Application of isoacteoside in preparation of product for preventing or treating hypertension or complications thereof

Abstract

The invention relates to the technical field of medicines, and mainly relates to application of isoacteoside in preparation of products for preventing or treating hypertension. The invention firstly provides application of isoacteoside or pharmaceutically acceptable salts thereof in preparation of products for preventing and / or treating hypertension and complications thereof. The invention finds that isoacteoside or pharmaceutically acceptable salts thereof can be effectively used for preventing or treating hypertension, and opens up a new way for treating hypertension and related diseases thereof.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to use of isoergoside in preparing products for preventing or treating hypertension. Background Art

[0002] Hypertension is one of the most common chronic diseases and an important risk factor for cardiovascular and cerebrovascular diseases. Data show that the number of patients with hypertension and the prevalence rate continue to grow. The harm of hypertension to human health cannot be underestimated. Cardiovascular and cerebrovascular diseases have become the main cause of death in the Chinese population, accounting for more than 45% of the total mortality rate, among which hypertension is the main risk factor for stroke and coronary heart disease. Studies have shown that the risk of cardiovascular and cerebrovascular diseases doubles for every 20 mmHg increase in systolic blood pressure or 10 mmHg increase in diastolic blood pressure. In addition, although the awareness, treatment and control rates of hypertension have increased, they are still at a low level overall. Therefore, exploring safer and more effective strategies for the prevention and treatment of hypertension has become an important topic at present.

[0003] Isoacteoside is widely present in many organisms. Studies in recent years have found that isoacteoside has anti-inflammatory, antioxidant and other pharmacological activities. Isoacteoside can inhibit the production of nitric oxide in cells and has a significant scavenging effect on nitric oxide in cells. In addition, it also shows certain antioxidant properties, which helps to remove free radicals in the body and protect cells from oxidative stress damage. However, there is currently a lack of sufficient scientific evidence on its specific effects on cardiovascular diseases such as hypertension. Summary of the invention

[0004] In view of the above-mentioned shortcomings of the prior art, the purpose of the present invention is to provide a use of isoergosterol in the preparation of a product for preventing or treating hypertension, so as to solve the problems in the prior art.

[0005] To achieve the above-mentioned object and other related objects, the present invention provides the use of isoergoside in preparing a product for preventing or treating hypertension or its complications.

[0006] The present invention also provides a product, which comprises an effective dose of isoergoside or a pharmaceutically acceptable salt thereof.

[0007] As described above, the use of isoergosides of the present invention in the preparation of products for preventing or treating hypertension or its complications has the following beneficial effects:

[0008] 1) The present invention first discovered that isoergosterol can be used in the preparation of drugs for treating hypertension or heart and vascular diseases caused by hypertension, with good and safe therapeutic effects, providing a new treatment approach for treating hypertension or hypertension-related diseases;

[0009] 2) The present invention has proved through experiments that isoergosterol can significantly reduce the blood pressure of Ang II model mice, improve vascular function, and relieve abdominal aortic thickening and pathological changes, while also having the effect of improving cardiac pathological morphological changes and mesenteric artery function caused by hypertension. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 The figure shows the effect of the isoergosterol of the present invention on the systolic blood pressure of mice after Ang II modeling. The data are presented as mean ± standard deviation, and one-way analysis of variance and turkey test are used; * indicates that P < 0.05 is statistically significant compared with the Control group, and # indicates that P < 0.05 is statistically significant compared with the Ang II group.

[0011] Figure 2 The figure shows the effect of the isoergosterol of the present invention on the diastolic blood pressure of mice after Ang II modeling. * indicates that P<0.05 is statistically significant compared with the Control group, and # indicates that P<0.05 is statistically significant compared with the Ang II group.

[0012] Figure 3 The figure shows the effect of the isoergosterol of the present invention on the mean arterial pressure of mice after Ang II modeling. * indicates that P<0.05 is statistically significant compared with the Control group, and # indicates that P<0.05 is statistically significant compared with the Ang II group.

[0013] Figure 4 The graph shows the effect of the isoergosides of the present invention on the body weight of mice after Ang II modeling.

[0014] Figure 5 The figure shows the effect of the isoergosides of the present invention on the pathological morphology of the abdominal aorta of mice after Ang II modeling.

[0015] Figure 6 The graph shows the effect of the isoergosterol of the present invention on the thickness of the abdominal aorta of mice after Ang II modeling. * indicates that P<0.05 is statistically significant compared with the Control group, and # indicates that P<0.05 is statistically significant compared with the Ang II group.

[0016] Figure 7 The figure shows the effect of the isoergosides of the present invention on the pathological morphology of the heart in mice after Ang II modeling.

[0017] Figure 8 Ultrasound images showing the effect of the isoergosides of the present invention on the function of the superior mesenteric artery in mice after Ang II modeling.

[0018] Fig. 9The figure shows the effect of the isoergosterol of the present invention on the superior mesenteric artery pulsatility index (SMA PI) of mice after Ang II modeling. * indicates that P<0.05 is statistically significant compared with the Control group, and # indicates that P<0.05 is statistically significant compared with the AngII group.

[0019] Fig.10 The figure shows the effect of the isoergosterol of the present invention on the mesenteric artery resistance index (SMARI) of mice after Ang II modeling. * indicates that P<0.05 is statistically significant compared with the Control group, and # indicates that P<0.05 is statistically significant compared with the AngII group.

[0020] Fig.11 The figure shows the effect of the isoergosides of the present invention on the pathological morphology of the mesenteric artery in mice after Ang II modeling. DETAILED DESCRIPTION

[0021] In the process of screening a large number of compounds for their effects on hypertension, the present study accidentally discovered that the compound isoergosterol has an anti-hypertensive effect and can improve heart and vascular lesions caused by hypertension. On this basis, the present invention was completed.

[0022] The present invention first provides use of isoergoside or a pharmaceutically acceptable salt thereof in preparing a product for preventing or treating hypertension or its complications.

[0023] In the present invention, the complication is heart disease and / or vascular disease caused by hypertension.

[0024] In the present invention, 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, which is taking measures before the disease occurs, with the purpose of preventing the disease from occurring; secondary prevention, which aims to detect and treat the disease in its early stages to prevent the development and deterioration of the disease; and tertiary prevention, which 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 product of the present invention.

[0025] In the present invention, 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 further evolving 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, symptom or the direction or severity of the progression of the disease to a certain extent. However, it should be clear that this treatment does not necessarily mean that it can involve the complete elimination of all signs, symptoms, symptoms or disorders related to the disease, but improve the state of the disease and slow down the signs, symptoms, symptoms or disorders related to the disease.

[0026] In the present invention, the "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base. All compounds of the present invention in the form of free base or free acid can be converted into their pharmaceutically acceptable salts by treating with appropriate inorganic acid or base or organic acid or base according to methods known to those skilled in the art, and the salts of the compounds of the present invention can be converted into their free acid or base forms by standard techniques.

[0027] The pharmaceutically acceptable salts of isoergosterol in the present invention include salts derived from inorganic acids or bases or organic acids or bases. Examples of pharmaceutically acceptable non-toxic acids for preparing salts are salts with amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or formed by using other methods such as ion exchange used in the art. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, citrate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate heptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from certain bases include alkali metal salts, alkaline earth metal salts, ammonium salts. Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc. In some cases, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfonates and aryl sulfonates. Other pharmaceutically acceptable salts include salts formed by quaternization of amines, which are carried out using appropriate electrophilic reagents (e.g., alkyl halides) to form quaternized alkylated amino salts.

[0028] The molecular formula of the isoacteoside is C 29 H 36 O 15 , CAS No. 61303-13-7, its structural formula is as follows:

[0029]

[0030] In certain embodiments of the present invention, the product has any one or more of the following effects:

[0031] 1) Lower blood pressure;

[0032] 2) Improve vascular function;

[0033] 3) Prevents blood vessel wall thickening;

[0034] 4) Improve cardiomyocyte hypertrophy;

[0035] 5) Prevent and / or treat hypertension.

[0036] The efficacy refers to the positive effect of the product drug in the organism.

[0037] The present invention also provides use of isoergosterol or a pharmaceutically acceptable salt thereof in preparing a product, wherein the product is used for any one or more of the following:

[0038] 1) Lower blood pressure;

[0039] 2) Improve vascular function;

[0040] 3) Prevents blood vessel wall thickening;

[0041] 4) Improve cardiomyocyte hypertrophy.

[0042] In certain embodiments of the present invention, the above-mentioned lowering of blood pressure includes but is not limited to lowering the systolic blood pressure (SBP) of the subject, and / or lowering the diastolic blood pressure (DBP) of the subject, and / or lowering the mean arterial pressure (MAP) of the subject.

[0043] In certain embodiments of the present invention, the lowering of the systolic blood pressure of the subject, the lowering of the diastolic blood pressure of the subject, and the lowering of the mean arterial pressure of the subject means that when isoergoside is administered to the subject, the SBP, DBP, and MAP of the subject are significantly decreased compared to a control group without administration of isoergoside (#P<0.05).

[0044] In certain embodiments of the present invention, the improvement of vascular function refers to reducing the vascular pulse wave propagation velocity, reducing the resistance index and / or reducing the pulsatility index.

[0045] Specifically, the reduction of the vascular pulse wave propagation velocity refers to making the vascular pulse wave propagation velocity of the target close to or reach the velocity of healthy blood vessels. For example, based on healthy blood vessels, the product can restore the vascular pulse wave propagation velocity of the target to at least 70%, 80%, 90% or 100% of that of healthy blood vessels;

[0046] The lowering of the resistance index refers to the speed at which the vascular resistance index of the subject is close to or reaches that of a healthy blood vessel. For example, based on a healthy blood vessel, the product can restore the vascular resistance index of the subject to at least 70%, 80%, 90% or 100% of that of a healthy blood vessel.

[0047] The pulsatility index reduction refers to bringing the pulsatility index of the subject's blood vessels close to or reaching the speed of healthy blood vessels. For example, based on healthy blood vessels, the product can restore the pulsatility index of the subject's blood vessels to at least 70%, 80%, 90% or 100% of that of healthy blood vessels.

[0048] The vascular function is the function of the abdominal aorta, renal arteries and mesenteric arteries.

[0049] The pulse wave velocity of the abdominal aorta reflects the stiffness of the abdominal aorta. An increase in the pulse wave velocity of the abdominal aorta means an increase in vascular stiffness, which may be caused by diseases such as atherosclerosis, hypertension, and diabetes, and is also related to vascular aging. The resistance index and pulsatility index of the superior mesenteric artery are important indicators for evaluating the hemodynamic state of the superior mesenteric artery. The resistance index reflects the degree of resistance to blood flow in the blood vessels. A high resistance index may indicate lesions such as vascular stenosis and arteriosclerosis, resulting in greater resistance when blood flows through. On the contrary, a low resistance index may indicate better vascular elasticity and less blood flow resistance. The pulsatility index reflects the pulsation characteristics of the blood vessels. It is closely related to factors such as the contraction and relaxation function of the heart and the elasticity of the blood vessels. Abnormal pulsatility index may indicate abnormal heart function or vascular lesions, which affect the normal pulsation of the superior mesenteric artery.

[0050] In certain embodiments of the present invention, the reduction of vascular pulse wave propagation velocity means that when isoergoside is administered to the subject, the vascular pulse wave propagation velocity of the subject is significantly reduced compared with the unadministered control group (#P<0.05).

[0051] In the present invention, when isoergoside is used on the subject, the effect of reducing the vascular pulse wave propagation velocity is better than the existing drugs for treating hypertension compared with the unused control group.

[0052] In certain embodiments of the present invention, the lowering of the resistance index means that when isoergoside is administered to a subject, the vascular resistance index of the subject is significantly lowered compared to a control group without administration of isoergoside (#P<0.05).

[0053] In the present invention, when isoergoside is used on the subject, the effect of reducing the vascular resistance index is better than that of the existing drugs for treating hypertension compared with the unused control group.

[0054] In certain embodiments of the present invention, the reduction of the pulsatility index means that when isoergoside is administered to a subject, the pulsatility index of the subject is significantly reduced compared to a control group without administration of isoergoside (#P<0.05).

[0055] In the present invention, when isoergoside is used on the subject, the effect of reducing the vascular pulsatility index is better than that of the existing drugs for treating hypertension compared with the unused control group.

[0056] In certain embodiments of the present invention, the prevention of blood vessel thickening refers to preventing the thickness of the blood vessel wall from increasing, and the prevention of the thickness of the blood vessel wall from increasing refers to making the blood vessel wall of the subject approach or reach the thickness of a healthy blood vessel. For example, based on a healthy blood vessel, the product can make the thickness of the blood vessel wall of the subject not exceed 130%, 120%, 110% or 100% of the thickness of a healthy blood vessel.

[0057] In certain embodiments of the present invention, the prevention of the increase in the thickness of the blood vessel wall means that when isoergoside is administered to the subject, the thickness of the blood vessel wall of the subject is significantly reduced compared with a control group without administration of isoergoside (#P<0.05).

[0058] In the present invention, when isoergoside is used to the subject, compared with the unused control group, the effect of preventing the increase of the thickness of the blood vessel wall is better than the existing drugs for treating hypertension.

[0059] In certain embodiments of the present invention, the improvement of cardiomyocyte hypertrophy refers to making the cardiomyocytes of the subject approach or reach a healthy size. For example, based on healthy cardiomyocytes, the product can make the size of the cardiomyocytes of the subject no more than 130%, 120%, 110% or 100% of the healthy cardiomyocytes.

[0060] In the present invention, when isoergosterol is used on the subject, the effect of improving cardiomyocyte hypertrophy is better than the existing drugs for treating hypertension compared with the unused control group.

[0061] In certain embodiments of the present invention, the symptoms of reduced vascular function, thickening of vascular walls or hypertrophy of myocardial cells are caused by hypertension, and are specifically related to angiotensin II (AngⅡ).

[0062] Blood vessels play an important role in regulating changes in blood pressure. They can secrete a variety of vasoactive substances to regulate the structure and function of blood vessels, mainly involving the renin-angiotensin-aldosterone system (RAAS) and other growth factors and cytokines. RAAS is an endocrine system that plays an important role in cardiovascular physiological regulation. Its overactivation can cause abnormal increases in AngⅡ and its downstream aldosterone, promote the remodeling of vascular smooth muscle and myocardium, lead to vascular and ventricular stiffness, and ultimately lead to the occurrence and development of hypertension, atherosclerosis, myocardial hypertrophy, heart failure and ischemic heart disease. AngⅡ, as an important bioactive peptide in RAAS, can produce vasoconstriction and thus cause an increase in blood pressure.

[0063] The present invention also provides a product, which comprises an effective dose of isoergoside or a pharmaceutically acceptable salt thereof.

[0064] In certain embodiments of the present invention, the above-mentioned product necessarily includes various forms of isoergoline or its pharmaceutically acceptable salts, and uses isoergoline or its pharmaceutically acceptable salts as the only active ingredient or one of the active ingredients.

[0065] In the present invention, an effective dose refers to a dose of a drug, treatment or other intervention measure that achieves the desired 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.

[0066] The product can or can be used to lower blood pressure; improve reduced vascular function; improve vascular wall thickening; improve cardiomyocyte hypertrophy; the symptoms of reduced vascular function, vascular wall thickening or cardiomyocyte hypertrophy can be caused by hypertension.

[0067] The product is capable of or can be used for preventing and / or treating hypertension.

[0068] The products in the present invention include but are not limited to drugs, pharmaceutical compositions, drug combinations, reagents, kits, foods, and health products.

[0069] The dosage form or state of the product in the present invention is not limited. For example, when the product is a medicine, a pharmaceutical composition, or a combination of medicines, the dosage form can be one or more of a solution, an injection, a spray, a nasal drop, an aerosol, a powder spray, a tablet, a capsule, and a granule. The medicines in the above-mentioned various dosage forms can be prepared according to conventional methods in the pharmaceutical field; preferably, it is a solution; for another example, when the product is a food or a health product, the state can be liquid or solid.

[0070] The product of the present invention may include not only isoergoside or its pharmaceutically acceptable salt, but also pharmaceutically acceptable excipients.

[0071] The term "pharmaceutically acceptable" means that when the drug is properly administered to animals or humans, it will not produce adverse, allergic or other adverse reactions. The pharmaceutically acceptable excipients should be compatible with the isoergoline, that is, they can be blended with it without significantly reducing the effect of the isoergoline under normal circumstances.

[0072] In the present invention, the pharmaceutically acceptable excipient is selected from one or more of a carrier, a diluent, a binder, a lubricant and a wetting agent. Specific examples of some substances that can be used as pharmaceutically acceptable carriers, diluents, binders, lubricants and wetting agents are sugars, such as lactose, glucose and sucrose; binders, specifically starch, such as corn starch and potato starch; cellulose and its derivatives, such as sodium methylcellulose, ethyl cellulose and methyl cellulose; tragacanth powder; malt; gelatin; lubricants, specifically talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols, such as propylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers, such as Tween; wetting agents, such as sodium lauryl sulfate; colorants; flavorings; tablets, stabilizers; antioxidants; preservatives; diluents, such as pyrogen-free water; isotonic saline solution; and phosphate buffer, etc. These substances are used as needed to help the stability of the formulation or to help improve the activity or its bioavailability or to produce an acceptable taste or smell in the case of oral administration. The types and proportions of these excipients or carriers can be adjusted according to the type and requirements of the final pharmaceutical preparation.

[0073] For example, when the product is a drug, a combination of drugs or a pharmaceutical composition, it can be administered orally, and dosage forms suitable for oral administration include solid dosage forms and liquid preparations. The solid dosage forms include capsules, tablets, pills, powders and granules. In these solid dosage forms, isoergosterol or its pharmaceutically acceptable salt is obtained according to the prior art with at least one conventional inert excipient, filler or solubilizer, adhesive, humectant, disintegrant, solubilizer, adsorbent, lubricant. In capsules, tablets and pills, the dosage form may also contain a buffer. Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compound in this composition can be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and wax substances. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers, emulsifiers, etc.

[0074] In the present invention, when the product is a drug, a pharmaceutical composition, or a combination of drugs, the dosage form of the drug, the pharmaceutical composition, or the combination of drugs should be selected to match the mode of administration. The pharmaceutical composition of the present invention can be introduced into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, spraying, nasal drops, eye drops, penetration, absorption, physical or chemical mediation; or introduced into the body after being mixed or wrapped with other substances. Preferably, it is introduced into the body subcutaneously. The pharmaceutical composition can also be used in combination with other treatment methods, including surgery, radiotherapy, chemotherapy, and targeted therapy.

[0075] In the product of the present invention, the isoergosterol or its pharmaceutically acceptable salt can be a single active ingredient, or it can be combined with one or more other active ingredients that have therapeutic effects on hypertension to form a combined preparation, and the efficacy and safety of each component do not conflict. Other active ingredients can be other various drugs that can be used to treat hypertension, such as diuretics (hydrochlorothiazide, indapamide), calcium channel blockers (nifedipine controlled release tablets, amlodipine, levamlodipine), angiotensin converting enzyme inhibitors (benazepril, enalapril, perindopril), angiotensin receptor antagonists (losartan, valsartan, irbesartan), beta-blockers (metoprolol, bisoprolol), alpha-blockers (prazosin, terazosin), renin inhibitors (such as remicycline), angiotensin receptor neprilysin inhibitors (such as sacubitril valsartan). The content of each ingredient in the combined preparation is generally a safe and effective amount, which can be adjusted based on actual usage (eg, patient weight, application type, disease condition, severity).

[0076] When the product of the present invention is used as a preparation, it is preferably in unit dosage form, which means that the preparation is subdivided into unit doses containing appropriate amounts 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 10 mg, depending on the specific application and efficacy of the active ingredient.

[0077] In a specific embodiment of the present invention, when the drug is used to treat hypertension in a subject, the product must be accurately administered to the subject at an effective dose, so that the hypertension originally suffered by the subject can be effectively inhibited, reduced or even alleviated, and / or the reduced vascular function caused by hypertension can be successfully curbed, including the adverse trend of vascular wall thickening can be slowed down and the condition of myocardial cell hypertrophy can be improved.

[0078] The effective dose of the isoergosterol or its pharmaceutically acceptable salt administered to the subject is 0.1-10 mg / kg body weight / time per day, and the administration is continued for 20-30 days. Specifically, the effective dose is 0.1-10 mg / kg body weight / time per day, and the administration is continued for 28 days. Using 0.1-10 mg / kg / d on the subject can be effectively used to prevent or treat hypertension, and at the same time has a good therapeutic effect on heart and vascular lesions caused by hypertension, can improve reduced vascular function, improve blood vessel thickness thickening, improve myocardial cell hypertrophy, and has a high degree of safety.

[0079] The product of the present invention is directed to an organism suffering from hypertension, or an organism in need of prevention and / or treatment of hypertension, specifically various mammals, including but not limited to rodents, artiodactyls, perissodactyls, lagomorphs, primates, such as humans, monkeys, apes, other primates, sheep, cattle, horses, donkeys, pigs, dogs, cats, mice, rabbits, rats, guinea pigs, hamsters, foxes, deer, etc.; in a preferred embodiment of the present invention, the target of action is a human or a mouse.

[0080] The product of the present invention can also be used in combination with other methods for treating hypertension, which can be used simultaneously or in a sequential order. Other methods for treating hypertension include but are not limited to other drug treatments or non-drug treatments, such as diet adjustment, weight control, regular exercise, smoking cessation and alcohol restriction, stress management, and adequate sleep.

[0081] The following describes the embodiments of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, 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 invention.

[0082] Before further describing the specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terms used in the examples of the present invention are for describing the specific embodiments rather than for limiting the scope of protection of the present invention; in the present specification and claims, unless otherwise expressly stated herein, the singular forms "a", "an" and "the" include plural forms.

[0083] When the embodiments give numerical ranges, it should be understood that, unless otherwise specified in the present invention, both 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 invention 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 invention, any methods, equipment, and materials of the prior art similar or equivalent to the methods, equipment, and materials described in the embodiments of the present invention can also be used to realize the present invention.

[0084] Unless otherwise stated, the experimental methods, detection methods, and preparation methods disclosed in the present invention all adopt conventional techniques in the field of molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology, and related fields.

[0085] The following examples all used IBM SPSS Statistics (version 29.0.1.0) software for data statistical analysis.

[0086] The Shapiro-Wilk test was used to test the normality of the data. Indicates. When comparing differences between three or more groups, ANOVA was used to compare the data under the premise of normal distribution (when the data variances were equal, LSD was used for post hoc test; otherwise, Games-Howell was used for post hoc test); when the data did not conform to normal distribution, the non-parametric Kruskal-Wallis test was used to compare the differences between groups. P < 0.05 indicated a significant difference and was considered statistically significant.

[0087] Example 1: Animal model construction and treatment

[0088] 1.1 Experimental animals

[0089] Twelve 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 Animal Ethics of Experimental Animals and the Animal Management Association of Fujian University of Traditional Chinese Medicine, and the Ethical Review Form for Experimental Animals has been approved with the approval number 2W2024005.

[0090] 1.2 Drug preparation

[0091] Weigh an appropriate amount of isoergoside 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 ultrasound machine and maintain low-temperature ultrasound for about 1 hour after preparation, and store it in a 4°C refrigerator for use to obtain isoergoside solution.

[0092] Weigh an appropriate amount of angiotensin Ang II powder and dissolve it in high-pressure water to prepare a mother solution with a concentration of 1 mM. After preparation, store it in a -80°C refrigerator for later use to obtain an Ang II solution.

[0093] 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.

[0094] 1.3 Animal grouping and model construction

[0095] Animal grouping: Twelve male C57BL / 6 mice were randomly divided into 4 groups according to basal blood pressure: Control group, Ang II group, Ang II + Isoacteoside (10 mg / kg / d) group, and Ang II + Valsartan (10 mg / kg / d) group. Each group had 3 mice.

[0096] Preparation of osmotic micropumps: The day before surgery, the osmotic micropumps were taken out in the clean bench, and 200 μL of Ang II solution was injected into the osmotic micropumps of the Ang II group, Ang II + Isoacteoside (10 mg / kg / d) group, and Ang II + Valsartan (10 mg / kg / d) group, respectively, to obtain preset osmotic micropumps containing Ang II.

[0097] The osmotic minipumps in the Control group were injected with 200 μL of saline solution to obtain osmotic minipumps containing saline.

[0098] The osmotic mini-pumps of all groups were immersed in physiological saline in a 37°C cell culture incubator for 24 hours and used for pump implantation surgery the next day.

[0099] 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 by disinfection with iodine. The mice in the Ang II group, Ang II + Isoacteoside (10 mg / kg / d) group, and Ang II + Valsartan (10 mg / kg / d) group were subcutaneously implanted with a pre-placed osmotic mini-pump containing Ang II, and the mice in the Control group were subcutaneously implanted with a pre-placed osmotic mini-pump containing saline. After the corresponding osmotic mini-pumps were implanted in each group, the skin was sutured and disinfected.

[0100] Starting from the second day after pump implantation, mice in the Ang II+Isoacteoside group were given intragastric administration of 10 mg / kg / d of isoacteoside solution, and mice in the Ang II+Valsartan group were given intragastric administration of 10 mg / kg / d of valsartan solution. The Control group and the Ang II group were given intragastric administration of an equal volume of distilled water once a day for a total of 4 weeks of intervention.

[0101] Example 2: Effects of isoergosides on blood pressure and body weight in mice

[0102] 2.1 Blood pressure and weight measurement

[0103] During the experiment, the CODA TMThe non-invasive precision blood pressure meter measures the mean arterial pressure (MAP), systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the experimental mice once a week, and performs statistical analysis on the data. The weight changes of each mouse are also recorded weekly. The specific operation is as follows:

[0104] (1) Check whether there are any abnormalities in the equipment and assemble the mouse heating plate, sensor and computer completely;

[0105] (2) Place the mouse in a restrainer and place it steadily on a mouse heating plate. Turn on the mouse heating plate to maintain the mouse's body temperature and smooth blood flow in the tail artery.

[0106] (3) Ensure that the mouse is in a quiet state and put the occlusion suit and volume pressure sensor on the mouse tail;

[0107] (4) Open Coda 4.1 software and set the blood pressure test to 15 cycles per cycle. The first 5 cycles are adaptive tests and the last 10 cycles are formal tests. Wait for the mouse to calm down for 10 minutes before starting the measurement. Pay attention to the measurement period and keep the surrounding environment in a quiet state. After the measurement is completed, the volume pressure sensor transmits the value of each measurement to the computer;

[0108] (5) Record the systolic blood pressure, diastolic blood pressure, and mean arterial pressure of each animal each week and weigh the body weight each week, and take the mean and standard deviation.

[0109] (6) After the measurement, weigh the mice and place them back in their cages.

[0110] 2.2 Analysis results

[0111] Effects of isoergosterol on blood pressure Figure 1 to Figure 3 shown.

[0112] like Figure 1 As shown in the figure, compared with the Control group, the SBP of mice after Ang II intervention was significantly increased, P<0.05. Compared with the Ang II group, after the intervention of isoacteoside, the SBP of the Ang II+Isoacteoside group was significantly reduced, P<0.05. The results showed that the intervention of isoacteoside could significantly inhibit the increase of SBP in the Ang II group.

[0113] like Figure 2As shown in the figure, compared with the Control group, the DBP of mice after Ang II intervention was significantly increased, P<0.05. Compared with the Ang II group, after the intervention of isoacteoside, the DBP of the Ang II+Isoacteoside group was significantly reduced, P<0.05. The results showed that the intervention of isoacteoside could significantly inhibit the increase of DBP in the Ang II group.

[0114] like Figure 3 As shown in the figure, compared with the Control group, the MAP of mice was significantly increased after Ang II intervention, P<0.05. Compared with the Ang II group, the MAP of the Ang II+Isoacteoside group was significantly decreased after Isoacteoside intervention, P<0.05. The results showed that Isoacteoside intervention could significantly inhibit the increase of MAP in the Ang II group.

[0115] picture Figure 1 to Figure 3 It can be seen that isoergosterol can reduce the systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) of mice, and the effect is significant.

[0116] like Figure 4 As shown, isoergosterol intervention had no significant effect on the body weight of mice.

[0117] Example 3: Effects of isoergosterol on pathological morphology of aorta and heart

[0118] 3.1 HE staining to detect the pathological morphology of aorta and heart

[0119] (1)Fixed:

[0120] Mouse abdominal aorta and heart tissue samples were immersed in 4% paraformaldehyde for fixation for 48 h, taken out, trimmed, placed in an embedding box, and placed in 70% ethanol.

[0121] (2) Alcohol gradient dehydration and wax immersion:

[0122] The heart tissue samples were immersed in the following reagents for dehydration: 70% anhydrous ethanol for 60 min → 80% anhydrous ethanol for 60 min → 90% anhydrous ethanol for 60 min → 95% anhydrous ethanol for 60 min → 100% anhydrous ethanol I for 20 min → 100% anhydrous ethanol II for 20 min → 100% anhydrous ethanol III for 50 min → xylene I for 5 min → xylene II for 20 min. The dehydrated tissues were immersed in wax in the following order: paraffin I for 10 min → paraffin II for 20 min → paraffin III for 30 min.

[0123] The abdominal aorta tissue samples were immersed in the following reagents for dehydration: 70% anhydrous ethanol for 30 min → 80% anhydrous ethanol for 30 min → 90% anhydrous ethanol for 30 min → 95% anhydrous ethanol for 30 min → 100% anhydrous ethanol I for 10 min → 100% anhydrous ethanol II for 10 min → 100% anhydrous ethanol III for 30 min → xylene I for 5 min → xylene II for 15 min. The dehydrated tissues were immersed in wax in the following order: paraffin I for 10 min → paraffin II for 10 min → paraffin III for 25 min.

[0124] (3) Embedding:

[0125] First inject a little liquid paraffin into the bottom of the embedding box, then place the abdominal aorta vertically into the embedding box, and then fill it with liquid paraffin to prevent the formation of bubbles. After the paraffin solidifies, pry the wax block out of the mold and trim it.

[0126] (4) Slicing:

[0127] Place the wax block in a -20℃ refrigerator for precooling and then fix it on the slicer. First, use 10μm thickness for rough trimming. When the tissue sample is cut, change to 0.4μm thickness for fine trimming. Use a brush to pick up the complete slice and spread it in 41℃ water. Use a glass slide to gently pick it up and stick it flat on the carrier. Bake the slice at 60℃ for 2h, dry it for 3h, and store the slice at room temperature for subsequent experiments.

[0128] (5) Dewaxing:

[0129] Immerse the heart tissue in the reagents for dewaxing in the following order: xylene I 25 min→xylene II 20 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.

[0130] The abdominal aorta tissue was immersed in reagents for dewaxing in the following order: xylene I 20 min→xylene II 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.

[0131] (6) Hematoxylin staining:

[0132] The slides were immersed in hematoxylin solution for 1 min and then washed with pure water.

[0133] (7) Eosin staining:

[0134] The above slides were immersed in eosin solution for staining for 3 seconds, and then washed with pure water.

[0135] (8) Sealing:

[0136] After staining, blow dry the slices immediately, gently add an appropriate amount of neutral gum, take a cover slip and stick it on the slide along one side, then squeeze it hard. There should be no bubbles around the tissue.

[0137] (9) Microscope observation:

[0138] Using the intelligent tissue section analysis system, the stained tissue sections of each sample were imaged at 400× magnification, and 6 fields of view were randomly selected to take pictures and save them to observe the pathological changes of each group of samples.

[0139] 3.2 Analysis results

[0140] HE staining was used to observe the effect of isoergosterol on the morphology of abdominal aorta in mice.

[0141] like Figure 5 , Figure 6 As shown, compared with the Control group, the abdominal aorta wall of the mice in the Ang II group was thickened; compared with the Ang II group, the thickening of the abdominal aorta wall of the mice was alleviated after the intervention of isoergosterol.

[0142] HE staining was used to evaluate the effect of isoergoside on the pathological morphology of cardiac tissue in Ang II model mice.

[0143] like Figure 7 As shown, 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 Ang II group showed obvious changes: the neatness of the arrangement of the cardiomyocytes was significantly decreased; compared with the Ang II group, the pathological morphology of the myocardial tissue of the mice after modeling with isoergoside intervention was significantly improved.

[0144] Example 4: Effects of isoergoside on the function and pathological morphology of mesenteric arteries in mice

[0145] 4.1 Ultrasonic measurement of mouse mesenteric artery pulsatility index and resistance index

[0146] The steps of hair removal and animal anesthesia are the same as 3.1. 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 angle of blood flow and sound beam, 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 mesenteric artery blood flow. The pulsatility index and resistance index are calculated 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] HE staining method is the same as 3.1.

[0150] 4.2 Analysis results

[0151] Small animal ultrasound was used to evaluate changes in superior mesenteric artery function.

[0152] like Figure 8 , Fig. 9 and Fig.10 As shown, compared with those in the Control group, the mesenteric artery pulsatility index (SMAPI) and mesenteric artery resistance index (SMARI) of the mice in the Ang II group were significantly increased, P<0.05; compared with those in the Ang II group, the mesenteric artery pulsatility index and mesenteric artery resistance index were significantly decreased after the intervention of isoergosterol, P<0.05.

[0153] HE staining was used to observe the effect of isoergosterol on the morphology of mouse mesenteric artery.

[0154] like Fig.11 As shown, compared with the Control group, the mesenteric artery wall of the mice in the Ang II group was thickened; compared with the Ang II group, the thickening of the mesenteric artery wall of the mice was alleviated after the intervention of isoergosterol.

[0155] In summary, isoergoside can significantly reduce blood pressure, improve vascular function, and relieve abdominal aorta thickening and pathological changes in Ang II model mice. It also has the effect of improving cardiac pathological morphological changes and mesenteric artery function caused by hypertension.

[0156] The above examples are for the purpose of illustrating the embodiments disclosed by the present invention and are not to be construed as limiting the present invention. In addition, the various modifications listed herein and the variations of the methods in the invention are obvious to those skilled in the art without departing from the scope and spirit of the present invention. Although the present invention has been specifically described in conjunction with various specific preferred embodiments of the present invention, it should be understood that the present invention should not be limited to these specific embodiments. In fact, various modifications as described above that are obvious to those skilled in the art to obtain the invention should be included within the scope of the present invention.

Claims

1. Use of isoergoside or a pharmaceutically acceptable salt thereof in the preparation of a product for preventing or treating hypertension or its complications.

2. The use according to claim 1, characterized in that The complications are heart disease and / or vascular disease caused by hypertension.

3. The use according to claim 1 or 2, characterized in that The product has any one or more of the following effects: 1) Lower blood pressure; 2) Improve vascular function; 3) Prevents blood vessel wall thickening; 4) Improve cardiomyocyte hypertrophy; 5) Prevent and / or treat hypertension.

4. The use according to claim 3, characterized in that The product has one or more of the following characteristics: I. The lowering of blood pressure is selected from the group consisting of lowering systolic pressure, lowering diastolic pressure and / or lowering mean arterial pressure; II. The improvement of vascular function is to reduce the vascular pulse wave propagation velocity, reduce the resistance index and / or reduce the pulsatility index.

5. The use according to claim 1, characterized in that: The product is selected from one or more of medicines, foods or health products.

6. The use according to claim 1, characterized in that: The product is a medicine or a health product, and the product also includes pharmaceutically acceptable excipients.

7. The use according to claim 6, characterized in that The pharmaceutically acceptable excipient is selected from one or more of a carrier, a diluent, a binder, a lubricant and a wetting agent.

8. The use according to claim 1, characterized in that The product is a medicine, and the dosage form of the medicine is selected from one or more of solution, injection, spray, nasal drops, aerosol, powder spray, tablet, capsule and granule.

9. The use according to claim 1, characterized in that The pharmaceutically acceptable salt of isoergoside is selected from one or more of isoergoside hydrochloride, isoergoside lactate, isoergoside succinate, isoergoside potassium salt, isoergoside sodium salt, isoergoside lithium salt, isoergoside magnesium salt and isoergoside calcium salt.

10. A product for preventing or treating hypertension, characterized in that: The product comprises an effective dose of isoergoside or a pharmaceutically acceptable salt thereof.

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