Application of oroxin A in preparation of hypertension drugs

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of oroxin A in preparation of hypertension medicines. The invention provides application of oroxin A or pharmaceutically acceptable salt thereof in preparation of a medicine for preventing and / or relieving and / or treating hypertension or complications thereof. The complications are selected from any one or more of abdominal main arteriosclerosis, heart disease, mesenteric artery disease, stroke and renal failure. The application finds that the oroxin A has the effect of treating hypertension and complications thereof, and provides a new treatment scheme for treating hypertension and complications thereof.

Description

Technical Field

[0001] The present application belongs to the field of medical technology, and specifically relates to the use of oroxylin A in the preparation of hypertension drugs. Background Art

[0002] With the development of social economy and the changes in people's lifestyles, especially the aging of the population and the acceleration of urbanization, the unhealthy lifestyles of residents are becoming increasingly prominent, and the impact of cardiovascular disease risk factors on residents' health is becoming more and more significant. Hypertension is a clinical syndrome characterized by a sustained increase in arterial blood pressure. It is the most common and most important risk factor for cardiovascular and cerebrovascular diseases, affecting more than 1 billion people worldwide. From 1958 to 2022, a nationwide sampling survey on the prevalence of hypertension showed that the prevalence of hypertension was on the rise overall, especially among young and middle-aged people and people in rural areas. The rising trend of the prevalence was more significant. The prevalence of hypertension among residents aged 18 and above was 31.6%, and the male (36.8%) was higher than the female (26.3%), and the rural (33.7%) was higher than the urban (29.1%). Although the awareness, treatment and control rates of hypertension have been continuously improving, the blood pressure control rate is still at a low level of only 26.8%. Improper control of hypertension can cause related complications, such as stroke, renal failure, cardiac hypertrophy, myocardial infarction and heart failure, mainly involving important organs such as the heart, brain, kidneys and eyes. Therefore, it is necessary to explore more effective treatments for hypertension with milder side effects.

[0003] Oroxylin A (OA), also known as Oroxylin A-7-O-glucose, is an active flavonoid component isolated from the seeds of the Bignoniaceae plant Oroxylumindicum. Oroxylin A has antioxidant, anti-inflammatory, antibacterial, and anti-tumor effects. Current studies have shown that total flavonoids from Oroxylin can increase the viability of rat cardiomyocytes H9C2 cells and the activity of SOD and GSH-Px. In addition, studies have shown that Oroxylin can reduce rat arterial systolic blood pressure. Increasing superoxide dismutase in serum has a certain improvement effect on the serum microenvironment. As for whether Oroxylin A can have an effect on hypertension, there is no relevant report yet. Summary of the invention

[0004] In order to solve the defects of the prior art, the present application discovered that oroxylin A has the effect of treating hypertension and its complications, can lower the blood pressure of the subject, reduce the thickened abdominal aorta vascular wall of the subject, improve the pathological morphology of the myocardial tissue of the subject, increase the reduced left ventricular ejection fraction and left ventricular short-axis shortening rate of the subject, and reduce the increased mesenteric artery pulsatility index and mesenteric artery resistance index of the subject.

[0005] Therefore, the first aspect of the present application provides the use of orchidinoside A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or alleviating and / or treating hypertension or its complications.

[0006] The complications are selected from any one or more of abdominal aortic sclerosis, heart disease, mesenteric artery disease, stroke, and renal failure.

[0007] The drug is used for any one or more of the following:

[0008] 1) Lower blood pressure;

[0009] 2) Improve the thickness of the abdominal aorta;

[0010] 3) Improve abnormal pathological morphology of cardiac tissue;

[0011] 4) Improve abnormal heart function;

[0012] 5) Improve mesenteric artery dysfunction.

[0013] The drug comprises an effective amount of oroxylin A or a pharmaceutically acceptable salt thereof, and the effective amount of oroxylin A or a pharmaceutically acceptable salt thereof in the drug is greater than or equal to 10 mg / kg.

[0014] The second aspect of the present application provides a drug for preventing and / or alleviating and / or treating hypertension and its complications, comprising an effective amount of oroxylin A or a pharmaceutically acceptable salt thereof.

[0015] The complications are selected from any one or more of abdominal aortic sclerosis, heart disease, mesenteric artery disease, stroke, and renal failure.

[0016] The effective amount of the oroxylin A or its pharmaceutically acceptable salt in the medicine is greater than or equal to 10 mg / kg.

[0017] The beneficial effects of this application are:

[0018] The present application discovered that oroxylin A has the effect of treating hypertension and its complications. In animal experiments, only a dose of 10 mg / kg / d is needed to reduce the elevated blood pressure of the subject, the thickened abdominal aorta vascular wall of the subject, the elevated mesenteric artery pulsatility index and the mesenteric artery resistance index of the subject, increase the reduced left ventricular ejection fraction and the left ventricular short-axis shortening rate of the subject, and improve the pathological morphology of the myocardial tissue of the subject. The therapeutic effect is better than that of the existing hypertension drug valsartan, and a new treatment plan is provided for the treatment of hypertension and its complications. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1These are the SBP results of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 2.

[0020] Figure 2 These are the DBP results of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 2.

[0021] Figure 3 These are the MAP results of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 2.

[0022] Figure 4 This is the body weight of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 2.

[0023] Figure 5 Ultrasound images of the abdominal aorta thickness of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 3.

[0024] Figure 6 These are the results of abdominal aorta thickness of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 3.

[0025] Figure 7 The figure shows the pathological morphology of the abdominal aorta of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 4.

[0026] Figure 8 The cardiac tissue pathological morphology of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 5.

[0027] Fig. 9 These are the LVEF results of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 6.

[0028] Fig.10 These are the LVFS results of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 6.

[0029] Fig.11 Ultrasound images of the mesenteric arteries of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 7.

[0030] Fig.12 These are the results of the superior mesenteric artery pulsatility index of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 7.

[0031] Fig.13 These are the results of the superior mesenteric artery resistance index of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 7. DETAILED DESCRIPTION

[0032] The following describes the implementation of the present application through specific examples, and those skilled in the art can easily understand other advantages and effects of the present application from the contents disclosed in this specification. The present application can also be implemented or applied through other different specific implementations, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present application.

[0033] Before further describing the specific implementation methods of the present application, it should be understood that the scope of protection of the present application is not limited to the specific specific implementation methods described below; it should also be understood that the terms used in the examples of the present application are for describing specific specific implementation methods rather than for limiting the scope of protection of the present application; in the specification and claims of the present application, unless otherwise expressly stated herein, the singular forms "a", "an" and "the" include plural forms.

[0034] When the embodiments give numerical ranges, it should be understood that, unless otherwise specified in the present application, the two endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present application have the same meaning as those generally understood by those skilled in the art. In addition to the specific methods, equipment, and materials used in the embodiments, according to the grasp of the prior art by those skilled in the art and the record of the present application, any method, equipment, and material of the prior art similar or equivalent to the methods, equipment, and materials described in the embodiments of the present application can also be used to realize the present application.

[0035] The present application first provides the use of oroxylin A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or alleviating and / or treating hypertension or its complications.

[0036] The molecular formula of oroxylin A is C 21 H 20 O 10 , molecular weight is 432.378, CAS number is: 57396-78-8, and the structural formula is shown in the following formula I:

[0037]

[0038] In the present application, the pharmaceutically acceptable salt refers to the salt of orchid glycoside A, which is prepared by orchid glycoside A and a relatively non-toxic acid or base. When orchid glycoside A contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound of the present application with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable bases include salts prepared from inorganic bases and organic bases, and the salts of the inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. The salts of the organic non-toxic bases include salts of primary amines, secondary amines and tertiary amines, including substituted amines and cyclic amines. For example: N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, guaizan, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, etc. When oroxylin A contains relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid and the like.

[0039] In this application, prevention refers to taking measures to prevent the occurrence of a disease or reduce the risk of a disease, which can be divided into primary prevention, taking measures before the disease occurs, with the purpose of preventing the disease from occurring; secondary prevention: the purpose is to detect and treat the disease in its early stages to prevent the development and deterioration of the disease; tertiary prevention is taking measures after the disease has occurred to prevent further deterioration of the disease or complications. Specifically, it refers to all behaviors that suppress symptoms or delay specific symptoms by administering the drugs described in this application.

[0040] In this application, the remission refers to a state in which the symptoms of the disease are significantly reduced or disappear, and the patient's health condition is improved, such as complete remission: all measurable signs and symptoms of the disease disappear completely, usually for a period of time (for example, one month or longer); partial remission: the symptoms of the disease are alleviated, but the standard of complete remission is not met; clinical remission: the patient's symptoms and signs are significantly improved, and the quality of life is improved, but there may still be some mild symptoms or signs; biochemical remission: laboratory tests (such as blood, urine and other biochemical indicators) show that the disease activity is reduced, but there may be no obvious improvement in clinical symptoms; molecular remission: in some diseases (such as some types of cancer), no evidence of the disease can be found even under a microscope, and the level of disease markers drops to undetectable levels. Remission means that the treatment is effective and the patient's prognosis is improved. However, disease remission does not always mean that the disease is completely cured, because some diseases may relapse. In some chronic diseases, such as diabetes, hypertension, etc., disease remission may mean that the condition is effectively controlled, but continuous management is required to maintain the remission state.

[0041] In this application, the treatment refers to a series of positive effects after the disease has begun to develop. Specifically, it can slow down the progression of the disease so that the originally rapid development trend can be controlled; it can interrupt the process of continuous deterioration of the disease and prevent the disease from evolving further in a serious direction; effectively control the severity of the disease to prevent it from exceeding the range that the body can bear; stop the adverse development trend of the disease so that it no longer continues to deteriorate; alleviate the various uncomfortable symptoms caused by the disease and relieve the patient's pain; and even reverse a specific sign, symptom, disorder, disease or the direction or severity of the progression of the disease to a certain extent. However, it should be made clear that this treatment does not necessarily mean that it can involve the complete elimination of all signs, symptoms, diseases or disorders related to the disease, but improves the state of the disease and slows down the signs, symptoms, diseases or disorders related to the disease.

[0042] In the present application, the complications are selected from any one or more of abdominal aortic sclerosis, heart disease, mesenteric artery disease, stroke, and renal failure.

[0043] In a specific embodiment of the present application, the abdominal aorta sclerosis is manifested as thickening of the abdominal aorta.

[0044] In a specific embodiment of the present application, the cardiac disease manifests as cardiac hypertrophy, and / or myocardial infarction, and / or heart failure. Specifically, cardiac hypertrophy, and / or myocardial infarction, and / or heart failure can be manifested as abnormal pathological morphology of cardiac tissue and / or abnormal cardiac function.

[0045] In a specific embodiment of the present application, the mesenteric artery lesions are manifested as abnormal mesenteric artery function.

[0046] In a specific embodiment of the present application, the drug is used to lower blood pressure, specifically refers to lowering mean arterial pressure, and / or lowering systolic blood pressure, and / or lowering diastolic blood pressure; more specifically, lowering the elevated mean arterial pressure of the subject, and / or lowering the elevated systolic blood pressure of the subject, and / or lowering the elevated diastolic blood pressure of the subject; or, inhibiting the increase in the mean arterial pressure of the subject, and / or inhibiting the increase in systolic blood pressure of the subject, and / or inhibiting the increase in diastolic blood pressure of the subject.

[0047] In certain embodiments of the present application, the mean arterial pressure, systolic blood pressure, and diastolic blood pressure of patients with hypertension or its complications are higher than those of a healthy group. When oroxylin A is administered to the patient, the mean arterial pressure, systolic blood pressure, and diastolic blood pressure of the patient are decreased compared to when oroxylin A is not administered.

[0048] In a specific embodiment of the present application, the drug is used to improve the thickening of the abdominal aorta, specifically to reduce the thickness of the abdominal aorta; more specifically, to reduce the thickness of the thickened abdominal aorta.

[0049] In certain embodiments of the present application, the thickness of the abdominal aorta of patients with hypertension or its complications is thicker than that of a healthy group. After oroxylin A is administered to the patient, the thickness of the abdominal aorta of the patient is reduced compared to when oroxylin A is not administered.

[0050] In a specific embodiment of the present application, the drug is used to improve abnormal pathological morphology of cardiac tissue, specifically to arrange cardiomyocytes neatly, and / or to make the nuclei of cardiomyocytes clear, and / or to make the cytoplasm of cardiomyocytes uniformly stained with HE, and / or to reduce the degeneration and necrosis of cardiomyocytes; more specifically, to make the cardiomyocytes with disordered arrangement or reduced neatness of the target become tightly arranged, and / or to make the nuclei of cardiomyocytes that are blurred in HE staining become clear in HE staining, and / or to make the cytoplasm of cardiomyocytes that are unevenly stained in HE staining become uniformly stained in HE staining, and / or to reduce the degeneration and necrosis of the cardiomyocytes of the target.

[0051] In certain embodiments of the present application, the cardiomyocytes of patients with hypertension or its complications have blurred nuclei, uneven cytoplasm staining, disordered arrangement or reduced neatness of arrangement in HE staining compared to healthy people. After oroxylin A is administered to the patient, the cardiomyocytes of the patient have clear nuclei, more uniform cytoplasm staining, more neat arrangement or improved neatness of arrangement in HE staining compared to when oroxylin A is not administered, and the cardiomyocytes have less degeneration and necrosis.

[0052] In a specific embodiment of the present application, the drug is used to improve abnormal cardiac function, specifically to increase the left ventricular ejection fraction and / or increase the left ventricular short-axis shortening rate; more specifically, to increase the reduced left ventricular ejection fraction of the subject, and / or to increase the reduced left ventricular short-axis shortening rate of the subject; or, to inhibit the reduction of the left ventricular ejection fraction of the subject, and / or to inhibit the reduction of the left ventricular short-axis shortening rate of the subject.

[0053] In certain embodiments of the present application, the left ventricular ejection fraction and left ventricular short-axis shortening rate of patients with hypertension or its complications are lower than those of a healthy group. When oroxylin A is administered to the patient, the left ventricular ejection fraction and left ventricular short-axis shortening rate of the patient are improved compared to when oroxylin A is not administered.

[0054] In a specific embodiment of the present application, the drug is used to improve mesenteric artery dysfunction, specifically to reduce the mesenteric artery pulsation index and / or reduce the mesenteric artery resistance index; more specifically, to reduce the elevated mesenteric artery pulsation index of the subject, and / or reduce the elevated mesenteric artery resistance index of the subject; or, to inhibit the elevated mesenteric artery pulsation index of the subject, and / or inhibit the elevated mesenteric artery resistance index of the subject.

[0055] In certain embodiments of the present application, the mesenteric artery pulsation index and mesenteric artery resistance index of patients with hypertension or its complications are increased compared with those of a healthy group. When oroxylin A is administered to the patient, the mesenteric artery pulsation index and mesenteric artery resistance index of the patient are decreased compared with when oroxylin A is not administered.

[0056] In the present application, the subjects may be a group of people who have suffered from, are suffering from, or are likely to suffer from hypertension or its complications.

[0057] In the present application, the healthy group refers to a group that does not suffer from hypertension or its complications and whose indicators involved in the present application are normal.

[0058] In a specific embodiment of the present application, the drug comprises an effective amount of oroxylin A or a pharmaceutically acceptable salt thereof.

[0059] In the present application, the effective dose refers to the dose of the drug, treatment or other intervention measure that achieves the expected therapeutic effect without causing unacceptable side effects or toxicity. The effective dose is expressed as the weight of the drug administered per kilogram of body weight to each individual and is administered to the subject every day during the use period, such as an effective dose of greater than or equal to 10 mg / kg / d.

[0060] In a specific embodiment of the present application, the effective amount of oroxylin A or its pharmaceutically acceptable salt in the medicine is greater than or equal to 10 mg / kg, for example, it can be 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, greater than 40 mg / kg.

[0061] The present application also provides a drug for preventing and / or alleviating and / or treating hypertension and its complications, comprising an effective amount of oroxylin A or a pharmaceutically acceptable salt thereof.

[0062] In a specific embodiment of the present application, the complications are selected from any one or more of abdominal aortic sclerosis, heart disease, mesenteric artery disease, stroke, and renal failure, which are the same as described above and will not be repeated here.

[0063] In a specific embodiment of the present application, the drug is used for any one or more of the following: 1) lowering blood pressure; 2) improving thickening of the abdominal aorta; 3) improving abnormal pathological morphology of cardiac tissue; 4) improving abnormal cardiac function; 5) improving abnormal mesenteric artery function; the details are the same as described above and will not be repeated here.

[0064] In a specific embodiment of the present application, the effective amount of oroxylin A or its pharmaceutically acceptable salt in the medicine is greater than or equal to 10 mg / kg, for example, it can be 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, greater than 40 mg / kg.

[0065] The dosage form of the drug in the present application is not limited, for example, it can be one or more of spray, nasal drops, solution, granules, aerosol, powder spray, tablet, injection, capsule.

[0066] The drug in the present application may also include pharmaceutically acceptable excipients or carriers. Pharmaceutically acceptable excipients refer to auxiliary materials that do not affect the efficacy and safety of the main ingredient of the drug, oroxylin A, are non-toxic in themselves, do not produce adverse, allergic or other adverse reactions, and should be compatible with oroxylin A, that is, they can be mixed with it without significantly reducing its effect under normal circumstances. Examples of these excipients include: sterile water or saline, which serves as a solvent or diluent for the drug; stabilizers, which are used to maintain the stability of the drug and prevent decomposition; antioxidants, such as ascorbic acid, which prevent the drug from oxidizing; buffers, such as phosphates, citric acid, etc., which are used to maintain the pH value of the drug; excipients, which help form the drug into a specific form, such as tablets, capsules, etc.; preservatives, which prevent the drug from being contaminated by microorganisms during storage; surfactants, such as polyethylene glycol (PEG), Tween, etc., which are used to increase the solubility or stability of the drug; binders, which are used to fix the drug components together; suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum methylate and agar or a mixture of these substances; chelating agents, such as EDTA, which are used to bind to metal ions to prevent drug degradation. In addition, the pharmaceutical preparation may also contain: low molecular weight polypeptides; proteins, such as immunoglobulins, serum albumin, or gelatin; amino acids, such as glycine, glutamic acid, arginine, asparagine, and lysine; sugars or carbohydrates, such as polysaccharides and monosaccharides; sugar alcohols, such as sorbitol or mannitol. When preparing aqueous solutions for injection, the following may also be used: physiological saline; isotonic solutions containing glucose or other auxiliary drugs; solubilizers, such as alcohols (ethanol), polyols (such as propylene glycol, PEG) and non-ionic surfactants (such as Tween 80, HCO-50); wetting agents; sweeteners; flavoring agents; emulsifiers; suspending agents; and flavoring agents. The types and proportions of these excipients or carriers may be adjusted according to the type and requirements of the final pharmaceutical preparation.

[0067] In the drugs of the present application, the oroxylin A can be a single active ingredient, or it can be combined with one or more other active ingredients that have therapeutic effects on hypertension or its complications to form a combined preparation, and there is no conflict in the efficacy and safety of the components. Other active ingredients may be other various drugs that can be used to treat hypertension or its complications, such as other drugs for treating hypertension, other drugs for treating abdominal aortic sclerosis, other drugs for treating heart disease, other drugs for treating mesenteric artery disease, other drugs for treating stroke, and other drugs for treating renal failure. Specific examples may be: drugs for treating hypertension, such as calcium channel blockers (such as amlodipine, nifedipine, nitrendipine), angiotensin converting enzyme inhibitors (such as enalapril, ramipril, captopril), angiotensin receptor blockers (such as valsartan, losartan, candesartan, irbesartan, olmesartan medoxomil), diuretics (such as furosemide tablets, hydrochlorothiazide, spironolactone, furosemide), beta-blockers (such as metoprolol, atenolol, bisoprolol), angiotensin receptor neprilysin inhibitors (such as sacubitril valsartan sodium); drugs for treating abdominal aortic sclerosis, such as antiplatelet drugs (such as aspirin, clopidogrel, tegrin Relo), lipid-lowering drugs (such as statins such as atorvastatin and rosuvastatin), glucose-lowering drugs (such as metformin and acarbose), vasodilators (such as isosorbide mononitrate, nifedipine extended-release tablets, and diltiazem), drugs that lower triglycerides (such as fenofibrate and atorvastatin), drugs that lower cholesterol (such as simvastatin and pravastatin), anticoagulants (such as unfractionated heparin, low molecular weight heparin, dabigatran, and xaban), for example, drugs for the treatment of heart disease, such as nitrates. Ester drugs (such as nitroglycerin, isosorbide dinitrate), renin-angiotensin-aldosterone system inhibitors (including angiotensin converting enzyme inhibitors (ACEI) such as perindopril), statins (such as lovastatin, fluvastatin), antiarrhythmic drugs (such as lidocaine, amiodarone, propafenone, ivabradine), myocardial energizing drugs (such as sodium fructose diphosphate, coenzyme Q10, L-carnitine or sodium creatine phosphate for injection), cardiotonic drugs (such as cedilanid, digoxin). The content of each component in the combined preparation is usually a safe and effective amount, which can be adjusted based on actual usage (such as patient weight, application type, disease condition, severity).

[0068] When the drug in this application is used as a preparation, it is preferably in unit dosage form, which means that the preparation is subdivided into unit doses containing an appropriate amount of active ingredients. The unit dosage form can be a solution, injection, injection, capsule, tablet or any dosage form; in addition, the unit dosage form can also be a packaged preparation, such as a solution, injection, tablet, capsule and powder packaged in a vial or ampoule. The amount of the active ingredient in the unit dosage preparation can be changed or adjusted from 0.1 mg to 1000 mg, depending on the specific application and efficacy of the active ingredient.

[0069] When the drug described in the present application is used to treat hypertension or its complications of a subject, the product in an effective dose must be accurately administered to the subject, so that the hypertension or its complications originally suffered by the subject can be effectively suppressed, reduced or even alleviated.

[0070] The present application also provides a method for treating hypertension or its complications, which comprises administering an effective dose of the above-mentioned drug to a subject.

[0071] In a specific embodiment of the present application, the complications are selected from any one or more of abdominal aortic sclerosis, heart disease, mesenteric artery disease, stroke, and renal failure, which are the same as described above and will not be repeated here.

[0072] The subjects of the drugs and methods in the present application can specifically be various mammals, including but not limited to rodents, artiodactyls, perissodactyls, lagomorphs, primates, such as humans, monkeys, other primates, migratory owls, cattle, horses, donkeys, pigs, dogs, cats, mice, rabbits, rats, guinea pigs, hamsters, foxes, deer, etc.; in a preferred embodiment of the present application, the subject of action is human or mouse.

[0073] The present application is further described below by way of examples, but the scope of the present application is not limited thereby. Unless otherwise stated, the experimental methods, detection methods, and preparation methods disclosed in the present application all adopt conventional techniques in molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology, and related fields conventional in the art. These techniques have been fully described in the existing literature. Unless otherwise stated, the instruments, reagents, and materials used in the examples of the present application can be obtained by conventional means.

[0074] Experimental animals used in the examples:

[0075] In the examples of this application, the material information used is as follows:

[0076] Experimental animals: SPF-grade C57BL / 6 male mice were purchased from Slack Laboratory Animal Co., Ltd., with the experimental animal use license number: SYXK(Min)2020-0002.

[0077] Experimental drugs and main reagents: osmotic micropump (Alzet, 2004D); angiotensin II (AngII; Abcam, ab120183); oroxylin A (Shanghai Yuanye Biotechnology Co., Ltd., B20880); eosin staining solution (Beijing Solebold Technology Co., Ltd., g1100); hematoxylin staining solution (Beijing Solebold Technology Co., Ltd., g1140); isoflurane (Shenzhen Ruiwode Life Science Co., Ltd., 970-00026-00); paraformaldehyde (Fuzhou Feijing Biotechnology Co., Ltd. LA0427), anhydrous ethanol (Xilong Science Co., Ltd., 1280340101602), xylene (Xilong Science Co., Ltd., 1430030101600) and other chemical reagents.

[0078] The main instruments of the experiment are: pipette (Raining Company, USA); electronic balance scale (Ohaus Instrument Co., Ltd., Shanghai); non-invasive rat tail sphygmomanometer (Kent Co., Ltd., USA); small animal ultrasound imaging system Vevo2100 (Fujifilm Investment Co., Ltd.); inhalation small animal anesthesia machine (Shenzhen Ruiwode Life Science Technology Co., Ltd.); pathological slicer (Leica Company, Germany); paraffin embedding machine (Hubei Xiaogan Yaguang Medical Electronic Technology Co., Ltd.).

[0079] Statistical analysis:

[0080] IBM SPSS Statistics (version 29.0.1.0) software was used for statistical analysis. The Shapiro-Wilk test was used to test the normality of the data. The data were presented as mean values ​​with standard deviations. If the data met the conditions for normal distribution, ANOVA (one-way analysis of variance) was used to evaluate the differences. At this time, according to the homogeneity of the data variance, LSD (least significant difference method) was selected for post hoc test (when the variances were homogeneous), or Games-Howell method was selected for post hoc test (when the variances were unequal). For data sets that did not conform to the normal distribution, the nonparametric Kruskal-Wallis test was used to compare the data differences between the groups. When the P value was less than 0.05, the difference between the groups was considered statistically significant.

[0081] Example 1 Drug preparation, experimental animal feeding, animal grouping and model construction

[0082] Animal husbandry: 12 healthy male C57BL / 6 mice (weight 19±1g) were purchased from Slake Experimental Animal Co., Ltd. (license number: SYXK(Min)2020-0002). All animals were kept in the SPF-level laboratory of the Experimental Animal Center of Fujian University of Traditional Chinese Medicine, with adequate diet and water, 12h light / dark cycle, temperature 23±1℃, and humidity controlled at 50%, all within the acceptable range for experimental animals. Mice were used for experiments after 5-7 days of adaptive feeding. All animal experiments were carried out in accordance with the regulations of the Experimental Animal Ethics and the Animal Management Association of Fujian University of Traditional Chinese Medicine, and the Experimental Animal Ethics Review Form has been approved with the approval number 2W2024005.

[0083] Drug preparation:

[0084] Weigh an appropriate amount of oroxylin A powder, dissolve it in a corresponding volume of distilled water at a dose of 10 mg / kg / d according to the average weight of mice, place it in an ultrasonic device and maintain low-temperature ultrasound for about 1 hour, and store it in a 4°C refrigerator for use to obtain oroxylin A solution.

[0085] Weigh an appropriate amount of AngII powder and dissolve it in high-pressure water to prepare a mother solution concentration of 1 mM. After preparation, store it in a -80°C refrigerator for later use to obtain an AngII solution.

[0086] Meanwhile, an appropriate amount of valsartan powder was weighed and dissolved in a corresponding volume of distilled water at a dose of 10 mg / kg / d according to the weight of the mice. After preparation, the mixture was stored in a refrigerator at 4° C. for later use to obtain a valsartan solution.

[0087] Animal grouping: Twelve male C57BL / 6 mice were randomly divided into 4 groups according to basal blood pressure: Control group, AngII group, AngII+Oroxin A (10 mg / kg / d) group, and AngII+Valsartan (10 mg / kg / d) group, with 3 mice in each group.

[0088] Preparation of osmotic micropumps: The day before the operation, the osmotic micropumps were taken out in the clean bench, and 200 μL of AngII solution was injected into the osmotic micropumps of the AngII group, AngII+Oroxin A (10 mg / kg / d) group, and AngII+Valsartan (10 mg / kg / d) group, respectively, to obtain preset osmotic micropumps containing AngII.

[0089] The osmotic minipumps in the Control group were injected with 200 μL of saline solution to obtain osmotic minipumps containing saline.

[0090] The osmotic mini-pumps of all groups were immersed in physiological saline in a 37°C cell culture incubator overnight and used for pump implantation surgery the next day.

[0091] Model construction and treatment: On the day of surgery, the operating table was routinely disinfected, and the mice were anesthetized with isoflurane, placed in a prone position, and the hair on the back of the head and neck was removed. The skin was cut with scissors and the subcutaneous tissue was bluntly separated after disinfection with iodine. The mice in the AngII group, AngII+Oroxin A (10 mg / kg / d), and AngII+Valsartan (10 mg / kg / d) groups were subcutaneously implanted with pre-placed osmotic micropumps containing AngII, and the mice in the Control group were subcutaneously implanted with pre-placed osmotic micropumps containing saline. After the corresponding osmotic micropumps were implanted in each group, the skin was sutured and disinfected.

[0092] On the day after pump implantation, mice in the AngII+Oroxin A (10 mg / kg / d) group were gavaged with 10 mg / kg / d Oroxin A solution, and mice in the AngII+Valsartan group were gavaged with 10 mg / kg / d valsartan solution. The Control group and the AngII group were gavaged with an equal volume of distilled water, once a day, for a total of 4 weeks of intervention.

[0093] Example 2 Effect of Oroxylin A on Blood Pressure and Body Weight of Mice

[0094] Blood pressure measurement:

[0095] During the experimental period, CODA TM The non-invasive precision blood pressure meter regularly monitors the key blood pressure indicators of experimental mice, including mean arterial pressure (MAP), systolic blood pressure (SBP) and diastolic blood pressure (DBP). The frequency is set to once a week, and the obtained data are carefully statistically analyzed. The specific operation process is as follows:

[0096] (1) Ensure that the mouse heating plate, sensors, computer and other equipment are properly assembled and connected to prepare for the experiment.

[0097] (2) Gently place the experimental mouse in the restraint and place it steadily on the mouse heating plate. Turn on the heating plate function to maintain the mouse's constant body temperature and promote smooth blood flow in the tail artery.

[0098] (3) Carefully place the occlusion suit and volume pressure sensor on the mouse's tail to ensure the accuracy and stability of the measurement process.

[0099] (4) Start the Coda 4.1 software and set the corresponding measurement parameters according to the experimental requirements. Each measurement cycle contains 15 cycles. Before the formal measurement, let the mice rest quietly on the heating plate for 10 minutes to reduce the influence of external interference on the measurement results. At the same time, keep the surrounding environment quiet and stable during the entire measurement process. After the measurement, the volume pressure sensor will automatically transmit the data of each measurement to the computer for storage and analysis.

[0100] (5) The systolic blood pressure, diastolic blood pressure, mean arterial pressure, and body weight data of each mouse were recorded in detail every week, and their mean and standard deviation were calculated for subsequent statistical analysis.

[0101] The results of the effects of oroxylin A on blood pressure are shown in Figure 1 , Figure 2 and Figure 3 .

[0102] like Figure 1 As shown in the figure, the SBP of mice increased significantly after AngII intervention, and the statistical difference was significant compared with the Control group (P<0.05). After intervention with Oroxin A, the SBP of the AngII+Oroxin A group decreased significantly compared with the AngII group. The results showed that Oroxin A intervention could significantly inhibit the increase of SBP in the AngII group.

[0103] like Figure 2 As shown in the figure, the DBP of mice increased significantly after AngII intervention, and the statistical difference was significant compared with the Control group (P<0.05). After intervention with Oroxin A, the DBP of the AngII+Oroxin A group decreased significantly compared with the AngII group. The results showed that Oroxin A intervention could significantly inhibit the increase of DBP in the AngII group.

[0104] like Figure 3 As shown in the figure, the MAP of mice increased significantly after AngII intervention, and the statistical difference was significant compared with the Control group (P<0.05). After Oroxin A intervention, the MAP of the AngII+Oroxin A group decreased significantly compared with the AngII group. The results showed that Oroxin A intervention could significantly inhibit the increase of MAP in the AngII group.

[0105] At the same time, body weight measurements showed that oroxylin A intervention had no significant effect on the body weight of mice ( Figure 4 ).

[0106] Example 3 Study on the effect of oroxylin A on the thickness of abdominal aorta in mice

[0107] The mice were first induced with AngII and then intervened with oroxylin A for 4 weeks. The vascular thickness of each group of mice was detected and analyzed using small animal ultrasound.

[0108] Abdominal aorta thickness measurement:

[0109] (1) Echocardiography testing period: The abdominal aorta vascular function of mice in each experimental group was comprehensively tested using the Vevo 2100 small animal-specific ultrasound imaging system.

[0110] (2) Abdominal hair removal and animal anesthesia process: First, use a depilatory cream to carefully remove the hair on the mouse's abdomen to ensure clear contact with the ultrasound probe. Then, use 1.5% isoflurane for inhalation anesthesia, and securely fix the mouse in a supine position on a 37°C constant temperature heating plate to prepare for the subsequent ultrasound examination.

[0111] (3) Obtaining abdominal aorta imaging sections: Ultrasound coupling agent was evenly applied to the mouse's chest and abdomen to fully expose the abdominal aorta area. High-quality abdominal aorta section images were obtained by adjusting the probe position and angle. The probe operating frequency was set to 30 MHz to ensure imaging clarity and accuracy.

[0112] (4) Ultrasound data analysis and calculation method: After the test, Vevo Strain Software (version Vevo LAB1.7.1) was used to perform in-depth analysis on the acquired ultrasound data. The thickness of the abdominal aorta wall of each group of mice was calculated, and each index was based on the average of three independent measurements to ensure the reliability of the data.

[0113] from Figure 5 and Figure 6 It can be seen that compared with the Control group, the thickness of the abdominal aorta of mice in the AngII group was significantly thickened (P<0.05), while the thickness of the abdominal aorta of mice was significantly reduced after intervention with oroxylin A (P<0.05).

[0114] Example 4 Study on the effect of oroxylin A on the pathological morphology of abdominal aorta in mice

[0115] HE staining was used to observe the changes of oroxylin A on the morphology of abdominal aorta in mice.

[0116] HE staining:

[0117] (1)Fixed:

[0118] Mouse abdominal aorta and heart tissue samples were immersed in 4% paraformaldehyde and fixed for 48 h, placed in tissue embedding boxes and labeled with numbers.

[0119] (2) Dehydration and wax dipping:

[0120] The heart tissue samples were dehydrated in the following order: 70% anhydrous ethanol (60 min) → 80% anhydrous ethanol (60 min) → 90% anhydrous ethanol (60 min) → 95% anhydrous ethanol (60 min) → 100% anhydrous ethanol I (20 min) → 100% anhydrous ethanol II (20 min) → 100% anhydrous ethanol III (50 min) → xylene I (5 min) → xylene II (20 min) → paraffin I (10 min) → paraffin II (20 min) → paraffin III (30 min).

[0121] (3) Embedding:

[0122] Preheat the embedding mold, place the tissue upright in the center of the bottom of the embedding mold, add melted paraffin, and gently place the embedding box on top of the mold. Transfer the mold to a cooling table, wait for the paraffin to solidify, place the wax block in a -20℃ refrigerator overnight, separate the wax block from the mold, and store it at room temperature.

[0123] (4) Slicing:

[0124] Pre-cool the tissue wax block in a -20℃ refrigerator. Fix the wax block on the paraffin slicer and set the rough trimming thickness to 10μm for initial tissue trimming until the complete structure of the tissue can be seen. Then adjust the slice thickness to 4μm for fine trimming. Place the cut complete tissue slice in 39℃ warm water. After the tissue slice is flattened, use an adhesive slide to pick up the slice. Bake the slice at 60℃ for 1h, dry the slice for 3h, and store the slice at room temperature.

[0125] (5) Dewaxing:

[0126] Dewax by immersing in reagents in the following order: xylene I (25 min) → xylene II (25 min) → xylene III (15 min) → 100% anhydrous ethanol I (5 min) → 100% anhydrous ethanol II (5 min) → 95% anhydrous ethanol (5 min) → 80% anhydrous ethanol (5 min) → 70% anhydrous ethanol (5 min) → ultrapure water I (5 min) → ultrapure water II (5 min).

[0127] (6) Hematoxylin staining:

[0128] The slides were immersed in hematoxylin solution for 30 seconds and then washed three times with pure water.

[0129] (7) Eosin staining:

[0130] The above slides were immersed in eosin solution for staining for 15 seconds and then washed with pure water for 3 times.

[0131] (8) Sealing:

[0132] After staining, wait for the tissue sections to air dry and add neutral gum for sealing.

[0133] (9) Microscope observation:

[0134] The intelligent tissue section analysis system was used to observe the pathological changes of each group of samples. The whole sample was photographed at a 12.5× field of view for each sample, and 6 areas were randomly selected and photographed at a 400× field of view.

[0135] Results Figure 7 Compared with the control group, the abdominal aorta wall of the mice in the AngII group was thickened, while the thickening of the abdominal aorta wall of the mice was alleviated after the intervention of oroxylin A.

[0136] Example 5 Study on the effect of oroxylin A on the pathological morphology of cardiac tissue in mice

[0137] HE staining was used to evaluate the effect of oroxylin A on the pathological morphology of cardiac tissue in AngII model mice. The HE staining method was the same as that in Example 4.

[0138] Results Figure 8 The nuclei of the cardiomyocytes of the mice in the Control group were clear, the cytoplasm was evenly stained, and they were arranged tightly and neatly, without degeneration and necrosis. Compared with the Control group, the cardiac tissue morphology of the AngII group showed obvious changes: the neatness of the arrangement of the cardiomyocytes was significantly reduced; and the pathological morphology of the myocardial tissue of the mice modeled after intervention with oroxylin A was significantly improved.

[0139] Example 6 Investigation of the effect of oroxylin A on cardiac function in mice

[0140] The mice were first induced with AngII and then intervened with oroxylin A for 4 weeks. The left ventricular ejection fraction and left ventricular short-axis shortening rate of each group of mice were detected and analyzed by small animal ultrasound.

[0141] Specifically, as described in the "Abdominal Hair Removal and Animal Anesthesia Process" in Example 3 of abdominal hair removal and mouse anesthesia, the ultrasound probe is then placed vertically on the left chest of the mouse, and the probe is adjusted so that its notch faces the head of the mouse. In the B-Mode mode, slowly adjust the probe until a clear heart image is obtained. Then switch to the M-Mode mode to collect the cardiac cycle diagram of the mouse. At least three cardiac cycle data are measured for each mouse, and the average value is taken after the ultrasound scan is completed for subsequent statistical analysis. The measured cardiac function indicators are left ventricular ejection fraction (Left Ventricular Ejection Fractions; LVEF), left ventricular short-axis shortening (Left Ventricular Fraction Shortening; LVFS) and cardiac stroke volume (Stroke Volume; SV).

[0142] The main function of the heart is to pump blood. The amount of blood ejected by one ventricle in one heartbeat is called stroke volume, or stroke volume for short.

[0143] from Fig. 9 and Fig.10 It can be seen that compared with the Control group, the LVEF and LVFS of mice in the AngII group were significantly decreased (P<0.05), while the LVEF and LVFS of mice were increased after the intervention of oroxylin A (P<0.05).

[0144] Example 7 Investigation of Oroxylin A on the Function of Mouse Mesenteric Arteries

[0145] Mesenteric artery pulsatility index and resistance index measurement:

[0146] The steps of hair removal and animal anesthesia are the same as those in Example 3 "Abdominal hair removal and animal anesthesia process". The probe is placed in the middle of the abdomen along the longitudinal section to display the abdominal aorta, and the mesenteric artery is gradually found downward. The blood flow spectrum is displayed using pulsed Doppler. After adjusting the blood flow and the sound beam angle, the cross-sectional image of the mesenteric artery is obtained. The average value of each index is taken to calculate and analyze the changes in the blood flow of the mesenteric artery, and the calculation is performed according to the following formula:

[0147] Pulsatility index: PI = (peak velocity during systole - average velocity during diastole) / average velocity;

[0148] Resistance index: RI = (peak systolic velocity - end diastolic velocity) / peak systolic velocity.

[0149] Small animal ultrasound was used to evaluate changes in mesenteric artery function. Fig.11 , Fig.12 and Fig.13 As shown, compared with those of the Control group, the superior mesenteric artery pulsatility index (SMA PI) and superior mesenteric artery resistance index (SMA RI) of the mice in the AngII group were significantly increased, P<0.05; compared with those of the AngII group, the mesenteric artery pulsatility index and mesenteric artery resistance index were significantly decreased after oroxylin A intervention, P<0.05.

[0150] In summary, oroxylin A significantly reduces blood pressure in AngII model mice, improves vascular function, alleviates abdominal aorta thickening and pathological changes, improves cardiac function, and also has the effect of improving myocardial cell hypertrophy and vascular wall thickening caused by hypertension.

[0151] The above embodiments are merely illustrative of the principles and effects of the present application and are not intended to limit the present application. Anyone familiar with the technology may modify or change the above embodiments without violating the spirit and scope of the present application. Therefore, all equivalent modifications or changes made by a person of ordinary skill in the art without departing from the spirit and technical ideas disclosed in the present application shall still be covered by the claims of the present application.

Claims

1. Use of oroxylin A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or alleviating and / or treating hypertension or its complications.

2. The use according to claim 1, characterized in that The complications are selected from any one or more of abdominal aortic sclerosis, heart disease, mesenteric artery disease, stroke, and renal failure.

3. The use according to claim 2, characterized in that: The abdominal aorta sclerosis is manifested as thickening of the abdominal aorta; The heart disease is manifested as cardiac hypertrophy, and / or myocardial infarction, and / or heart failure; The mesenteric artery disease is manifested as abnormal function of the mesenteric artery.

4. The use according to claim 3, characterized in that The cardiac lesions are manifested as abnormal pathological morphology of cardiac tissue and / or abnormal cardiac function.

5. The use according to any one of claims 1 to 4, characterized in that: The drug is used for any one or more of the following: 1) Lower blood pressure; 2) Improve the thickness of the abdominal aorta; 3) Improve abnormal pathological morphology of cardiac tissue; 4) Improve abnormal heart function; 5) Improve mesenteric artery dysfunction.

6. The use according to claim 5, characterized in that Lowering blood pressure refers to lowering mean arterial pressure, and / or lowering systolic pressure, and / or lowering diastolic pressure; The improvement of abdominal aorta thickness refers to reducing the thickness of the abdominal aorta; Improving the pathological morphology of cardiac tissue refers to making the myocardial cells arranged neatly, and / or making the cell nuclei of myocardial cells clear, and / or making the cytoplasm of myocardial cells uniformly stained with HE, and / or reducing the degeneration and necrosis of myocardial cells; The improvement of cardiac function refers to increasing the left ventricular ejection fraction and / or increasing the left ventricular short axis shortening rate; Improving the mesenteric artery function refers to reducing the mesenteric artery pulsatility index and / or reducing the mesenteric artery resistance index.

7. The use according to claim 1, characterized in that The medicine comprises an effective amount of oroxylin A or a pharmaceutically acceptable salt thereof.

8. The use according to claim 7, characterized in that The effective amount of the oroxylin A or its pharmaceutically acceptable salt in the medicine is greater than or equal to 10 mg / kg.

9. A medicament for preventing and / or alleviating and / or treating hypertension and its complications, comprising an effective amount of oroxylin A or a pharmaceutically acceptable salt thereof.

10. The drug according to claim 9, characterized in that The complications are selected from any one or more of abdominal aortic sclerosis, heart disease, mesenteric artery disease, stroke, and renal failure; And / or, the effective amount of oroxylin A or a pharmaceutically acceptable salt thereof in the medicine is greater than or equal to 10 mg / kg.

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