Application of TRPV5 inhibitor in prevention and / or treatment of altitude sickness
By using ruthenium red as a TRPV5 inhibitor, the expression and function of TRPV5 are reduced, and the treatment problems of altitude sickness, especially in the high altitude low pressure environment are solved, and pulmonary hypertension and right ventricular hypertrophy are significantly alleviated, providing effective prevention and treatment plans.
Patent Information
- Application Number
- CN202411277225.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-12
- Publication Date
- 2024-12-06
AI Technical Summary
The existing TRPV5 inhibitors have not been used to prevent and treat altitude sickness, especially acute and chronic diseases caused by high-altitude low-pressure environments, such as plateau pulmonary edema, plateau cerebral edema, plateau heart disease, etc.
Ruthenium red or its pharmaceutically acceptable salt, hydrate or solvate is used as a TRPV5 inhibitor, thereby inhibiting the proliferation of pulmonary endothelial cells, inhibiting the migration of pulmonary artery smooth muscle cells, and reducing the pressure of right heart-pulmonary circulation by reducing the expression or function of TRPV5. Prevent and treat altitude sickness.
Effectively reduce the expression and function of TRPV5, reduce the symptoms of altitude sickness, especially in the low-pressure environment of altitude, significantly reduce pulmonary arterial hypertension and right ventricular hypertrophy, providing a prevention and treatment plan for altitude sickness.
Smart Images
Figure CN119074928A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of biomedicine technology, and in particular to the use of TRPV5 inhibitors in preventing and / or treating altitude sickness. Background Art
[0002] Altitude sickness is a disease caused by a series of physiological and pathological changes and compensatory adaptation changes caused by acute or chronic exposure of the human body to the low-pressure environment of the plateau. Among them, acute altitude sickness develops rapidly and is likely to develop into life-threatening diseases such as high-altitude pulmonary edema and high-altitude cerebral edema if not properly treated. Chronic altitude sickness, if not taken seriously, will cause damage to the patient's various systems.
[0003] Transient receptor potential cation channel, subfamily V, member 5 (TRPV5) is a newly discovered highly selective Ca 2+ Transmembrane transport channel, which is mainly responsible for Ca 2+ Active transmembrane transport from the outside of cells to the inside of cells is mainly distributed in the kidneys and participates in the regulation of multiple physiological activities in the body. So far, TRPV5 inhibitors are often used to treat bone degenerative diseases such as osteoporosis, bone metastasis of cancer, arthritis, etc., but there are no reports on the prevention and treatment of altitude sickness using TRPV5 inhibitors. Summary of the invention
[0004] The first aspect of the present invention provides a use of a TRPV5 inhibitor in the preparation of a product for preventing and / or treating altitude sickness.
[0005] Preferably, the altitude sickness includes diseases caused in a plateau low-pressure environment.
[0006] The altitude of the plateau low-pressure environment is above 2500m, above 3000m, above 4000m, above 5000m or above 5500m.
[0007] Preferably, the altitude of the plateau low-pressure environment is 2500-8000 m, and more preferably, the altitude of the plateau low-pressure environment is 4000-6500 m.
[0008] The altitude sickness includes acute altitude sickness or chronic altitude sickness.
[0009] Preferably, the acute mountain sickness includes high altitude coma, high altitude pulmonary edema, high altitude cerebral edema, pulmonary hypertension or a mixed disease in which abnormal brain and lung symptoms coexist.
[0010] Preferably, the chronic high altitude disease includes high altitude heart disease, high altitude polycythemia, high altitude hypertension or high altitude hypotension. The TRPV5 inhibitor is an agent that reduces the expression level of TRPV5 or an agent that reduces the function of TRPV5. The expression level is the mRNA expression level or the protein expression level.
[0011] Preferably, the TRPV5 inhibitor includes any one of econazole, miconazole, oxypapavine, vitamin D or ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof.
[0012] In some embodiments, the TRPV5 inhibitor is ruthenium red, the molecular formula of ruthenium red is C 16 H 42 N 14 O2Ru3, the chemical structure is shown in Formula I.
[0013]
[0014] Preferably, ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof prevents and / or treats altitude sickness by reducing TRPV5 (e.g., reducing TRPV5 expression, content or function) to inhibit one or both of pulmonary artery endothelial cell proliferation, inhibit pulmonary artery smooth muscle cell migration, reduce right heart-pulmonary circulation pressure or alleviate right ventricular hypertrophy.
[0015] Preferably, the product comprises one or more of medicine, food or health care products.
[0016] The product comprises ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a solvent.
[0017] The solvent includes PEG.
[0018] Preferably, the molecular weight of the PEG is 100-1000, such as 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000, etc.
[0019] Preferably, the volume percentage of PEG is 10-50%.
[0020] Preferably, the solvent further comprises water and / or DMSO.
[0021] Preferably, the product further comprises Tween 80. Further preferably, the volume percentage of Tween 80 is 1-10%.
[0022] The concentration of ruthenium red or its pharmaceutically acceptable salt, hydrate or solvate is 10-100000 nM, preferably 50-10000 nM.
[0023] In some specific embodiments, the product comprises: ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof at a concentration of 10-10000 nM, PEG at a volume percentage of 10-50%, Tween 80 at a volume percentage of 1-10%, DMSO and water at a volume percentage of 1-10%, and a pH of 6-8 (e.g., 6, 7 or 8).
[0024] The second aspect of the present invention provides a use of ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof in the preparation of a product for preventing and / or treating pulmonary hypertension caused by high-altitude low-pressure environment by reducing TRPV5 (for example, reducing TRPV5 expression, content or function) to inhibit pulmonary artery endothelial cell proliferation, inhibit pulmonary artery smooth muscle cell migration or reduce right heart-pulmonary circulation pressure.
[0025] Preferably, the product comprises one or more of medicine, food or health care products.
[0026] The product comprises ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a solvent.
[0027] The solvent comprises PEG;
[0028] Preferably, the molecular weight of the PEG is 100-1000, such as 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000, etc.
[0029] Preferably, the volume percentage of PEG is 10-50%.
[0030] Preferably, the solvent further comprises water and / or DMSO.
[0031] Preferably, the product further comprises Tween 80. Further preferably, the volume percentage of Tween 80 is 1-10%.
[0032] The concentration of ruthenium red or its pharmaceutically acceptable salt, hydrate or solvate is 10-100000 nM, preferably 50-10000 nM.
[0033] In some specific embodiments, the product comprises: ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof at a concentration of 10-10000 nM, PEG at a volume percentage of 10-50%, Tween 80 at a volume percentage of 1-10%, DMSO and water at a volume percentage of 1-10%, and a pH of 6-8 (e.g., 6, 7 or 8).
[0034] The altitude of the plateau low-pressure environment is above 2500m, above 3000m, above 4000m, above 5000m or above 5500m.
[0035] Preferably, the altitude of the plateau low-pressure environment is 2500-8000 m, and more preferably, the altitude of the plateau low-pressure environment is 4000-6500 m.
[0036] The third aspect of the present invention provides the use of ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof in the preparation of a product for preventing and / or treating high altitude heart disease to alleviate right ventricular hypertrophy by reducing TRPV5 (e.g., reducing TRPV5 expression, content or function).
[0037] Preferably, the high-altitude heart disease is caused by the low-pressure environment of the plateau.
[0038] The altitude of the plateau low-pressure environment is above 2500m, above 3000m, above 4000m, above 5000m or above 5500m.
[0039] Preferably, the altitude of the plateau low-pressure environment is 2500-8000 m, and more preferably, the altitude of the plateau low-pressure environment is 4000-6500 m.
[0040] Preferably, the product comprises one or more of medicine, food or health care products.
[0041] The product comprises ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a solvent.
[0042] The solvent includes PEG.
[0043] Preferably, the molecular weight of the PEG is 100-1000, such as 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000, etc.
[0044] Preferably, the volume percentage of PEG is 10-50%.
[0045] Preferably, the solvent further comprises water and / or DMSO.
[0046] Preferably, the product further comprises Tween 80. Further preferably, the volume percentage of Tween 80 is 1-10%.
[0047] The concentration of ruthenium red or its pharmaceutically acceptable salt, hydrate or solvate is 10-100000 nM, preferably 50-10000 nM.
[0048] In some specific embodiments, the product comprises: ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof at a concentration of 10-10000 nM, PEG at a volume percentage of 10-50%, Tween 80 at a volume percentage of 1-10%, DMSO and water at a volume percentage of 1-10%, and a pH of 6-8 (e.g., 6, 7 or 8).
[0049] In a fourth aspect of the present invention, a medicament is provided, which comprises a TRPV5 inhibitor or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more pharmaceutically acceptable excipients.
[0050] Specifically, the pharmaceutically acceptable excipients can be selected from one or a combination of two or more of carriers, excipients, diluents, lubricants, wetting agents, emulsifiers, preservatives, antioxidants, buffers, antibacterial agents, suspending agents, suspending aids, solubilizers, thickeners, stabilizers, sweeteners and flavors.
[0051] Specifically, the drug can be used alone or in combination with other types of active ingredients.
[0052] Specifically, the above-mentioned drugs can be in any dosage form or administration form, including but not limited to tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), lozenges, syrups, solutions, emulsions, suspensions, controlled release preparations (for example, instantaneous release preparations, sustained release preparations, sustained release microcapsules), aerosols, films (for example, orally disintegrating films, oral mucosa-adhesive films), injections (for example, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections), intravenous drips, transdermal absorption preparations, ointments, lotions, adhesive preparations, suppositories (for example, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc.; administration forms, for example, oral administration or parenteral administration (for example, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intrarectal, etc. administration forms).
[0053] The drug comprises ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a solvent.
[0054] The solvent includes PEG.
[0055] Preferably, the molecular weight of the PEG is 100-1000, such as 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000, etc.
[0056] Preferably, the volume percentage of PEG is 10-50%.
[0057] Preferably, the solvent further comprises water and / or DMSO.
[0058] Preferably, the drug further comprises Tween 80. Further preferably, the volume percentage of Tween 80 is 1-10%.
[0059] The concentration of ruthenium red or its pharmaceutically acceptable salt, hydrate or solvate is 10-100000 nM, preferably 50-10000 nM.
[0060] The drug comprises: ruthenium red or its pharmaceutically acceptable salt, hydrate or solvate at a concentration of 10-10000 nM, PEG at a volume percentage of 10-50%, Tween 80 at a volume percentage of 1-10%, DMSO and water at a volume percentage of 1-10%, and a pH of 6-8 (e.g., 6, 7 or 8).
[0061] The fifth aspect of the present invention provides a method for preventing and / or treating altitude sickness, which comprises administering an effective amount of a TRPV5 inhibitor or the drug to a subject in need thereof.
[0062] Preferably, an effective amount of ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof is administered to a subject in need thereof.
[0063] Preferably, the effective amount depends on many factors, including the patient's age, weight, sex, natural health, nutritional status, drug activity, time of administration, metabolic rate, severity of the disease, etc.
[0064] The "and / or" described in the present invention includes all combinations of items connected by the term, and each combination should be deemed to have been listed separately in the present application. For example, "A and / or B" includes "A", "A and B" and "B".
[0065] The term “comprising” described in the present invention is an open description, which includes the specified components or steps described, and other specified components or steps that will not be substantially affected.
[0066] As used herein, "treating" means slowing, interrupting, preventing, controlling, stopping, alleviating, or reversing the progression or severity of a sign, symptom, disorder, condition, or disease after the disease has begun to develop, but does not necessarily involve the complete elimination of all disease-related signs, symptoms, conditions, or disorders.
[0067] The term "prevention" as used in the present invention refers to any action that suppresses symptoms or delays the occurrence of specific symptoms by administering the product of the present invention.
[0068] The "effective amount" of the present invention refers to the amount or dosage of the product of the present invention that provides the desired treatment or prevention after administration to a patient or an organ in a single or multiple doses.
[0069] The "subject" described in the present invention can be a human or a non-human animal, such as a non-human mammal, and the non-human mammal can be a wild animal, a zoo animal, an economic animal, a pet, or an experimental animal, etc. Preferably, the non-human mammal includes but is not limited to pigs, cattle, sheep, horses, donkeys, foxes, minks, jackals, camels, dogs, cats, rabbits, mice (such as rats, mice, guinea pigs, hamsters, gerbils, chinchillas, squirrels) or monkeys, etc.
[0070] The "pharmaceutically acceptable salt" of the present invention refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, wherein the acid or base includes an inorganic acid or base or an organic acid or base. The inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, hydroiodic acid or sulfuric acid. The inorganic base is selected from calcium, magnesium, lithium, sodium, zinc, aluminum or potassium. The organic acid is selected from formic acid, glycolic acid, propionic acid, acetic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, glutamic acid, benzoic acid, stearic acid, alginic acid, benzenesulfonic acid, glucuronic acid, pamoic acid or galacturonic acid. The organic base is selected from diethanolamine, choline, procaine, lysine or 1,2-ethylenediamine.
[0071] The "hydrate" described in the present invention is a compound containing water, wherein the water can be connected to other parts by coordination bonds or by covalent bonds.
[0072] "Solvate" as used herein refers to the physical combination of the ruthenium red of the present invention and one or more solvent molecules. The physical combination includes various degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be separated, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid. Solvates include solution phases and separable solvates. Representative solvates include ethanolates, methanolates, etc.
[0073] The Chinese full names of some abbreviations used in the present invention are as follows:
[0074] TRPV5: transient receptor cation channel subfamily V member 5;
[0075] RuR: Ruthenium Red;
[0076] PASMC: pulmonary artery smooth muscle cells;
[0077] mPAP: mean pulmonary artery pressure;
[0078] RVSP: right ventricular systolic pressure;
[0079] RVAW: right ventricular anterior wall;
[0080] RVHI: right ventricular hypertrophy index. BRIEF DESCRIPTION OF THE DRAWINGS
[0081] The embodiments of the present invention are described in detail below with reference to the accompanying drawings, wherein:
[0082] Figure 1 Shown is the relative mRNA expression of TRPV5 under low pressure and normal pressure environments.
[0083] Figure 2 Shown is the expression level of TRPV5 protein in pulmonary artery smooth muscle cells under low pressure and normal pressure after knocking down PHPT1.
[0084] Figure 3 The figure shows the expression level of TRPV5 protein in pulmonary artery smooth muscle cells under low pressure and normal pressure after knocking down PHPT1, among which N-WT is the result of wild-type mice under normal pressure, N-PHPT1-KO is the result of PHPT1 knockout mice under normal pressure, H-WT is the result of wild-type mice under low pressure, and H-PHPT1-KO is the result of PHPT1 knockout mice under low pressure.
[0085] Figure 4 Shown is the effect of adding different concentrations of ruthenium red on the proliferation of pulmonary artery endothelial cells under normal environment and low pressure environment.
[0086] Figure 5 Shown are the effects of adding different concentrations of ruthenium red on PASMC migration in the normal pressure group and low pressure group.
[0087] Figure 6 Shown is a statistical graph showing the effect of adding different concentrations of ruthenium red on PASMC migration in the normal pressure group and the low pressure group.
[0088] Figure 7 Shown are the statistical results of mean pulmonary artery pressure (A) and right ventricular systolic pressure (B) of rats in the control group, model group, and RuR treatment group.
[0089] Figure 8 Shown are the statistical results of the right ventricular anterior wall (A) and right ventricular hypertrophy index (B) of rats in the control group, model group and RuR treatment group. DETAILED DESCRIPTION
[0090] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.
[0091] Reagents and samples used in the examples: RuR powder was purchased from selleck, DMSO was purchased from solaxbio, PEG300 was purchased from source leaf biotechnology, and Tween 80 was purchased from Meilun Biotechnology.
[0092] Animals used in the examples: SD rats, about 200 g, male, clean grade, purchased from Beijing Weitonglihua Experimental Animal Co., Ltd., license number: SCXK (Beijing) 2016-0006.
[0093] The feeding conditions of the rats in the examples are as follows: feeding with complete nutritional feed regularly, room temperature of 22-25° C., and humidity of 50%-70%.
[0094] The preparation method of RuR in the embodiment: the solvent is 5% DMSO + 30% PEG300 + 5% Tween 80 + 60% double distilled water, pH = 7, RuR is added, and the prepared RuR concentrations are 50nM, 500nM, and 5000nM for standby use.
[0095] The animal experiment instruments used in the examples are: multi-factor complex environment simulation medical science experiment chamber (model DYC-3285, Instrument Center of Beijing Academy of Military Medical Sciences); small animal ventilator (kent scientific); multifunctional physiological instrument (Millar); small animal ultrasound (Visual Sonics Inc)
[0096] Statistical methods: All data were expressed as Mean ± SD. The inter-group comparisons were performed using one-way analysis of variance. P < 0.05 was considered statistically significant. GraphPad Prism 5 software package was used for statistical analysis.
[0097] Example 1: Relationship between TRPV5 protein and altitude sickness
[0098] Wild-type rats were divided into two groups. One group was placed in an experimental chamber with the pressure adjusted to 380 mmHg to simulate the low-pressure environment of a plateau at an altitude of 5,500 meters. The chamber was opened for one hour every day to add feed and water to the animals, while the rats were kept in a 12:12 hour day and night cycle. The other group was placed in the same room under normal pressure and raised in the same manner.
[0099] The expression level of TRPV5 gene in rat pulmonary artery smooth muscle cells was detected. Figure 1 As shown in the figure, under low pressure environment, the relative mRNA expression level of TRPV5 was upregulated, and the difference was significant.
[0100] Example 2: TRPV5 is a cause of altitude sickness
[0101] Previous experiments by our research group have confirmed that overexpression of PHPT1 in rat pulmonary arteries, which results in high expression of PHPT1 in rat pulmonary arteries and lung tissues, can significantly reduce pulmonary artery pressure, right ventricular pressure, and right heart index caused by the low-pressure environment of the plateau, that is, overexpression of PHPT1 can inhibit the occurrence and development of plateau diseases. In addition, PHPT1 is specifically underexpressed in diseases, see patent document CN114703274B. This example further explores the mechanism of occurrence of altitude sickness.
[0102] 1. Experimental design
[0103] PHPT1 knockout rats were constructed using CRISPR-Cas9 technology and divided into two groups. One group was placed in an experimental cabin with the cabin pressure adjusted to 380 mmHg to simulate the low-pressure environment of a plateau at an altitude of 5,500 meters. The cabin was opened for 1 hour every day to add feed and water to the animals, while maintaining a 12:12 hour day and night alternation in the rats' environment. Another group of PHPT1 knockout rats were placed in the same room under normal pressure and raised in the same way. Two groups of wild-type rats were also set up, placed in an experimental cabin and in the same room under normal pressure, and raised in the same way as knockout rats.
[0104] 2. Results
[0105] The expression of TRPV5 protein in rat pulmonary artery smooth muscle cells was detected. Figure 2-3 As shown in the figure, PHPT1 knockout leads to upregulation of TRPV5 protein, and the upregulation is consistent in both normobaric and hypobaric environments. In summary, the therapeutic effect of overexpression of PHPT1 may be due to the reduction of TRPV5 expression.
[0106] Based on this, the present application further tests whether reducing TRPV5 has a therapeutic effect on altitude sickness. The following examples use a TRPV5 inhibitor (RuR) as an example for verification.
[0107] Example 3: Effects of RuR on HPAECs or PASMCs
[0108] 1. Experimental design
[0109] Pulmonary artery endothelial cells or pulmonary artery smooth muscle cells were cultured in DMEM medium containing 10% fetal bovine serum and randomly divided into two groups, a low-pressure group and a normal-pressure group. The cells in the low-pressure group were placed in an individualized cell precision control system to adjust the oxygen concentration to 1% and the oxygen partial pressure to 0.6PSI to simulate the low-pressure environment of the plateau, and the cells in the normal-pressure group were cultured in a normal-pressure and normoxic CO2 cell culture incubator for 48 hours. The cells in the low-pressure group and the normal-pressure group were given RuR concentrations of 0, 50nM, 500nM, and 5000nM, respectively.
[0110] 2. Cell viability detection method
[0111] Cell viability was determined using CCK8 (Dojindo laboratories, Shanghai, China). Cells were incubated at 37°C, 5% CO2 for 1.5 hours. The absorbance (OD) was measured using an ELISA reader at a wavelength of 450 nm.
[0112] 3. Cell migration detection method
[0113] After PASMCs were given RuR, the tip of the pipette was used to draw a line perpendicular to the cell plate. The cells were washed 3 times with PBS and added with cell culture medium. The cells were randomly divided into 2 groups, a low-pressure group and a normal-pressure group. The low-pressure group simulated the low-pressure environment of the plateau, while the normal-pressure group was in a normal-pressure environment. Samples were taken at 24 h, and photos were taken. After opening the pictures with Image J software, the cell migration area was calculated.
[0114] 4. Results
[0115] like Figure 4 As shown in the data, under the high-altitude low-pressure environment, the proliferation of pulmonary artery endothelial cells increased significantly. After the addition of RuR, the proliferation of HPAECs caused by the high-altitude low-pressure environment was inhibited in a dose-dependent manner.
[0116] The migration of PASMC cells Figure 5-6 As shown in the figure, the migration of PASMC was significantly increased in the simulated plateau low pressure environment, while the addition of RuR effectively reduced the migration of PASMC.
[0117] Example 4: Effect of RuR on right heart-lung circulation pressure in rats
[0118] 1. Experimental design
[0119] Thirty-six rats were randomly divided into three groups: model group, RuR treatment group and control group, with 12 rats in each group. The model group and RuR treatment group were placed in an experimental cabin, and the cabin pressure was adjusted to 380 mmHg to simulate the low-pressure environment of the plateau at an altitude of 5,500 meters. The experimental cabin was opened for 1 hour every day to add feed and water to the animals and give corresponding drug treatments. At the same time, the environment in which the rats were located was kept in a 12:12 hour day and night alternation. After 21 days, the model group was gavaged with solvent, and the RuR treatment group was gavaged with RuR (3 mg / kg) + solvent twice a day for 14 days. The control group rats were kept in the same room under normal pressure.
[0120] 2. Detection method
[0121] 3% sodium pentobarbital, 0.2ml / 100g, was injected intraperitoneally to anesthetize the rats and then subjected to ultrasound examination. The rats were then fixed on the operating table in a supine position, the trachea was cut, the ventilator was connected, the chest was opened, the heart was exposed, and the catheter was inserted into the right ventricle for right heart catheter examination. The rats were killed, the hearts were taken out, the atrial tissue and attached fat were removed, the left and right ventricles were separated, the water was absorbed by filter paper, and they were weighed separately.
[0122] 3. Results
[0123] After 35 days, the results of the right heart-lung circulation pressure of the rats were as follows Figure 7 As shown in the figure, compared with the control group, the mPAP and RVSP of the rats in the model group were significantly increased, and the difference was significant (P<0.05). Compared with the model group, the mPAP and RVSP of the rats in the RuR treatment group were significantly decreased, and the difference was statistically significant (P<0.05).
[0124] Example 5: Effects of RuR on right ventricular hypertrophy and right ventricular anterior wall thickness in rats
[0125] 1. Experimental design
[0126] Same as Example 4.
[0127] 2. Detection method
[0128] Same as Example 4.
[0129] 3. Results
[0130] like Figure 8 As shown in the figure, after 35 days, the RVAW and RVHI of the rats in the model group were significantly increased compared with those in the control group, and the difference was statistically significant (P < 0.05). Compared with the model group, the RVAW and RVHI of the rats in the RuR treatment group were significantly decreased, and the difference was statistically significant (P < 0.05).
[0131] The above results indicate that TRPV5 inhibitors, especially RuR, have a protective effect on pulmonary hypertension, right ventricular hypertrophy, etc. in rats exposed to a simulated 5,500-meter high-altitude low-pressure environment, and can be developed into drugs that protect against high-altitude low-pressure environments.
[0132] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.
Claims
1. Use of TRPV5 inhibitors in the preparation of products for preventing and / or treating altitude sickness.
2. The use according to claim 1, characterized in that: The altitude sickness includes diseases caused by low pressure in the plateau environment, preferably including acute altitude sickness or chronic altitude sickness.
3. The use according to claim 2, characterized in that: The acute mountain sickness includes high-altitude coma, high-altitude pulmonary edema, high-altitude cerebral edema, pulmonary hypertension or a mixed disease with the simultaneous presence of abnormal brain and lung symptoms; the chronic mountain sickness includes high-altitude heart disease, high-altitude polycythemia, high-altitude hypertension or high-altitude hypotension.
4. The use according to claim 2 or 3, characterized in that: The altitude of the plateau low-pressure environment is above 2500 m, preferably above 5500 m.
5. The use according to claim 1, characterized in that: The TRPV5 inhibitor is selected from econazole, miconazole, oxypapaveline, vitamin D or ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof.
6. The use according to any one of claims 1 to 5, characterized in that: The products include one or more of medicines, foods or health products.
7. The use according to any one of claims 1 to 6, characterized in that: Ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof prevents and / or treats altitude sickness by reducing TRPV5 to inhibit proliferation of pulmonary artery endothelial cells, inhibit migration of pulmonary artery smooth muscle cells, reduce right heart-pulmonary circulation pressure or alleviate right ventricular hypertrophy, or both thereof.
8. Use of ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof in the preparation of a product for preventing and / or treating pulmonary hypertension caused by high altitude low pressure environment by reducing TRPV5 to inhibit pulmonary artery endothelial cell proliferation, inhibit pulmonary artery smooth muscle cell migration or reduce right heart-pulmonary circulation pressure.
9. Use of ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof in the preparation of a product for preventing and / or treating high-altitude heart disease caused by a plateau low-pressure environment, for alleviating right ventricular hypertrophy by reducing TRPV5.
10. The use according to any one of claims 1 to 9, characterized in that: The product comprises ruthenium red or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a solvent; Preferably, the concentration of ruthenium red or its pharmaceutically acceptable salt, hydrate or solvate is 10-100000 nM, preferably 50-10000 nM.