 100% depending on the degree to which the reduction from the baseline value approaches the ideal value. If the reduction reaches or exceeds the ideal value, the associated percentage change would be 100% or > 100% respectively. In instances where post-dose values exceed pre-dose values the percentage toward ideal generates a negative value. Along with SBP reductions, these percentage toward ideal values are tabulated in Table 8 for each timepoint of the 5 days of dosing. As a result of the small groups and the fluctuation of SBP this metric generates a wide array of values. However, generally speaking, the maximum SBP reductions attain a percentage toward ideal of between 20 % to 100% for the 3, 4, 4.5, 7, and 6 μg / kg groups. Finally, it is noted that these SBP reductions and the percentage toward ideal SBPs are attained in DTC / RH subjects requiring at least three standard-of-care antihypertensive medications that includes a diuretic. Treatment for a single NAA patient in the 7 μg / kg group is discontinued due to a severe event of hypotension and moderate events of dizziness and tinnitus. The SBP of this patient falls from a baseline of 169 mmHg to 63 mmHg at the 1-hour timepoint on the first day of dosing, while the DBP falls from a baseline of 106 mmHg to 45 mmHg. In total, the patient’s BP is observed to fall 106 / 64 mmHg. These changes in BPs are accompanied by dizziness, tinnitus, pallor, and diaphoresis, but not tachycardia. The subject responds to an IV fluid bolus and by the 2- and 4-hour timepoints, had recovered their BP to 109 / 71 and 131 / 76 mmHg respectively. The patient received with no sequelae. This treatment emergent adverse effect (TEAE) is assessed as probably related to the study treatment and leads to the only patient withdrawal from the study drug. AA subjects report less TEAEs accounting for only 4 (20.0%) of all TEAEs reported. Similarly, only 1 AA subject has 2 treatment-related TEAEs, while 3 NAA subjects has 7 treatment-related TEAEs. None of the AA-associated TEAEs results in death, or were serious, severe, or led to premature drug withdrawal. This study also aims to assess the treatment effect of MANP in AA subjects by enrolling at least 3 AA subjects in each treatment cohort of 8 subjects. This results in 5 AAs of 9 subjects in the placebo group and 3 AAs of 6 subjects in each of the 3, 4, 4.5, and 6 μg / kg groups respectively. Thus, aside from the prematurely discontinued 7 μg / kg group which has 1 AA out of 4 subjects, AAs comprises at least 50% of treated subjects in each group. The results for the AA and NAA groups are contrasted in FIG.3 and FIG.4 for SBPs per dose group from the Screening Visit through the final visit at Visit 4 Day 21; FIG.5 and FIG.6 representing the average changes in sitting SBP for all treatment groups from baseline over the 5 Attorney Docket No. P35514WO00 / 1105770.00037 days of therapy, commencing on the morning of Day 1 and concluding on the morning of Day 6, twenty four hours after the last MANP dose on the morning of Day 5; and Table 9 and Table 10, representing the baseline SBP along with the maximum and minimum SBP changes and their associated time points for each treatment group for each of the 5 days of therapy. Note that all the graph figures use the same y-axis (SBP) scale to allow for ease of comparison. Table 9: Baseline SBP along with the maximum and minimum SBP changes ( ) and theirassociated time points (hours after dosing) for each of the 5 days of therapy –African Americans (Safety Population) Baseline is defined as Visit 2 Day 1 Pre-Dose. SBP changes ( ) = Post-Dose SBP value – Visit 2Day 1 Pre-Dose Baseline. Negative values indicate an SBP reduction; positive values an SBP increase. Thus, maximum changes (Max ) represent the largest SBP reductions (i.e., largest negative values) or the smallest positive value if all changes were positive (i.e., SBP increased). Minimum changes (Min ) represent the smallest SBP reductions (i.e., smallest negative values) or the largest positive value if all changes were positive (i.e., SBP increased). Attorney Docket No. P35514WO00 / 1105770.00037 Table 10: Baseline SBP along with the maximum and minimum SBP changes ( ) and theirassociated time points (hours after dosing) for each of the 5 days of therapy – Non-African Americans (Safety Population) Baseline is defined as Visit 2 Day 1 Pre-Dose. SBP changes ( ) = Post-Dose SBP value – Visit 2Day 1 Pre-Dose Baseline. Negative values indicate an SBP reduction; positive values an SBP increase. Thus, maximum changes (Max ) represent the largest SBP reductions (i.e., largest negative values) or the smallest positive value if all changes were positive (i.e., SBP increased). Minimum changes (Min ) represent the smallest SBP reductions (i.e., smallest negative values) or the largest positive value if all changes were positive (i.e., SBP increased). Acknowledging that there is only a single AA subject in the 7 μg / kg group, the SBP values for AA subjects (FIG.3) yielded greater degrees of separation between the treatment groups than was seen for NAA subjects (FIG.4). Similarly, reductions in SBP at each timepoint over the 5 treatment days were generally greater for AA subjects (FIG.5) than for NAA subjects (FIG.6). AA subjects generally have greater maximum SBP reductions than the NAA subjects in the 4, 4.5, 7 and 6 μg / kg treatment groups while NAA subjects have greater reductions in the 3 μg / kg group. While these comparisons are confounded by small group sizes, fluctuating SBPs, and Attorney Docket No. P35514WO00 / 1105770.00037 corresponding differences in baseline SBP, it appears that this study finds a signal for greater efficacy of MANP among AA subjects—especially at higher doses. Results – Change in sitting Diastolic BP from baseline For study qualification, DTC / RH subjects have clinical SBP 140 mmHg or DBP 90 mmHg (or SBP 130 mmHg or DBP 80 mmHg for diabetics) derived from the average BPs from Screening and Visit 1, while on at least three standard-of-care antihypertensive medications which must include a diuretic. The average qualifying Screening and Visit 1 DBPs per treatment group are depicted in the first two data points (from the left) in FIG.7. As is the case for SBP, the placebo group has the highest screening DBPs (93.1 mmHg) that are 7.6 mmHg higher than 3 μg / kg group (85.5 mmHg), 8.8 mmHg higher than 4 μg / kg group (84.3 mmHg), 3.8 mmHg higher than 4.5 μg / kg group (89.3 mmHg), 4.4 mmHg higher than 7 μg / kg group (88.8 mmHg), and 3.9 mmHg higher than 6 μg / kg group (89.2 mmHg). These differences generally persist through Visit 1 and Day 1 when study treatment dosing commenced except for the 7 μg / kg group which has the highest baseline DBP at Visit 2 Day1 and exceeds the placebo group’s DBP by 3.3 mmHg (Placebo = 90.7 mmHg vs.7 μg / kg group = 94.0 mmHg). While the screening and Visit 1 DBPs are typical daytime measures, the Day -1 DBPs are collected in the evening on the admission day approximately 12 hours before the administration of the first dose on Day 1 and cannot be reliably compared to the Screening, Visit 1 and Day 1 baseline DBPs. MANP dosing is administered in the morning (8 am ± 1-hour) on Days 1 through 5 and ended on the morning of Day 6. On each dosing day, DBPs are collected at 0.5, 1, 2, 4, 6, 12 and 24 hours after dosing and are represented by corresponding data point on Days 1 through 5 in FIG.7. Thus, Days 1 through 5 each have 7 data points. As noted with SBPs, DBPs exhibit considerable variability and overlap. Generally, DBPs of the 7 and 4 μg / kg groups aggregate around lower DBP values while those of the placebo, 3, 4.5, and 6 μg / kg groups show considerable overlap at higher DBP values. These changes are discussed in more detail below. The DBPs on Days 12 and 21 (on the right side of the figure) are collected at safety follow- up visits approximately 7 and 16 days after the last dose on MANP on the morning of Day 5. As for SBP, despite the absence of MANP over this period, these DBPs are lower than the Screening DBPs by 7.4 mmHg in the placebo group and by 1.5, 8.1, 11.6, 5.8, and 6.7 mmHg in the 3, 4, 4.5, 7, and 6 μg / kg groups respectively which may reflect the lingering antihypertensive and vascular effects of MANP. Attorney Docket No. P35514WO00 / 1105770.00037 For the purposes of assessing DBP effects, baseline DBP is determined as the Visit 2 Day 1 Pre-dose value, typically assessed at 8 am ± 1 hour just prior to the first dose of subcutaneous MANP or placebo on Visit 2 Day 1. Thereafter, subsequent doses of MANP or placebo are administered at approximate 24-hour intervals on Visit 2 Day 2, Visit 2 Day 3, Visit 2 Day 4, and Visit 2 Day 5. As is the case for Screening and Visit 1 DBPs, baseline DBPs (Table 11) differed considerably between the treatment groups with the placebo (90.7 mmHg) and the 7 μg / kg group (94.0 mmHg) having the highest baseline DBPs, while the 3 μg / kg (82.3 mmHg), 4 μg / kg (84.0 mmHg), 4.5 μg / kg (83.7 mmHg), and the 6 μg / kg (79.5 mmHg) groups had lower baseline DBPs that were respectively 8.4 mmHg, 6.7 mmHg, 7.0 mmHg, and 11.2 mmHg less than the placebo baseline DBP. Table 11: Baseline DBP along with the maximum and minimum DBP changes ( ) and theirassociated time points (hours after dosing) for each of the 5 days of therapy – All Subjects (Safety Population) Baseline is defined as Visit 2 Day 1 Pre-Dose. DBP changes ( ) = Post-Dose DBP value – Visit 2Day 1 Pre-Dose Baseline. Negative values indicate a DBP reduction; positive values a DBP Attorney Docket No. P35514WO00 / 1105770.00037 increase. Thus, maximum changes (Max ) represent the largest DBP reductions (i.e., largest negative values) or the smallest positive value if all changes were positive (i.e., DBP increased). Minimum changes (Min ) represent the smallest DBP reductions (i.e., smallest negative values) or the largest positive value if all changes were positive (i.e., DBP increased). Maintaining the pattern observed for SBP changes, changes in DBP from baseline depicted in FIG.8, reveal that the 7 μg / kg group has the greatest DBP reductions with considerable overlap among the remaining groups. DBP falls after each morning dose attaining a peak reduction around 4 to 6 hours after dosing and then gradually diminishes thereafter. Table 11 tabulates the baseline DBP along with the maximum and minimum DBP changes and their associated time points for each treatment group for each of the 5 days of therapy. Aside from the placebo group which is a compilation of the placebo treated subjects from each treatment group, the order of the treatment group columns from left to right represents the sequence of ascending doses from 3 μg / kg to 7 μg / kg, and then finally, the reduction to 6 μg / kg. As noted previously with SBP, the DBP reductions on placebo treatment group are likely a function of higher baseline BPs and the general sedentary nature associated with in-house confinement. Considering the maximum DBP reductions for the remaining treatment groups, especially on Day 1, there appears to be a dose-response relationship with increasing DBP reductions as one progresses from 3 μg / kg to 4 μg / kg, to 4.5 μg / kg and then to 7 μg / kg. While the 4.5 μg / kg generally had lower reductions than the 4 μg / kg group, considering the 4 and 4.5 μg / kg groups as a single entity did not detract from the general sense of a dose-response relationship as one progressed from 3 μg / kg, through the combined 4 and 4.5 μg / kg groups to the 7 μg / kg group. The DBP reductions for the 6 μg / kg group are among the lowest of the treatment groups, but again, as for the SBP findings, it is noted that this group’s starting baseline is 11.2 mmHg less than the placebo baseline and that if this difference is hypothetically added to the results of the 6 μg / kg group the general sense of a dose-response relationship is maintained. For each treatment group, peak reductions occur within the first 6 hours of dosing, while minimum reductions generally occurs beyond the 12-hour timepoint or very early in the next dosing cycle before the onset of activity of the next dose. Thus, peak DBP reductions cluster around the 4-to-6-hour timepoints after dosing while minimum reductions cluster around the latter part of the 24-hour dosing cycle. The methods of determining the percentage toward ideal DBP values are discussed above under the SBP section. The percentage toward ideal DBP values are tabulated in Table 11. for each Attorney Docket No. P35514WO00 / 1105770.00037 timepoint of the 5 days of dosing. As SBP, this DBP metric generates a wide array of values as shown in Table 11. However, generally speaking, the maximum DBP reductions attain a percentage toward ideal of between 20 % to 120% for the 3, 4, 4.5, 7, and 6 μg / kg groups. It is noted that these DBP reductions and the percentage toward ideal DBPs are attained in DTC / RH subjects requiring at least three standard-of-care antihypertensive medications that include a diuretic. Assessing the differing effects of MANP, the AA and NAA groups are contrasted in FIG.9 and FIG.10 for DBPs per dose group from the Screening Visit through the final visit at Visit 4 Day 21; FIG.11 and FIG.12 representing the average changes in sitting SBP for all treatment groups from baseline over the 5 days of therapy, commencing on the morning of Day 1 and concluding on the morning of Day 6, twenty four hours after the last MANP dose on the morning of Day 5; and Table 12 and Table 13, representing the baseline DBP along with the maximum and minimum SBP changes and their associated time points for each treatment group for each of the 5 days of therapy. Note that all the graph figures use the same y-axis (DBP) scale to allow for ease of comparison. While DBP values for AA subjects (FIG.9) did not indicate starkly differing effects between AA and NAA subjects (FIG.10). Reductions in DBP at each timepoint over the 5 treatment days were generally greater for AA subjects (FIG.11) than for NAA subjects (FIG.12). While acknowledging that there is only a single AA subject in the 7 μg / kg group, the AA response to 7 μg / kg dose yields approximately double the maximum reductions in DBP than is seen in the NAA group. To a lesser extent AA maximum DBP reductions are also greater for the 6 μg / kg (Days 4 and 5) and the 4.5 μg / kg dose group. NAA subjects have greater maximum DBP reductions in the 3 and 4 μg / kg dose groups. Thus, similar to SBP, and noting the small group sizes, fluctuating DBPs, and corresponding differences in baseline DBP, it appears that maximum reductions in DBP confirm a signal for greater efficacy of MANP among AA subjects—especially at higher doses. Table 12: Baseline DBP along with the maximum and minimum DBP changes ( ) and theirassociated time points (hours after dosing) for each of the 5 days of therapy –African Americans (Safety Population) Attorney Docket No. P35514WO00 / 1105770.00037 Baseline is defined as Visit 2 Day 1 Pre-Dose. DBP changes ( ) = Post-Dose DBP value – Visit 2Day 1 Pre-Dose Baseline. Negative values indicate a DBP reduction; positive values a DBP increase. Thus, maximum changes (Max ) represent the largest DBP reductions (i.e., largest negative values) or the smallest positive value if all changes were positive (i.e., DBP increased). Minimum changes (Min ) represent the smallest DBP reductions (i.e., smallest negative values) or the largest positive value if all changes were positive (i.e., DBP increased). Table 13: – Baseline DBP along with the maximum and minimum DBP changes ( ) andtheir associated time points for each of the 5 days of therapy – Non-African Americans (Safety Population) Attorney Docket No. P35514WO00 / 1105770.00037 Baseline is defined as Visit 2 Day 1 Pre-Dose. DBP changes ( ) = Post-Dose DBP value – Visit 2Day 1 Pre-Dose Baseline. Negative values indicate a DBP reduction; positive values a DBP increase. Thus, maximum changes (Max ) represent the largest DBP reductions (i.e., largest negative values) or the smallest positive value if all changes were positive (i.e., DBP increased). Minimum changes (Min ) represent the smallest DBP reductions (i.e., smallest negative values) or the largest positive value if all changes were positive (i.e., DBP increased). Results – Baseline sitting SBP prior to dosing on each day and the change from the Visit 2 Day 1 baseline After 5 days of MANP dosing, the largest reduction in baseline SBP (i.e., the SBP 24 hours after the previous dose) occurred in the 7 μg / kg group (-18.7 mmHg). The placebo group had the next largest reduction of 12.2 mmHg while the 4 μg / kg and 3 μg / kg groups had respective reductions of 6.7 and 6.5 mmHg. While baseline SBP reductions varied considerably between groups and within a group from day-to-day, the greatest MANP reductions occurred in the 7 and 4 μg / kg groups (FIG.13F). Table 14 tabulates these SBPs and their change from the Visit 2 Day 1 baseline. Table 14: Mean baseline SBP prior to dosing on each day and the change from Visit 2 Day 1 Pre-Dose Baseline – All Subjects (Safety Population) Attorney Docket No. P35514WO00 / 1105770.00037 V = Visit; D = Visit 2 Dosing Day. Baseline is defined as Pre-Dose baseline on each dosing day. A similar pattern is observed for the AA (FIG.14 and Table 15) and NAA groups. There is only a single subject in the AA 7 μg / kg group. Table 15: Mean baseline SBP prior to dosing on each day and the change from Visit 2 Day 1 Pre-Dose Baseline – African Americans (Safety Population) V = Visit; D = Visit 2 Dosing Day. Baseline is defined as Pre-Dose baseline on each dosing day. FIG.15 and FIG.16 represents the average pre-dose changes in sitting SBP for all treatment groups from baseline over the 5 days of therapy for all subjects and the AA subjects, respectively. Results – Baseline sitting DBP prior to dosing on each day and the change from the Visit 2 Day 1 baseline After 5 days of MANP dosing, baseline DBP and their changes from baseline mirrors those for SBP in all subjects (FIG.17 and Table 16) and the AA subgroup (FIG.18 and Table 17). Only a single subject represents the AA 7 μg / kg group. Attorney Docket No. P35514WO00 / 1105770.00037 Table 16: Mean baseline DBP prior to dosing on each day and the change from Visit 2 Day 1 Pre-Dose Baseline – All Subjects (Safety Population) V = Visit; D = Visit 2 Dosing Day. Baseline is defined as Pre-Dose baseline on each dosing day. Table 17: Pre-Dose Diastolic Blood Pressure Over Time – African Americans (Safety Population) V = Visit; D = Visit 2 Dosing Day. Baseline is defined as Pre-Dose baseline on each dosing day. FIG.19 and FIG.20 represents the average pre-dose changes in sitting DBP for all treatment groups from baseline over the 5 days of therapy for all subjects and the AA subjects, respectively. Attorney Docket No. P35514WO00 / 1105770.00037 Results – Changes in eGFR from baseline The changes from Screening (baseline) in the eGFR at Visit 4 Day 21 are similar among treatment groups except for the MANP 3 g / kg cohort, where a single subject developed non- clinically significant values outside the normal laboratory range. The change from Screening (baseline) in eGFR (ml / min / 1.73m2) at Visit 4 Day 21 increased by 23.63 in the MANP 3 g / kg cohort, 8.82 in the MANP 4 g / kg cohort, and decreased by 3.77 in placebo, 2.35 in the MANP 4.5 g / kg cohort, 5.43 in the MANP 7 g / kg cohort, and 0.03 in the MANP 6 g / kg cohort. Table 18: eGFR levels in subjects One subject each in the Placebo, 3, 4, 4.5, and 6 μg / kg groups has a low eGFR at baseline, which is unsurprising given the average age of the subjects and their disease (difficult-to-control hypertension). However, this abnormality remains stable through the study and no new instances of significant derangements in renal function occur during the study. In general, any changes in eGFR were comparable for MANP and placebo groups and do not generate any clinically significant findings or adverse events. Attorney Docket No. P35514WO00 / 1105770.00037 Results – Changes in cGMP levels from baseline The cGMP levels by timepoint for all subjects is shown in Table 19. The summary of cGMP pharmacokinetic parameters for all subjects is shown in Table 20. While cGMP values are comparable at baseline on both Days 1 and 5, the different doses of MANP yields clear peak levels early in the dosing cycle, while placebo does not produce a clearly discernable peak level. The 3μg / kg dose leads to peak levels of 19.70 and 20.75 pmol / mL at hours 0.25 and 0.5 on days 1 and 5 respectively; the 4 ug / kg dose to peak levels of 31.97 and 32.60 pmol / mL at hours 0.5 and 0.5 on Days 1 and 5 respectively; the 4.5 μg / kg dose to peak levels of 21.85 and 22.66 pmol / mL at hours 0.5 and 1 on Days 1 and 5 respectively; the 7 μg / kg dose to peak levels of 37.97 and 27.50 pmol / mL at hours 1 and 1 on Days 1 and 5 respectively; and the 6 μg / kg dose to peak levels of 25.68 and 18.98 pmol / mL at hours 0.5 and 0.25 on Days 1 and 5 respectively. Placebo produces the highest levels of 12.02 and 9.03 pmol / mL at hours 1 and 1 on Days 1 and 5 respectively. Thus, the 7 μg / kg dose group produces the highest peak levels while the other doses ranges between that of placebo and 7 μg / kg (Table 19 and FIG.21). Among AA subjects, cGMP levels are generally higher with the exception of the 7 μg / kg which has only a single AA subject and some missing collection timepoints on Day 1 (see FIG.22). Table 19: cGMP Levels by Timepoint – All Subjects (PK Population) Attorney Docket No. P35514WO00 / 1105770.00037 Attorney Docket No. P35514WO00 / 1105770.00037 Attorney Docket No. P35514WO00 / 1105770.00037 Table 20: cGMP Parameters – All subjects Attorney Docket No. P35514WO00 / 1105770.00037 Results – Changes in aldosterone levels from baseline The summary of aldosterone levels and percentage change from baseline on Days 1 and 5 for all subjects is presented in Table 21 and FIG.23. The summary of aldosterone levels by timepoint and percentage change from baseline on Days 1 and 5 for AA subjects is presented in Table 22 and FIG.24. Aldosterone levels measured throughout the study graphed in FIG.23 shows considerable variability and overlap between the MANP dosing groups. Table 21 tabulates the aldosterone (ng / dL) levels by timepoint and percentage change form baseline on Days 1 and 5 and generally reveals that aldosterone levels were suppressed at the 1-hour timepoint in comparison with their baseline values for all doses including placebo on both Days 1 and 5. However, the percentage reduction in aldosterone for the MANP doses is generally 2 to 3-fold that achieved by placebo at the 1-hour timepoint on both Days 1 and 5. After the 1-hour timepoint on both days, aldosterone and the percentage aldosterone reduction generally remains suppressed compared to baseline (sometimes markedly), although some values are elevated and the differences from placebo attenuated. Table 21: Aldosterone (ng / dL) Levels by Timepoint and Percentage Change from Baseline on Days 1 and 5 – All Subjects Day 5 Attorney Docket No. P35514WO00 / 1105770.00037 Aldosterone levels measured throughout the study in AA subjects graphed in FIG.24 shows considerably more variability and overlap between the MANP dosing groups than the entire population. For AA subjects, Table 22 tabulates the aldosterone (ng / dL) levels by timepoint and percentage change form baseline on Days 1 and 5 does not generally reveal that aldosterone levels were suppressed to a greater degree among AA subjects because values varied widely in both directions, the groups were small, with the 7 μg / kg group containing only a single subject. Table 22: Aldosterone (ng / dL) Levels by Timepoint and Percentage Change from Baseline on Days 1 and 5 – African Americans Attorney Docket No. P35514WO00 / 1105770.00037 From the foregoing, it will be appreciated that the present invention can be embodied in various ways, which include but are not limited to the following: Embodiment 1. A method for lowering blood pressure in a patient in need thereof, comprising: administering one or more doses of MANP of at least 4 μg / kg, wherein a first blood pressure of the patient, measured at a first timepoint after one of the one or more doses, is reduced by at least 5 mmHg compared to an initial blood pressure measured before receiving the first dose of MANP. Embodiment 2. The method of Embodiment 1, wherein the patient has a body mass index (BMI) greater than 29.9 kg / m2. Embodiment 3. The method of Embodiment 1, wherein more than one dose of MANP is administered. Embodiment 4. The method of Embodiment 3, wherein the more than one dose is administered once every 24 hours. Embodiment 5. The method of Embodiment 1, wherein five doses of MANP is administered. Embodiment 6. The method of Embodiment 1, wherein MANP is a peptide with a sequence comprising at least 90% sequence identity to SEQ ID NO: 1. Embodiment 7. The method of Embodiment 1, further comprising administering one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. Embodiment 8. The method of Embodiment 1, wherein before receiving any MANP, the patient was receiving one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. Embodiment 9. The method of Embodiment 7 or 8, wherein the Ca2+ channel blocker is selected from the group consisting of amlodipine besilate, verapamil, diltiazem, and nifedipine. Attorney Docket No. P35514WO00 / 1105770.00037 Embodiment 10. The method of Embodiment 7 or 8, wherein the diuretic is selected from the group consisting of hydrochlorothiazide, spironolactone, bumetanide, chlorthalidone, furosemide, and hydralazine. Embodiment 11. The method of Embodiment 7 or 8, wherein the ACE inhibitor is selected from the group consisting of benazepril and lisinopril. Embodiment 12. The method of Embodiment 7 or 8, wherein the ARB is selected from the group consisting of losartan and olmesartan. Embodiment 13. The method of Embodiment 7 or 8, wherein the alpha-blocker is selected from the group consisting of doxazosin, prazosin, tamsulosin, and clonidine. Embodiment 14. The method of Embodiment 7 or 8, wherein the beta-blocker is selected from the group consisting of carvedilol, atenolol, bisoprolol, metoprolol, and nebivolol. Embodiment 15. The method of Embodiment 1, wherein the first blood pressure comprises a first systolic blood pressure. Embodiment 16. The method of Embodiment 1, wherein the first blood pressure comprises a first diastolic blood pressure. Embodiment 17. The method of Embodiment 1, wherein the first blood pressure is orthostatic blood pressure. Embodiment 18. The method of Embodiment 15, wherein the patient has an initial systolic blood pressure of greater than 140 mmHg before receiving the first dose of MANP. Embodiment 19. The method of Embodiment 15, wherein the patient has an initial systolic blood pressure of greater than 130 mmHg before receiving the first dose of MANP, and wherein the patient has diabetes. Embodiment 20. The method of Embodiment 16, wherein the patient has an initial diastolic blood pressure of greater than 90 mmHg before receiving the first dose of MANP. Embodiment 21. The method of Embodiment 16, wherein the patient has an initial diastolic blood pressure of greater than 80 mmHg before receiving the first dose of MANP, and wherein the patient has diabetes. Embodiment 22. The method of Embodiment 1, wherein the patient has been identified as having hypertension. Embodiment 23. The method of Embodiment 22, wherein the hypertension is resistant hypertension. Embodiment 24. The method of Embodiment 1, wherein the patient is identified as African American. Attorney Docket No. P35514WO00 / 1105770.00037 Embodiment 25. The method of Embodiment 1, wherein the MANP is administered at a dose of about 4 μg / kg. Embodiment 26. The method of Embodiment 1, wherein the MANP is administered at a dose of about 4.5 μg / kg. Embodiment 27. The method of Embodiment 1, wherein the MANP is administered at a dose of about 7 μg / kg. Embodiment 28. The method of Embodiment 1, wherein the first timepoint is about 30 min. Embodiment 29. The method of Embodiment 1, wherein the first timepoint is about 1 hour. Embodiment 30. The method of Embodiment 1, wherein the first timepoint is about 2 hours. Embodiment 31. The method of Embodiment 1, wherein the first timepoint is about 4 hours. Embodiment 32. The method of Embodiment 1, wherein the first timepoint is about 6 hours. Embodiment 33. The method of Embodiment 1, wherein the first timepoint is about 12 hours. Embodiment 34. The method of Embodiment 1, wherein the first timepoint is about 24 hours. Embodiment 35. The method of Embodiment 1, wherein a second blood pressure of the patient measured at a second timepoint after one of the one or more doses is reduced by at least 5 mmHg, compared to the initial blood pressure measured before receiving the first dose of MANP. Embodiment 36. The method of Embodiment 1, wherein a first estimated glomerular filtration rate (eGFR) of the patient measured at a first timepoint after the one or more doses is equal to or greater than an initial eGFR of the patient measured before the one or more doses. Embodiment 37. A method for sustained lowering of blood pressure in a patient in need thereof, comprising: administering one or more doses of MANP, wherein a first blood pressure of the patient, measured at a first time interval of at least 24 hours after the one or more doses of MANP is administered, is at least 5 mmHg lower than an initial blood pressure of the patient measured before receiving the first dose of MANP. Embodiment 38. The method of Embodiment 37, wherein the patient has a body mass index (BMI) greater than 29.9 kg / m2. Embodiment 39. The method of Embodiment 37, wherein more than one dose of MANP is administered. Embodiment 40. The method of Embodiment 37, wherein the more than one dose is administered once every 24 hours. Embodiment 41. The method of Embodiment 37, wherein five doses of MANP is administered. Attorney Docket No. P35514WO00 / 1105770.00037 Embodiment 42. The method of Embodiment 37, wherein MANP is a peptide comprising at least 90% sequence identity to SEQ ID NO: 1. Embodiment 43. The method of Embodiment 37, further comprising administering one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. Embodiment 44. The method of Embodiment 37, wherein before receiving any MANP, the patient was receiving one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker. Embodiment 45. The method of Embodiment 43 or 44, wherein the Ca2+ channel blocker is selected from the group consisting of amlodipine besilate, verapamil, diltiazem, and nifedipine. Embodiment 46. The method of Embodiment 43 or 44, wherein the diuretic is selected from the group consisting of hydrochlorothiazide, spironolactone, bumetanide, chlorthalidone, furosemide, and hydralazine. Embodiment 47. The method of Embodiment 43 or 44, wherein the ACE inhibitor is selected from the group consisting of benazepril and lisinopril. Embodiment 48. The method of Embodiment 43 or 44, wherein the ARB is selected from the group consisting of losartan and olmesartan. Embodiment 49. The method of Embodiment 43 or 44, wherein the alpha-blocker is selected from the group consisting of doxazosin, prazosin, tamsulosin, and clonidine. Embodiment 50. The method of Embodiment 43 or 44, wherein the beta-blocker is selected from the group consisting of carvedilol, atenolol, bisoprolol, metoprolol, and nebivolol. Embodiment 51. The method of Embodiment 37, wherein the blood pressure is systolic blood pressure. Embodiment 52. The method of Embodiment 37, wherein the blood pressure is diastolic blood pressure. Embodiment 53. The method of Embodiment 37, wherein the blood pressure is orthostatic blood pressure. Embodiment 54. The method of Embodiment 51, wherein the patient has a systolic blood pressure of greater than 140 mmHg before receiving the first dose of MANP. Embodiment 55. The method of Embodiment 51, wherein the patient has a systolic blood pressure of greater than 130 mmHg before receiving the first dose of MANP, and wherein the patient has diabetes. Attorney Docket No. P35514WO00 / 1105770.00037 Embodiment 56. The method of Embodiment 52, wherein the patient has a diastolic blood pressure of greater than 90 mmHg before receiving the first dose of MANP. Embodiment 57. The method of Embodiment 52, wherein the patient has a diastolic blood pressure of greater than 80 mmHg before receiving the first dose of MANP, and wherein the patient has diabetes. Embodiment 58. The method of Embodiment 37, wherein the patient is African American. Embodiment 59. The method of Embodiment 37, wherein the MANP is administered at a dose of at least 3 μg / kg. Embodiment 60. The method of Embodiment 37, wherein the MANP is administered at a dose of about 3 μg / kg. Embodiment 61. The method of Embodiment 37, wherein the MANP is administered at a dose of about 4 μg / kg. Embodiment 62. The method of Embodiment 37, wherein the MANP is administered at a dose of about 4.5 μg / kg. Embodiment 63. The method of Embodiment 37, wherein the MANP is administered at a dose of about 6 μg / kg. Embodiment 64. The method of Embodiment 37, wherein the MANP is administered at a dose of about 7 μg / kg. Embodiment 65. The method of Embodiment 37, wherein the first time interval is about 36 hours. Embodiment 66. The method of Embodiment 37, wherein the first time interval is about 2 days. Embodiment 67. The method of Embodiment 37, wherein the first time interval is about 5 days. Embodiment 68. The method of Embodiment 37, wherein the first time interval is about 10 days. Embodiment 69. The method of Embodiment 37, wherein the first time interval is about 15 days. Embodiment 70. The method of Embodiment 37, wherein the first time interval is about 16 days. Embodiment 71. The method of Embodiment 37, wherein the patient’s blood pressure measured at a second timepoint after the first time interval is reduced by at least 5 mmHg, compared to that measured before receiving the first dose of MANP. Attorney Docket No. P35514WO00 / 1105770.00037 Embodiment 72. The method of Embodiment 37, wherein the patient has been identified as having hypertension. Embodiment 73. The method of Embodiment 72, wherein the hypertension is resistant hypertension. Embodiment 74. The method of Embodiment 37, wherein a first estimated glomerular filtration rate (eGFR) of the patient measured at a first timepoint after the one or more doses is equal to or greater than an initial eGFR of the patient measured before the one or more doses. Embodiment 75. A method for lowering blood pressure in a subject identified as having a loss of kidney function, comprising: administering one or more doses of MANP, wherein a first estimated glomerular filtration rate (eGFR) of the patient, measured at a first timepoint after one of the one or more doses, is equal to or greater than an initial eGFR measured before receiving the first dose of MANP. Embodiment 76. The method of Embodiment 75, wherein the subject has a body mass index (BMI) greater than 29.9 kg / m2. Embodiment 77. The method of Embodiment 75, wherein the subject has a mild loss of kidney function. Embodiment 78. The method of Embodiment 75, wherein the subject has resistant hypertension. Embodiment 79. The method of Embodiment 75, wherein the first eGFR is between 60 mL / min / 1.73m2and 89 mL / min / 1.73m2. Embodiment 80. A method for lowering blood pressure in a subject identified as having a BMI greater than 29.9 kg / m2and hypertension, comprising: administering one or more doses of MANP, wherein a first blood pressure of the patient, measured at a first timepoint after one of the one or more doses, is reduced by at least 5mmHg compared to an initial blood pressure measured before receiving the first does of MANP. Embodiment 81. The method of Embodiment 80, wherein the hypertension is resistant hypertension. While the invention has been described with reference to particular aspects, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to a particular situation or material to the teachings of the invention without departing from the scope of the invention. Therefore, it is intended that the invention not be limited to the particular aspects disclosed but that the invention will include all aspects falling within the scope and spirit of the appended claims.

Claims

Attorney Docket No. P35514WO00 / 1105770.00037 CLAIMS 1. A method for lowering blood pressure in a patient in need thereof, comprising: administering one or more doses of MANP of at least 4 μg / kg, wherein a first blood pressure of the patient, measured at a first timepoint after one of the one or more doses, is reduced by at least 5 mmHg compared to an initial blood pressure measured before receiving the first dose of MANP.

2. The method of claim 1, wherein the patient has a body mass index (BMI) greater than 29.9 kg / m2.

3. The method of claim 1, wherein more than one dose of MANP is administered.

4. The method of claim 3, wherein the more than one dose is administered once every 24 hours.

5. The method of claim 1, wherein five doses of MANP are administered.

6. The method of claim 1, wherein MANP is a peptide with a sequence comprising at least 90% sequence identity to SEQ ID NO:

1.

7. The method of claim 1, further comprising administering one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker.

8. The method of claim 1, wherein before receiving any MANP, the patient was receiving one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker.

9. The method of claim 7 or 8, wherein the Ca2+channel blocker is selected from the group consisting of amlodipine besilate, verapamil, diltiazem, and nifedipine.

10. The method of claim 7 or 8, wherein the diuretic is selected from the group consisting of hydrochlorothiazide, spironolactone, bumetanide, chlorthalidone, furosemide, and hydralazine.

11. The method of claim 7 or 8, wherein the ACE inhibitor is selected from the group consisting of benazepril and lisinopril.Attorney Docket No. P35514WO00 / 1105770.00037 12. The method of claim 7 or 8, wherein the ARB is selected from the group consisting of losartan and olmesartan.

13. The method of claim 7 or 8, wherein the alpha-blocker is selected from the group consisting of doxazosin, prazosin, tamsulosin, and clonidine.

14. The method of claim 7 or 8, wherein the beta-blocker is selected from the group consisting of carvedilol, atenolol, bisoprolol, metoprolol, and nebivolol.

15. The method of claim 1, wherein the first blood pressure comprises a first systolic blood pressure.

16. The method of claim 1, wherein the first blood pressure comprises a first diastolic blood pressure.

17. The method of claim 1, wherein the first blood pressure is orthostatic blood pressure.

18. The method of claim 15, wherein the patient has an initial systolic blood pressure of greater than 140 mmHg before receiving the first dose of MANP.

19. The method of claim 15, wherein the patient has an initial systolic blood pressure of greater than 130 mmHg before receiving the first dose of MANP, and wherein the patient has diabetes.

20. The method of claim 16, wherein the patient has an initial diastolic blood pressure of greater than 90 mmHg before receiving the first dose of MANP.

21. The method of claim 16, wherein the patient has an initial diastolic blood pressure of greater than 80 mmHg before receiving the first dose of MANP, and wherein the patient has diabetes.

22. The method of claim 1, wherein the patient has been identified as having hypertension.

23. The method of claim 22, wherein the hypertension is resistant hypertension.

24. The method of claim 1, wherein the patient is identified as African American.

25. The method of claim 1, wherein the MANP is administered at a dose of about 4 g / kg.

26. The method of claim 1, wherein the MANP is administered at a dose of about 4.5 g / kg.

27. The method of claim 1, wherein the MANP is administered at a dose of about 7 g / kg.Attorney Docket No. P35514WO00 / 1105770.00037 28. The method of claim 1, wherein the first timepoint is about 30 min.

29. The method of claim 1, wherein the first timepoint is about 1 hour.

30. The method of claim 1, wherein the first timepoint is about 2 hours.

31. The method of claim 1, wherein the first timepoint is about 4 hours.

32. The method of claim 1, wherein the first timepoint is about 6 hours.

33. The method of claim 1, wherein the first timepoint is about 12 hours.

34. The method of claim 1, wherein the first timepoint is about 24 hours.

35. The method of claim 1, wherein a second blood pressure of the patient measured at a second timepoint after one of the one or more doses is reduced by at least 5 mmHg, compared to the initial blood pressure measured before receiving the first dose of MANP.

36. The method of claim 1, wherein a first estimated glomerular filtration rate (eGFR) of the patient measured at a first timepoint after the one or more doses is equal to or greater than an initial eGFR of the patient measured before the one or more doses.

37. A method for sustained lowering of blood pressure in a patient in need thereof, comprising: administering one or more doses of MANP, wherein a first blood pressure of the patient, measured at a first time interval of at least 24 hours after the one or more doses of MANP is administered, is at least 5 mmHg lower than an initial blood pressure of the patient measured before receiving the first dose of MANP.

38. The method of claim 37, wherein the patient has a body mass index (BMI) greater than 29.9 kg / m2.

39. The method of claim 37, wherein more than one dose of MANP is administered.

40. The method of claim 39, wherein the more than one dose is administered once every 24 hours.

41. The method of claim 37, wherein five doses of MANP are administered.

42. The method of claim 37, wherein MANP is a peptide comprising at least 90% sequence identity to SEQ ID NO: 1.Attorney Docket No. P35514WO00 / 1105770.00037 43. The method of claim 37, further comprising administering one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker.

44. The method of claim 37, wherein before receiving any MANP, the patient was receiving one or more doses of medication selected from the group consisting of an antihypertensive drug, a diuretic, a Ca2+ channel blocker, an ACE inhibitor, an angiotensin II receptor blocker (ARB), an alpha-blocker, and a beta-blocker.

45. The method of claim 43 or 44, wherein the Ca2+ channel blocker is selected from the group consisting of amlodipine besilate, verapamil, diltiazem, and nifedipine.

46. The method of claim 43 or 44, wherein the diuretic is selected from the group consisting of hydrochlorothiazide, spironolactone, bumetanide, chlorthalidone, furosemide, and hydralazine.

47. The method of claim 43 or 44, wherein the ACE inhibitor is selected from the group consisting of benazepril and lisinopril.

48. The method of claim 43 or 44, wherein the ARB is selected from the group consisting of losartan and olmesartan.

49. The method of claim 43 or 44, wherein the alpha-blocker is selected from the group consisting of doxazosin, prazosin, tamsulosin, and clonidine.

50. The method of claim 43 or 44, wherein the beta-blocker is selected from the group consisting of carvedilol, atenolol, bisoprolol, metoprolol, and nebivolol.

51. The method of claim 37, wherein the blood pressure is systolic blood pressure.

52. The method of claim 37, wherein the blood pressure is diastolic blood pressure.

53. The method of claim 38, wherein the blood pressure is orthostatic blood pressure.

54. The method of claim 51, wherein the patient has a systolic blood pressure of greater than 140 mmHg before receiving the first dose of MANP.

55. The method of claim 51, wherein the patient has a systolic blood pressure of greater than 130 mmHg before receiving the first dose of MANP, and wherein the patient has diabetes.Attorney Docket No. P35514WO00 / 1105770.00037 56. The method of claim 52, wherein the patient has a diastolic blood pressure of greater than 90 mmHg before receiving the first dose of MANP.

57. The method of claim 52, wherein the patient has a diastolic blood pressure of greater than 80 mmHg before receiving the first dose of MANP, and wherein the patient has diabetes.

58. The method of claim 37, wherein the patient is identified as African American.

59. The method of claim 37, wherein the MANP is administered at a dose of at least 3 g / kg.

60. The method of claim 37, wherein the MANP is administered at a dose of about 3 g / kg.

61. The method of claim 37, wherein the MANP is administered at a dose of about 4 g / kg.

62. The method of claim 37, wherein the MANP is administered at a dose of about 4.5 g / kg.

63. The method of claim 37, wherein the MANP is administered at a dose of about 6 g / kg.

64. The method of claim 37, wherein the MANP is administered at a dose of about 7 g / kg.

65. The method of claim 37, wherein the first time interval is about 36 hours.

66. The method of claim 37, wherein the first time interval is about 2 days.

67. The method of claim 37, wherein the first time interval is about 5 days.

68. The method of claim 37, wherein the first time interval is about 10 days.

69. The method of claim 37, wherein the first time interval is about 15 days.

70. The method of claim 37, wherein the first time interval is about 16 days.

71. The method of claim 37, wherein the patient’s blood pressure measured at a second timepoint after the first time interval is reduced by at least 5 mmHg, compared to that measured before receiving the first dose of MANP.

72. The method of claim 37, wherein the patient has been identified as having hypertension.

73. The method of claim 72, wherein the hypertension is resistant hypertension.Attorney Docket No. P35514WO00 / 1105770.00037 74. The method of claim 37, wherein a first estimated glomerular filtration rate (eGFR) of the patient measured at a first timepoint after the one or more doses is equal to or greater than an initial eGFR of the patient measured before the one or more doses.

75. A method for lowering blood pressure in a subject identified as having a loss of kidney function, comprising: administering one or more doses of MANP, wherein a first estimated glomerular filtration rate (eGFR) of the patient, measured at a first timepoint after one of the one or more doses, is equal to or greater than an initial eGFR measured before receiving the first dose of MANP.

76. The method of claim 75, wherein the subject has a body mass index (BMI) greater than 29.9 kg / m2.

77. The method of claim 75, wherein the subject has a mild loss of kidney function.

78. The method of claim 75, wherein the subject has resistant hypertension.

79. The method of claim 75, wherein the first eGFR is between 60 mL / min / 1.73m2and 89 mL / min / 1.73m2.

80. A method for lowering blood pressure in a subject identified as having a BMI greater than 29.9 kg / m2and hypertension, comprising: administering one or more doses of MANP, wherein a first blood pressure of the patient, measured at a first timepoint after one of the one or more doses, is reduced by at least 5 mmHg compared to an initial blood pressure measured before receiving the first dose of MANP.

81. The method of claim 80, wherein the hypertension is resistant hypertension.