Application of taurochenodeoxycholic acid in preparation of medicine for preventing and treating hypertension

Abstract

The invention relates to application of taurochenodeoxycholic acid in preparation of a medicine for preventing and treating hypertension. The key effect of the taurochenodeoxycholic acid in prevention and treatment of hypertension is found for the first time, that is, the taurochenodeoxycholic acid can significantly enhance the diastolic function of arteriole of a hypertensive patient, so that the effect of reducing blood pressure is achieved. Therefore, the invention provides a new application of taurochenodeoxycholic acid in preparation of the medicine for preventing and treating hypertension, a new medicine for preventing and treating hypertension is provided clinically, and the taurochenodeoxycholic acid has a good clinical application value and a wide application prospect. The taurochenodeoxycholic acid can be prepared into a medicine, a pharmaceutical composition, food, a health care product or a food additive by utilizing the key effect of the taurochenodeoxycholic acid in hypertension diseases, can be used for treating hypertension diseases including primary hypertension and salt-sensitive hypertension, and has important application value.

Description

Technical Field

[0001] This invention relates to the application of taurine chenodeoxycholic acid in the preparation of drugs for the prevention and treatment of hypertension, and belongs to the field of biomedical technology. Background Technology

[0002] Hypertension is a cardiovascular disease characterized primarily by elevated arterial blood pressure. It is defined as a systolic blood pressure ≥140 mmHg and / or a diastolic blood pressure ≥90 mmHg without the use of antihypertensive medication, which can ultimately lead to damage to vital organs such as the heart, brain, and kidneys. Although global average blood pressure has remained relatively stable or even slightly decreased over the past few decades thanks to the widespread use of antihypertensive drugs, the number of people with hypertension continues to increase gradually. With urbanization, increased per capita income, and a growing aging population, the number and proportion of people with hypertension in my country have risen rapidly over the past few decades. According to data from the "China Cardiovascular Health and Disease Report 2021," the prevalence of hypertension showed an upward trend between 1958 and 2018, with an estimated 245 million people in my country suffering from hypertension, and a prevalence rate as high as 27.5% among adults aged 18 and above. Hypertension has become one of the most common chronic diseases and a major risk factor for cardiovascular disease and death. Therefore, intervention for hypertension has become an important part of human health management, and the monitoring, prevention, and treatment of hypertension are of considerable significance.

[0003] Multiple risk factors, including genetics, environment, and society, contribute to the onset and progression of hypertension. Its pathophysiological mechanisms are highly complex, primarily including the following aspects: First, sodium-water imbalance. Sodium-water balance is crucial for blood volume and blood pressure stability. Endothelial function is closely related to sodium-water balance; endothelial dysfunction leads to sodium-water imbalance, and conversely, long-term high salt intake also leads to endothelial dysfunction, further exacerbating hypertension. Second, imbalance in the renin-angiotensin-aldosterone system affects water and sodium storage, salt sensitivity, vasoconstriction, and endothelial function, playing a key role in blood pressure regulation. Third, sympathetic nervous system hyperactivity. Due to abnormal activation of the sympathetic nervous system in hypertensive patients, the hypertension level reported by baroreceptors is difficult to regulate through the sympathetic and parasympathetic nervous systems, making it difficult for blood pressure to drop to normal levels. Fourth, inflammatory response activation. Inflammation not only participates in the occurrence of hypertension but also plays a leading role in the damage of target organs. Immunoglobulins and cytokines produced during the inflammatory process, such as interleukin-6, interferon, and tumor necrosis factor-α, can damage target organs such as the heart, brain, and kidneys. At the same time, it also activates the reactive oxygen species system, which seriously impairs endothelial function; 5. Endothelial dysfunction.

[0004] Currently, hypertension control faces numerous challenges. Despite the widespread use of existing medications such as diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin II receptor blockers (ARBs), a large number of patients still experience poor blood pressure control. Hypertension treatment suffers from poor medication adherence, low rates of achieving treatment targets, slow development of new drugs, and a heavy economic burden. Furthermore, existing medications still have shortcomings in terms of efficacy, side effects, and long-term safety; some patients develop drug resistance, leading to poor treatment outcomes. Due to the limitations of current treatment methods, hypertension control has not reached ideal levels, and many patients' blood pressure remains uncontrolled, even increasing the risk of complications. Therefore, developing new drugs and exploring new treatment strategies are particularly important.

[0005] Bile acids are important metabolic products synthesized by the liver in the human body, primarily involved in the digestion and absorption of fats, as well as regulating lipid metabolism, maintaining bile flow, and promoting intestinal health. Bile acids not only play a vital role in normal physiological processes but also have a crucial role in the occurrence and development of various diseases. In terms of treatment, bile acids and their derivatives have potential applications in treating a variety of diseases. For example, bile acid derivatives such as ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) have been used to treat cholestatic liver disease, primary biliary cirrhosis, and cholelithiasis. Furthermore, bile acids and their signaling pathways (such as FXR and TGR5 receptors) have therapeutic potential in inflammatory, metabolic, cardiovascular, and neurodegenerative diseases. The therapeutic applications of bile acids are not limited to hepatobiliary diseases but also extend to metabolic, inflammatory, and neurological disorders. For instance, bile acids may exert therapeutic effects in cardiovascular diseases, diabetes, and neurodegenerative diseases through mechanisms such as regulating lipid metabolism, anti-inflammation, anti-oxidation, and improving cell function. Although bile acids have broad application prospects in treatment, their mechanisms of action are complex, involving multiple signaling pathways and molecular mechanisms. Therefore, further research is needed to clarify their specific roles and therapeutic potential in different diseases. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides the application of taurine chenodeoxycholic acid in the preparation of drugs for the prevention and treatment of hypertension.

[0007] The technical solution of the present invention is as follows:

[0008] This invention provides the application of taurine chenodeoxycholic acid in the preparation of drugs for the prevention and treatment of hypertension;

[0009] The chemical formula of the taurine chenodeoxycholic acid (TCDCA) is C. 26 H 45 NO6S, with a molecular weight of 499.7, has the following structural formula:

[0010]

[0011] According to a preferred embodiment of the present invention, the hypertension is primary hypertension or salt-sensitive hypertension.

[0012] According to a preferred embodiment of the present invention, the antihypertensive drug achieves the effect of lowering blood pressure by enhancing the diastolic function of microarteries.

[0013] According to a preferred embodiment of the present invention, the antihypertensive drug contains a pharmaceutically effective dose of taurine chenodeoxycholic acid (TCDCA) and a pharmaceutically acceptable carrier.

[0014] More preferably, the pharmaceutically acceptable carrier is one or more of the following: skim milk, lactose, glucose, sucrose, sorbitol, mannose, trehalose, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, fine crystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylparaben, propylparaben, talc, magnesium stearate, or mineral oil.

[0015] According to a preferred embodiment of the present invention, the antihypertensive drug may be any one or more pharmaceutically feasible dosage forms, including but not limited to tablets, pills, injections, capsules, oral liquids or lyophilized powders.

[0016] This invention first fully demonstrates, through microvascular experiments in hypertensive patients and arterial vascular experiments in hypertensive mice, that taurine chenodeoxycholic acid (TCDCA) incubation significantly enhances the diastolic function of microarteries in hypertensive patients and arteries in mice. A large portion of human blood pressure originates from these resistance vessels, microarteries. Furthermore, through injection experiments in hypertensive mice, it is confirmed that direct administration of TCDCA significantly reduces blood pressure in hypertensive mice. This indicates that TCDCA can lower blood pressure by promoting the diastolic function of vascular endothelium.

[0017] Technical features and beneficial effects of the present invention:

[0018] 1. This invention is the first to discover the crucial role of taurine chenodeoxycholic acid (TCDCA) in the prevention and treatment of hypertension. Specifically, TCDCA can significantly enhance the diastolic function of microarteries in hypertensive patients, thereby achieving a blood pressure-lowering effect. Therefore, this invention provides a novel use for taurine chenodeoxycholic acid (TCDCA) in the preparation of drugs for the prevention and treatment of hypertension, offering a new approach for clinical application with significant clinical value and broad prospects.

[0019] 2. Utilizing the key role of taurine chenodeoxycholic acid (TCDCA) in hypertension, as described in this invention, it can be prepared into the form of drugs, pharmaceutical compositions, foods, health products, or food additives. These drugs, pharmaceutical compositions, foods, health products, or food additives contain taurine chenodeoxycholic acid (TCDCA) and can be used to treat hypertension, including essential hypertension and salt-sensitive hypertension, thus possessing significant application value. Attached Figure Description

[0020] Figure 1 This is a flowchart and result diagram of the measurement of isolated blood vessel tension in a hypertensive patient in Example 1;

[0021] In the figure, A is the flowchart of the isolated blood vessel tension measurement of hypertensive patients; B is the degree of vasodilation induced by acetylcholine (ACH) concentration gradient; and C is the degree of vasodilation induced by bradykinin (BK) concentration gradient.

[0022] Figure 2 This is a flowchart and result diagram of the determination of isolated blood vessel tension in hypertensive mice in Example 2;

[0023] In the figure, A is the flowchart of the isolated vascular tension measurement of hypertensive mice; B is the degree of vasodilation induced by concentration gradient ACH; and C is the degree of vasodilation induced by concentration gradient BK.

[0024] Figure 3 This is a flowchart and result diagram showing how TCDCA reduced blood pressure in hypertensive mice in Example 3;

[0025] In the figure, A is the flowchart of TCDCA lowering blood pressure in hypertensive mice; B is the result of systolic blood pressure measurement in hypertensive mice; and C is the result of diastolic blood pressure measurement in hypertensive mice. Detailed Implementation

[0026] The present invention will be further illustrated below with reference to embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of protection of the present invention.

[0027] Unless otherwise specified, the drugs and reagents mentioned in the examples are all commercially available products. Unless otherwise specified, the experimental operations mentioned in the examples are performed in accordance with conventional practices in the field.

[0028] Taurine chenodeoxycholic acid (TCDCA) has the chemical formula C1. 26 H 45 NO6S, CAS number 516-35-8, molecular weight 499.7, structural formula is shown below:

[0029]

[0030] Preparation of TCDCA solution: Dissolve TCDCA in Krebs solution and stir until homogeneous to obtain a TCDCA solution with a concentration of 50 mM.

[0031] Example 1: TCDCA incubation can enhance the diastolic function of omental adipose microarteries in hypertensive patients.

[0032] This embodiment involved isolating omental adipose microarteries from hypertensive patients collected during bariatric surgery. The blood vessels from the same patient were incubated for 12 hours in control and TCDCA solutions, respectively. The DMT630 ex vivo vascular tension measurement system was used to detect: ① the degree of vasodilation induced by acetylcholine (ACH) concentration gradients; ② the degree of vasodilation induced by bradykinin (BK) concentration gradients. This experiment was approved by the Ethics Committee of Qilu Hospital, Shandong University, and informed consent was obtained from all patients for the collection of all clinical samples.

[0033] The specific method is as follows: Figure 1 As shown in Figure A, omental fat was collected from hypertensive patients undergoing bariatric surgery and placed in Krebs solution at 4°C. Microarteries with diameters of 150–300 μm were carefully dissected, and perivascular fat was completely removed. The microarteries from the same patient were cut into uniformly long segments and divided into: ① control group; ② TCDCA treatment group. The segments were placed in Krebs solution or TCDCA solution, respectively, and incubated at 4°C for 12 hours to obtain the incubated microarteries.

[0034] Using a DMT630MA ex vivo vascular tension measurement system, a 2mm segment of a cleaned and incubated microartery was cut. Two 40μm steel wires were threaded through the lumen and fixed in the chamber. Krebs solution preheated to 37°C was placed inside, and a gas mixture containing 95% O2 and 5% CO2 was introduced. The vessel was stretched laterally to the optimal initial tension. After stabilization, 60mM high-potassium Krebs solution was added for three stimulations. Then, a final concentration of 10 was added to the Krebs solution. -5 Add phenylephrine (Phe) to M until the contraction stabilizes, then add to a final concentration of 10. -9 -10 -5 ACH induced vasodilation with M concentration gradient, and the tension of isolated blood vessels was measured. The results are as follows: Figure 1 As shown in B. After washing the chamber with Krebs solution, add Krebs solution to a final concentration of 10. -5 M is depleted until the contraction stabilizes, then a final concentration of 10 is added. -10 -10 -6 BK concentration gradient induced vasodilation, and the tension of isolated blood vessels was measured. The results are as follows: Figure 1 As shown in C.

[0035] Depend on Figure 1 As shown in B and 1C, TCDCA incubation can significantly enhance the diastolic function of microarteries in hypertensive patients. Since a large part of human blood pressure comes from resistance vessels such as microarteries, this experiment suggests that TCDCA can reduce blood pressure by promoting endothelial diastolic function.

[0036] Example 2: TCDCA incubation can enhance the diastolic function of the mesenteric arteries in hypertensive mice.

[0037] In this embodiment, a hypertensive mouse model was established by subcutaneous infusion of AngII for 28 days. Mesenteric arteries of mice were isolated, and blood vessels from the same mouse were incubated in control solution and TCDCA solution for 12 hours, respectively. The following were measured using a DMT630 isolated blood vessel tension measurement system: ① the degree of vasodilation induced by acetylcholine (ACH) concentration gradient; ② the degree of vasodilation induced by bradykinin (BK) concentration gradient.

[0038] The specific method is as follows: Figure 2 As shown in Figure A, an 8-week-old male C57BL / 6J mouse model of hypertension was established by subcutaneously infusing AngII for 28 consecutive days. The small intestine of the mice was isolated, and the mesenteric artery was carefully dissected and the perivascular fat was completely removed in Krebs solution at 4°C. The mesenteric artery of the same mouse was cut into uniformly long segments and divided into: ① control group; ② TCDCA treatment group. The segments were placed in Krebs solution or TCDCA solution, respectively, and incubated at 4°C for 12 hours to obtain the incubated mesenteric artery vessels.

[0039] Using a DMT630MA ex vivo vascular tension measurement system, a 2mm segment of a cleaned and incubated mesenteric artery was cut. Two 40μm steel wires were threaded through the lumen and fixed in a chamber. The chamber was then immersed in preheated Krebs solution at 37°C, and a gas mixture containing 95% O2 and 5% CO2 was introduced. The vessel was stretched laterally to achieve optimal initial tension. After stabilization, 60mM high-potassium Krebs solution was added for three stimulations. A final concentration of 10 was added to the Krebs solution. -5 M was added to Phe until the contraction stabilized, and then a final concentration of 10 was added. -10 -10 -4 ACH induced vasodilation with M concentration gradient, and the tension of isolated blood vessels was measured. The results are as follows: Figure 2 As shown in B. After washing the chamber with Krebs solution, add Krebs solution to a final concentration of 10. -5 M is depleted until the contraction stabilizes, then a final concentration of 10 is added. -11 -10 -5 BK concentration gradient induced vasodilation, and the tension of isolated blood vessels was measured. The results are as follows: Figure 2 As shown in C.

[0040] Depend on Figure 2 As shown in B and 2C, TCDCA incubation of blood vessels can significantly enhance the diastolic function of the mesenteric arteries in hypertensive mice, further demonstrating that TCDCA can reduce blood pressure by promoting vascular endothelial diastolic function.

[0041] Example 3

[0042] In this embodiment, a hypertensive mouse model was established by subcutaneous infusion of AngII for 28 days, while the mice were treated with intraperitoneal injection of TCDCA. During this period, the blood pressure of the mice was monitored using a blood pressure telemetry system.

[0043] The specific method is as follows: Figure 3 As shown in Figure A, 8-week-old male C57BL / 6J mice were selected and divided into: ① control group; ② TCDCA treatment group. Mice in the TCDCA treatment group received subcutaneous AngII infusion for 28 consecutive days, and simultaneously received TCDCA solution (20 mg / kg / day) via intraperitoneal injection for 28 consecutive days. Mice in the control group received subcutaneous AngII infusion for 28 consecutive days, and simultaneously received an equal volume of control solution via intraperitoneal injection for 28 consecutive days. Blood pressure changes in the mice were then monitored using an implantable blood pressure telemetry method. Mice were anesthetized with sodium pentobarbital, their necks were shaved and fixed, and the necks were disinfected with iodine. The neck skin was then incised along the midline of the neck to expose the left common carotid artery. The catheter tip of the implant was checked for air bubbles. The distal end of the left common carotid artery was ligated beforehand, and the implant was inserted from the bifurcation of the left common carotid artery to the aorta. The catheter was then ligated and fixed. The skin on the mouse's back was bluntly dissected, and the implant was then buried subcutaneously. The neck skin was sutured and disinfected with iodine. The mice were returned to their cages for individual rearing only after waking up. Postoperatively, the mice's wound healing, mental state, and various physiological indicators were closely monitored. Blood pressure was monitored weekly for a fixed 24-hour period. Systolic and diastolic blood pressure data were received and recorded in real time using data acquisition equipment and software. Results are as follows: Figure 3 B and Figure 3 As shown in C.

[0044] Depend on Figure 3 B and Figure 3 As shown in Figure C, TCDCA treatment significantly reduced systolic and diastolic blood pressure in mice. Combined with data from Examples 1 and 2, this fully demonstrates that taurine chenodeoxycholic acid (TCDCA) can significantly enhance the diastolic function of microarteries in hypertensive patients, thereby achieving a blood pressure-lowering effect. Therefore, this invention provides a novel use of taurine chenodeoxycholic acid (TCDCA) in the preparation of drugs for the prevention and treatment of hypertension, offering a new drug for clinical use with good clinical application value and broad application prospects.

Claims

1. The application of taurine chenodeoxycholic acid in the preparation of drugs for the prevention and treatment of hypertension, characterized in that, The structural formula of taurine chenodeoxycholic acid is shown below:

2. The application as described in claim 1, characterized in that, The hypertension referred to is either primary hypertension or salt-sensitive hypertension.

3. The application as described in claim 1, characterized in that, The aforementioned antihypertensive drugs achieve their blood pressure-lowering effect by enhancing the diastolic function of microarteries.

4. The application as described in claim 1, characterized in that, The antihypertensive drug contains a pharmaceutically effective dose of taurine chenodeoxycholic acid and a pharmaceutically acceptable carrier.

5. The application as described in claim 4, characterized in that, The pharmaceutically acceptable carrier is one or more of the following: skim milk, lactose, glucose, sucrose, sorbitol, mannose, trehalose, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, fine crystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylparaben, propylparaben, talc, magnesium stearate, or mineral oil.

6. The application as described in claim 1, characterized in that, The antihypertensive drug may be any one or more pharmaceutically feasible dosage forms, including but not limited to tablets, pills, injections, capsules, oral liquids, or lyophilized powders.

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