|Year : 2021 | Volume
| Issue : 6 | Page : 274-280
Vasorelaxation effect of oxysophoridine on isolated thoracicc aorta rings of rats
Nan Li1, Yefeng Chen2, Yanmin Pei1, Liangjuan Han3, Jun Ren4, Wei Zhou5, Ru Zhou6
1 Department of Pharmacology, School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, China
2 College of Clinical Medicine, Ningxia Medical University, Yinchuan, Ningxia, China
3 Department of Pharmaceutical, The First People's Hospital of Yinchuan, Yinchuan, Ningxia, China
4 Department of Health Supervision, Health Education Institute of Dawukou District, Shizuishan, Shizushan, Ningxia, China
5 Respiratory and Critical Care Medicine, General Hospital of Ningxia Medical University, Xingqing, Yinchuan, Ningxia, China
6 Department of Pharmacology, School of Pharmacy; Key Laboratory of Hui Ethnic Medicine Modernization, Ministry of Education; Ningxia Hui Medicine Modern Engineering Research Center and Collaborative Innovation Center, Ningxia Medical University, Yinchuan, Ningxia, China
|Date of Submission||30-Jun-2021|
|Date of Decision||16-Oct-2021|
|Date of Acceptance||02-Nov-2021|
|Date of Web Publication||27-Dec-2021|
Dr. Ru Zhou
Department of Pharmacology, Ningxia Medical University, 1160, Shengli Street, Xingqing, Yinchuan 750004
Prof. Wei Zhou
Respiratory and Critical Care Medicine, General Hospital of Ningxia Medical University, 804, Shengli Street, Xingqing, Yinchuan 750004
Source of Support: None, Conflict of Interest: None
Oxysophoridine (OSR) is a main active alkaloid extracted from Sophora alopecuroides, which is a traditional Chinese herbal medicine that has been used widely. In this study, we used thoracic aorta rings isolated from Sprague–Dawley rats to explore the vasodilative activity of OSR and its potential mechanisms. The isolated rat thoracic aorta rings were used to observe the effects of different concentrations of OSR (0.4–2.0 g·L−1) on the resting normal rings and the phenylephrine precontracted endothelium-intact or endothelium-denudedisolated thoracic aorta rings, respectively. The interactions among OSR and barium chloride (BaCl2), tetraethylamine, 4-aminopyridine, glibenclamide (Gli), L-nitroarginine methyl ester (L-NAME), and cyclooxygenase (COX) inhibitor indomethacin (INDO) were evaluated. The experimental results show that OSR had no effect on the tension of resting vascular rings, but the vasodilating effect could be confirmed in a concentration-dependent manner on both endothelium-intact and endothelium-denuded vascular rings. This vasodilation effect of OSR on thoracic aorta vascular rings could be inhibited significantly by potassium channel blockers glibenclamide (Gli, 10 μmol·L−1) and 4-aminopyridine (4-AP, 5 mmol·L−1). In addition, vasodilatory effects of OSR were not inhibited in the presence of potassium channel blockers barium chloride (BaCl2, 1 mmol·L−1) and tetraethylamine (TEA, 10 mmol·L−1), nitric oxide synthase inhibitor (L-NAME, 0.1 mmol·L−1) and COX inhibitor (INDO, 10 μmol·L−1). In conclusion, the vasodilatory effects of OSR on thoracic aorta rings is associated with KV and KATP.
Keywords: Endothelium, endothelium-denuded, potassium channel, traditional Chinese medicine monomer, vasodilator factors
|How to cite this article:|
Li N, Chen Y, Pei Y, Han L, Ren J, Zhou W, Zhou R. Vasorelaxation effect of oxysophoridine on isolated thoracicc aorta rings of rats. Chin J Physiol 2021;64:274-80
|How to cite this URL:|
Li N, Chen Y, Pei Y, Han L, Ren J, Zhou W, Zhou R. Vasorelaxation effect of oxysophoridine on isolated thoracicc aorta rings of rats. Chin J Physiol [serial online] 2021 [cited 2022 May 21];64:274-80. Available from: https://www.cjphysiology.org/text.asp?2021/64/6/274/333798
Nan Li and Yefeng Chen contributed equally to this work.
| Introduction|| |
There are many types of vascular-related diseases,taking cardiovascular disease as an example, and is associated with high morbidity, disability, and mortality in China. According to reports, cardiovascular disease is the cause of nearly one-third of deaths in the world. Hypertension is a major cardiovascular disease, and its main pathogenesis is the imbalance between the vasoconstrictor system and the vasodilator system in the body,,, which leads to vasoconstriction, blood pressure rise, and ultimately hypertension. Abnormal changes in vascular tone play a central role in inducing the occurrence and development of vascular-related diseases, and its changes play a very critical role in regulating blood pressure. The pharmacological experiment rats' thoracic aorta vascular rings are mainly to detect the influence of the tested substance on the vascular tension. Although many antihypertensive drugs have been put into use at present, many drugs do not directly improve the changes in vascular tone and their side effects are relatively large. Therefore, it is necessary to find drugs that can dilate blood vessels for the treatment of cardiovascular diseases.
Traditional Chinese medicine has a long history of use in China, and it has shown several advantages, such as cost-efficacy, wide range of applications, and less side effects., Sophora alopecuroides is a Sophora plant in Leguminosae. According to the records of traditional Chinese medicine, Sophora alopecuroides have functions of clearing away heat and detoxification, antibacterial and anti-inflammatory, relieving pain and insects, and anti-arrhythmia.,, Oxysophoridine [OSR, [Figure 1]] is an important alkaloid extracted from Sophora alopecuroides. Its basic structure is a double piperidine ring condensed by two trivalent nitrogen atoms. It has various pharmacological properties such as antibacterial, anti-inflammatory, anti-oxidant, and anti-apoptosis.,, Through previous studies, our groups found that aloperine extracted from Sophora alopecuroides showed the vasodilatory effect of rat thoracic aorta rings. OSR is also a kind of alkaloids extracted from Sophora alopecuroides, but whether it can dilate the thoracic aorta rings is not clear, which makes us interested in the vasodilative effect of OSR.
Therefore, the purpose of this study was to investigate the vasodilatory effect of OSR on isolated thoracic aorta rings in rats and its possible mechanisms. Hence that could provide a theoretical basis for the clinical treatment of cardiovascular diseases by OSR.
| Materials and Methods|| |
Medicines and reagents
OSR was purchased from Pharmacy Laboratory, School of Pharmacy, Ningxia Medical University (Ningxia, China). Phenylephrine (PE) was purchased from Shanghai Hefeng Pharmaceutical Co., Ltd. (Shanghai, China). Acetylcholine (Ach) was purchased from Beijing Suo Laibao Technology Co., Ltd. (Beijing, China). Glibenclamide (Gli) was purchased from Shanghai Yien Chemical Technology Co., Ltd. (Shanghai, China). BaCl2 was purchased from Shanghai Yuanye Biotechnology Co., Ltd. (Shanghai, China). TEA was purchased from Shanghai Beat Pharmaceutical Technology Co., Ltd. (Shanghai, China). 4-AP was purchased from Tokyo Chemical Industry Co., Ltd (Tokyo, Japan). NG-nitro-L-arginine methyl ester (L-NAME) was purchased from Shanghai Yien Chemical Technology Co., Ltd. (Shanghai, China). Indomethacin (INDO) was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. (Shanghai, China). Sodium hydrogen carbonate (NaHCO2), glucose, calcium chloride hexahydrate (CaCl2·2H2O), anhydrous magnesium sulfate (MgSO4·7H2O), and sodium chloride (NaCl) were purchased from Tianjin Damao Chemical Reagent Factory (Tianjin, China). Potassium chloride (KCl) was purchased from Minsheng Pharmaceutical Co., Ltd. (Zhejiang, China). Potassium dihydrogen phosphate (KH2PO4) was purchased from Beichenzheng Reagent Factory (Tianjin, China).
Preparation of Krebs-Henseleit (KH) nutrient solution: Added 0.35 g KCl, 0.29 g MgSO4·7H2O, 0.28 g CaCl2, 0.16 g KH2PO4, 2.0 g glucose, 6.92 g NaCl, 2.21 g NaHCO3 to 1000 mL double distilled water in a beaker, and mixed until the medicine completely dissolved. Prepare the NaOH solution (pH to 7.4 with 10 mmol·L−1), and store in a constant temperature water bath at 37°C.
Sprague–Dawley (SD) rats (220-320 g) were purchased by the experimental animal center of Ningxia Medical University. All experimental rats were reviewed and approved by the Animal Experimental Committee of the Ningxia Medical University (Certificate no. SYXK Ningxia 2015-0001). Our animal experiment procedures should be as humane as possible and use 10% urethane to anesthetize animals. Experimental rats were kept in a temperature-controlled room (12-h light-dark cycles) with free access to food and water.
Preparation of isolated rat thoracic aorta vascular rings
Firstly, male SD rats (each group, n = 6) intraperitoneally injected with 10% urethane (10 mL·kg−1), were fixed on the operating plate. The thoracic aortas were found in the middle of the chest and retrieved. Then the thoracic aortas were removed and quickly moved into the K-H solution with a mixed standard gas (95% O2 + 5% CO2). Thereafter, the thoracic aortas were carefully cleaned the fat and connective tissue around it, and cut into 3–4 mm rings. The thoracic aorta vascular rings surface was rubbed with cotton swabs, and part of the thoracic aorta vascular rings prepare the endothelial removal model. The isolated rat thoracic aorta vascular rings were suspended in a 10 mL bath with preheated at 37°C, that was continuously ventilated with mixed gas (95% O2 + 5% CO2). One was fixed with an m-hook, and the other was connected with a biological information acquisition system through a tension transducer. The isolated rat thoracic aorta vascular rings were stretched at resting tension of 2.0 g, and the K-H solution was changed every 20 min before the experiment and equilibrated for 60 min. Thoracic aorta vascular rings were pre-constricted repeated twice with 40 mmol·L−1 KCl, and the difference contraction amplitude of the two results <10% to prove the functional integrity of the thoracic aorta vascular rings. Next, the endothelial integrity was determined by verifying the response to ACh in the thoracic aorta vascular rings pre-contracted using PE (1 μmol·L−1). If the Ach-induced relaxation was >70%, the endothelium was considered intact, and if ACh does not produce a dilatory effect or the dilatory amplitude is less than the precontracted at 10%, the endothelium was considered incomplete.
Tension measurement of thoracic aorta vascular rings at rest
The intact and incomplete endothelium isolated rat thoracic aorta vascular rings were divided into control groups and the OSR administration groups. When they stabilized, OSR was added every 2 min to increase the final concentration to 0.40, 0.80, 1.20, 1.60, and 2.00 g·L−1; the control groups were added with an equal volume of K-H nutrient solutions. The purpose is to observe the change of vascular tension and calculate the dilatory rate.
Tension measurement of thoracic aorta vascular rings precontracted by phenylephrine
The intact and incomplete endothelium rat isolated thoracic aorta vascular rings were precontracted and stabilized using PE (1 μmol·L−1). The OSR administration groups will be given OSR cumulatively every 2 min (the method is the same as “Tension measurement of thoracic aorta vascular rings at rest”). The control groups were added with equal volume K-H nutrient solution. The purpose is to observe the changes in vascular tension and calculate the dilatory rate.
Tension measurement of potassium channel blocker preconstricted on thoracic aorta vascular rings by phenylephrine
The incomplete endothelium isolated rat thoracic aorta vascular rings in the OSR administration + potassium channel blocker groups were preincubate to BaCl2 (1 mmol·L−1), TEA (10 mmol·L−1), 4-AP (5 mmol·L−1), and Gli (10 μmol·L−1) for 20 min, OSR administration + potassium channel blocker groups and OSR groups followed by to exposure to PE (1 μmol·L−1) to pre-constriction the thoracic aortic vascular rings. After stable vasoconstriction was achieved, every group were added cumulatively every 2 min (the method is the same as “Tension measurement of thoracic aorta vascular rings at rest”). The OSR groups were incubated without the mechanism drugs, only added the cumulative concentration of OSR. The purpose is to calculate the vasodilation ratio of each concentration of OSR.
Tension measurement of L-nitroarginine methyl ester and indomethacin pre-contraction on thoracic aorta vascular rings by phenylephrine
The intact endothelium isolated rat thoracic aorta vascular rings in the OSR administration + L-NAME/INDO groups were pre-incubate with L-NAME (0.1 mmol·L−1) and INDO (10 μmol·L−1) for 20 min, OSR administration + L-NAME/INDO groups and OSR groups followed by to exposure to PE (1 μmol·L−1) pre-constriction the thoracic aorta vascular rings. After stable vasoconstriction was achieved, every group were given cumulatively every 2 min (the method is the same as “Tension measurement of thoracic aorta vascular rings at rest”). The OSR groups were incubated without the mechanism drugs, only added the cumulative concentration of OSR. The purpose is to calculate the vasodilation ratio of different concentrations of OSR.
Data processing analysis was performed using SPSS 24.0 statistical software and presented as mean ± standard error of the mean. The independent sample t-test was used to compare two samples. For all statistical tests, P < 0.05 was considered statistically significant.
| Results|| |
Effects of cumulative concentrations of oxysophoridine on normal thoracic aorta vascular rings in resting state
Compared with the control groups, OSR had no significant vasodilatory effects on intact and incomplete thoracic aorta vascular rings, which indicate that OSR had no vasodilatory effects on the normal thoracic aorta vascular rings [Figure 2].
|Figure 2: Effect of different concentrations of oxysophoridine on untreated rat thoracic aortic rings. (a) The typical original trace of intact thoracic aortic vascular ring group. (b) The typical original trace of the incomplete thoracic aortic vascular ring group.|
Click here to view
Vasodilatory effects of cumulative concentrations of oxysophoridine on pre-contracted thoracic aorta vascular rings using phenylephrine
Compared with the control groups, OSR showed a concentration-dependent vasodilatory affect on PE pre-contracted intact and incomplete thoracic aorta vascular rings (P < 0.05 or P < 0.01). The results are shown in [Figure 3] and [Figure 4].
|Figure 3: Effect of oxysophoridine on phenylephrine precontracted intact thoracic aortic rings. (a) The typical original trace of intact thoracic aortic ring group. (b) Effect of oxysophoridine on vasorelaxation action of phenylephrine precontracted intact thoracic aortic rings (n = 6 per group). Data are expressed as the mean ± standard error of the mean. *P < 0.05, **P < 0.01 versus the control group.|
Click here to view
|Figure 4: Effect of oxysophoridine on phenylephrine precontracted incomplete thoracic aortic rings. (a) The typical original trace of incomplete thoracic aortic ring group. (b) Effect of oxysophoridine on vasorelaxation action of phenylephrine pre-contracted incomplete thoracic aortic rings (n = 6 per group). Data are expressed as the mean ± standard error of the mean. *P < 0.05, **P < 0.01 versus the control group.|
Click here to view
Effect of potassium channels blockers on vasorelaxation due to oxysophoridine in incomplete endothelium thoracic aorta vascular rings
Compared with the OSR groups, both BaCl2 incubation groups and TEA incubation groups had no effect on the vasodilation due to OSR (P > 0.05). The results indicate that the BaCl2 and TEA were not affected the vasodilatory effects of OSR in thoracic aorta vascular rings. However, the Gli incubation groups and the 4-AP incubation groups significantly antagonized the vasodilatation due to OSR (P < 0.05 or P < 0.01). These experimental results indicate that the Gli and 4-AP were affected the vasodilation effects of OSR in thoracic aorta vascular rings. The results are shown in [Figure 5].
|Figure 5: Effect of potassium channels blockers on relaxation of endothelialized thoracic aortic rings by oxysophoridine under phenylephrine precontraction. Data are expressed as the mean ± standard error of the mean. *P < 0.05, **P < 0.01 versus the control group.|
Click here to view
Effect of L-nitroarginine methyl ester and indomethacin on vasodilation due to OSR in endothelially intact thoracic aorta vascular rings
Compared with the OSR groups, no change were evident vasodilation due to OSR in the thoracic aorta vascular rings after L-NAME pre-incubation and INDO pre-incubation (P > 0.05). These indicate that the vasodilatory effects of OSR is not related to the endothelium-dependent. The results are shown in [Figure 6] and [Figure 7].
|Figure 6: Effect of L-nitroarginine methyl ester on vasodilation of endothelially intact thoracic aortic rings by oxysophoridine under phenylephrine precontraction. Data are expressed as the mean ± standard error of the mean.|
Click here to view
|Figure 7: Effect of indomethacin on vasodilation of endothelially intact thoracic aortic rings by oxysophoridine under phenylephrine precontraction. Data are expressed as the mean ± standard error of the mean.|
Click here to view
| Discussion|| |
Sophora alopecuroides is authentic medicinal material of the Ningxia Hui Autonomous Region in Northwest China. It has many advantages such as easy availability, wide range of useful, and a good curative effect. OSR is one of the important extracts of Sophora alopecuroides, and it can lead to an improvement in acute lung injury and cardiovascular diseases such as chronic heart failure. In hypertensive diseases, the balance between vasoconstriction and dilation is a key factor for the stability of blood pressure. The regulation of blood pressure by a drug has an important relationship with its ability to balance the contraction and relaxation of blood vessels. There are roughly two types of diastolic effects on arterial blood vessels, one of which is dependent on the vasodilatory factors secreted by the vascular endothelium, and the other is to directly act on vascular smooth muscle cells, affecting calcium channels and potassium on vascular smooth muscle cells on channels. In vitro vascular rings, experiment is an experimental method to study vasomotor function. It is an important means to study vascular physiology, pathophysiology, and pharmacology. Through the study of vasomotor function, this paper discusses the essence of vascular diseases, to provide the scientific basis for the prevention and treatment of cardiovascular diseases such as hypertension. There are two main types of vessels that can be used in vitro experiments: conduit and resistance vessels, such as the aorta, pulmonary artery, coronary artery, mesenteric artery, cerebral basilar artery, renal artery, and so on.,,,,, It is generally believed that resistance vessels can change peripheral vascular resistance through their contraction and relaxation, which has become one of the main factors determining blood pressure. Moreover, the onset of cardiovascular disease first occurs in the resistance vessels, and the later stage is related to conduit remodeling and narrowing.,,, Although conduits and resistance vessels are similar in morphology and anatomy, there are significant differences in size, function, and local environment. Theoretically, the tertiary resistance vessels of the mesenteric artery are more important to the regulation of arterial blood pressure, but in the course of hypertension, it was also found that the major coronary arteries were affected earlier and more significantly than the resistance vessels, and more researchers have studied a vasodilatory effect of the thoracic aorta in spontaneously hypertensive rats.,, Most of the traditional Chinese medicine monomers used rat thoracic aorta vascular rings to study vasodilation activity. Therefore, this study selected the thoracic aorta vascular rings which is more related and basic to cardiovascular disease. It is the purpose to explore whether OSR has vasodilatory effects on rat thoracic aorta vascular rings.
In this experiment, we found that OSR has no significant effect on thoracic aorta vascular rings in the resting state, which suggests that OSR has no effects on the normal thoracic aorta vascular rings.
In vascular smooth muscles, Ca2+ is necessary to maintain basic vascular tension, which is regulated by the release of Ca2+ stored in cells in the sarcolemmic reticulum and mitochondria and the entry of Ca2+ from outside the cell through the Ca2+ channels in the plasma membrane. The Ca2+ is released from storage and the Ca2+ flowing from the extracellular space through ROCCs or VDCCs in the plasma membrane channels both regulate the contraction and relaxation of vascular smooth muscles,, increase the concentration of Ca2+ in cells and cause the contraction of blood vessels. PE is an α1 adrenergic receptor agonist, which can cause a significant increase concentration of inositol triphosphate (IP3) and diacylglycerol in smooth muscle cells through binds to adrenergic receptors and activates phospholipase C. IP3 activates the IP3 receptors, which induces the release of Ca2+ in the sarcoplasmic reticulum. Diacylglycerol activates protein kinase C, and phosphocreatine activates the lectin light chain and triggers ROCCs, leading to extracellular Ca2+ internalization. This study found that OSR showed a concentration-dependent vasodilatory effect on PE precontracted intact endothelial vascular thoracic aorta rings and thoracic aorta vascular rings without endothelium. OSR has a vasodilatory effect on PE precontracted thoracic aorta vascular rings, and its effects are concentration dependent, and vasodilatory effects of thoracic aorta vascular rings without endothelium is slightly stronger than intact endothelial thoracic aorta vascular rings, which indicates that vasodilation effects of OSR are not endothelial dependent, but not completely dependent on incomplete endothelium.
K+ channels in arterial smooth muscle cells regulate the contraction and relaxation of blood vessels. The opening of K+ channels leads to hyperpolarization and relaxation of vascular smooth muscle cells, followed by increased blood flow and decreased blood pressure. There are four kinds of potassium channels on vascular smooth muscles: ATP-sensitive potassium channels (KATP), inward rectifier potassium channels (Kir), Ca2+ activated potassium channels (KCa), and voltage-sensitive potassium channels (Kv). In the experiment, rat thoracic aorta vascular rings were pre-incubated with Ca2+ activated potassium channels (KCa)-TEA, voltage-sensitive potassium channels (KV)-4-AP, inward rectifier potassium channels (Kir)-BaCl2 and ATP-sensitive potassium channels (KATP)–Gli. Among the these drugs, TEA has low channel subtype selectivity and is often regarded as a nonselective potassium channel blocker, 4-AP and BaCl2 selectively block voltage-sensitive potassium channels (KV) and inward rectifier potassium channels (Kir), Gli has been shown to selectively block ATP-sensitive potassium channels (KATP). BaCl2, 4-AP, and TEA can affect vascular tension, with poor tissue selectivity, may produce smooth muscles contraction, cause high blood pressure and other side effects, so they can only be used as tool drugs. The important reason why Gli can be used as a clinical drug is that they have high tissue selectivity, and can not shrink vascular smooth muscles whether used alone or in the presence of PE. The results showed that both 4-AP and Gli could partially inhibit the vasodilation of OSR, suggesting that 4-AP and Gli were involved in the vasodilation induced by OSR and the vasodilation effect of OSR may be related to voltage-sensitive potassium channels (KV) and ATP sensitive potassium channels (KATP). The inhibitory effect of 4-AP on PE-induced vasoconstriction may also be due to its blocking of α1 adrenoceptor on vascular smooth muscles.
The vascular endothelium is a major metabolic and endocrine tissue of the body. It can synthesize and secrete a variety of vasoactive substances, maintain blood vessel tension, and regulate blood vessel growth., Endothelial cells can synthesize and secrete a variety of vasoactive substances that act on vascular smooth muscle cells. For example, endothelial cells can secrete vasodilator factors, such as nitric oxide (NO) and prostacyclin I2 (PGI2). NO is a substance synthesized by vascular endothelial cells with a potent vasodilator effect,, and endothelial NO synthase (eNOS) can produce NO, it can activate guanylyl cyclase and induce the increase of cyclic guanosine phosphate (cGMP) in cells. cGMP can inhibit calcium channels, reduce intracellular Ca2+ and cause vasodilation,,, eNOS inhibitors can block it and cause vasoconstriction and blood pressure increased. The experimental results showed that when the thoracic aorta vascular rings were incubated with L-NAME (an eNOS inhibitor), the vasodilation effect of OSR did not weaken. Vascular endothelial cells produce prostacyclin (PGI2). Arachidonic acid produces PGI2 under the action of cyclooxygenase (COX) and prostacyclin synthase, which is mediated by prostacyclin receptors. They produce the secondary messenger cyclic adenosine monophosphate, activates protein kinase A signal transduction, and ultimately produces vasodilation.,, INDO is a non-selective COX inhibitor, which inhibits the activity of COX-1 and COX-2, so that arachidonic acid can not be oxidized to prostaglandins, so it can not relax blood vessels. The experimental results showed that when the thoracic aorta vascular rings were incubated with INDO (a COX inhibitor), the vasodilatory effect of OSR was not weakened. The above experimental results show that the vasodilatory effect of OSR has nothing to do with the release of NO and PGI2. Its vasodilator effect is likely to be endothelium independent, but whether its vasodilatory effect is mediated by other endothelium-dependent factors such as gas signal molecular pathways (CO and H2S) remain to be further verified.
| Conclusion|| |
The results of this study confirmed for the first time that OSR causes a concentration-dependent vasodilatory effect in PE-precontracted rat thoracic aorta vascular rings, and the mechanisms of vasodilation may be associated with KV and KATP Although further long-term prospective studies should analyze the specific mechanisms, this experiment provides necessary experimental data and new options in the treatment of cardiovascular diseases. In the future, to fully confirm whether OSR has the effect of vasodilation and its specific mechanisms, we will continue to conduct in vitro mesenteric artery experiments and in vitro models to continue to verify its effect on cardiovascular diseases such as hypertension. The ultimate goal is to obtain drugs that have good effects in the prevention and treatment of cardiovascular diseases such as hypertension.
Financial support and sponsorship
This project was supported by the “2017 Ningxia Hui Autonomous Region Science and Technology Innovation Leader Training Project, grant number KJT2017005”, “2017 Ningxia Medical University Youth Backbone Talent Cultivation Selected Project”.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Engin E, Alp Yildirim Fİ, Kaleli Durman D, Ömeroğlu SN, Göksedef D, Teskin Ö, et al.
Relaxant effect of the prostacyclin analogue iloprost on isolated human radial artery: An approach for the reversal of graft spasm. Prostaglandins Other Lipid Mediat 2017;133:35-41.
GBD 2013 Risk Factors Collaborators; Forouzanfar MH, Alexander L, Anderson HR, Bachman VF, Biryukov S, et al.
Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;386:2287-323.
Norman PE, Powell JT. Vitamin D and cardiovascular disease. Circ Res 2014;114:379-93.
Al-Mallah MH, Sakr S, Al-Qunaibet A. Cardiorespiratory fitness and cardiovascular disease prevention: An update. Curr Atheroscler Rep 2018;20:1.
Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: Structure, function and inhibition. Biochem J 2001;357:593-615.
Feng Y, Peng K, Luo R, Wang F, Yang T. Site-1 protease-derived soluble (Pro) renin receptor contributes to angiotensin II-induced hypertension in mice. Hypertension 2021;77:405-16.
Aryal D, Roy T, Chamcheu JC, Jackson KE. Chronic metabolic acidosis elicits hypertension via upregulation of intrarenal angiotensin II and induction of oxidative stress. Antioxidants (Basel) 2020;10:E2.
Laurent S. Antihypertensive drugs. Pharmacol Res 2017;124:116-25.
Anwar MA, Samaha AA, Ballan S, Saleh AI, Iratni R, Eid AH. Salvia fruticosa
induces vasorelaxation in rat isolated thoracic aorta: Role of the PI3K/Akt/eNOS/NO/cGMP signaling pathway. Sci Rep 2017;7:686.
Anwar MA, Samaha AA, Baydoun S, Iratni R, Eid AH. Rhus coriaria
L. (Sumac) evokes endothelium-dependent vasorelaxation of rat aorta: Involvement of the cAMP and cGMP pathways. Front Pharmacol 2018;9:688.
Li W, Li Y, Zhao Y, Ren L. The protective effects of aloperine against ox-LDL-induced endothelial dysfunction and inflammation in HUVECs. Artif Cells Nanomed Biotechnol 2020;48:107-15.
Xu YQ, Jin SJ, Liu N, Li YX, Zheng J, Ma L, et al.
Aloperine attenuated neuropathic pain induced by chronic constriction injury via anti-oxidation activity and suppression of the nuclear factor kappa B pathway. Biochem Biophys Res Commun 2014;451:568-73.
Ling Z, Guan H, You Z, Wang C, Hu L, Zhang L, et al.
Aloperine executes antitumor effects through the induction of apoptosis and cell cycle arrest in prostate cancer in vitro
and in vivo
. Onco Targets Ther 2018;11:2735-43.
Rui C, Yuxiang L, Ning J, Ningtian M, Qingluan Z, Yinju H, et al.
Anti-apoptotic and neuroprotective effects of oxysophoridine on cerebral ischemia both in vivo
and in vitro
. Planta Med 2013;79:916-23.
Fu J, Wang Y, Zhang J, Wu W, Chen X, Yang Y. Anti-inflammatory and anti-apoptotic effects of oxysophoridine on lipopolysaccharide-induced acute lung injury in mice. Am J Transl Res 2015;7:2672-82.
Wang TF, Lei Z, Li YX, Wang YS, Wang J, Wang SJ, et al.
Oxysophoridine protects against focal cerebral ischemic injury by inhibiting oxidative stress and apoptosis in mice. Neurochem Res 2013;38:2408-17.
Yang C, Yu Y, Wu F, Wu Y, Feng J, Yan L, et al.
Vasodilatory effects of aloperine in rat aorta and its possible mechanisms. Chin J Physiol 2018;61:293-301.
Sun X, Yang Y, Liu T, Huang H, Kuang Y, Chen L. Evaluation of the wound healing potential of Sophora alopecuroides
in SD rat's skin. J Ethnopharmacol 2021;273:113998.
Hu ST, Shen YF, Gong JM, Yang YJ. Effect of sophoridine on Ca2+
release during heart failure. Physiol Res 2016;65:43-52.
Phan TX, Ton HT, Gulyás H, Pórszász R, Tóth A, Russo R, et al.
TRPV1 expressed throughout the arterial circulation regulates vasoconstriction and blood pressure. J Physiol 2020;598:5639-59.
Zhou T, Wang Z, Guo M, Zhang K, Geng L, Mao A, et al.
Puerarin induces mouse mesenteric vasodilation and ameliorates hypertension involving endothelial TRPV4 channels. Food Funct 2020;11:10137-48.
Zhang DM, Lin SM, Lau CW, Yiu A, Wang J, Li Y, et al.
Anemoside A3-induced relaxation in rat renal arteries: Role of endothelium and Ca2+
channel inhibition. Planta Med 2010;76:1814-9.
Jing Y, Chen R, Dong M, Liu Y, Hou X, Guo P, et al.
Apigenin relaxes rat intrarenal arteries, depresses Ca2+
currents and augments voltage-dependent K+
currents of the arterial smooth muscle cells. Biomed Pharmacother 2019;115:108926.
Tew WY, Tan CS, Asmawi MZ, Yam MF. Underlying mechanism of vasorelaxant effect exerted by 3,5,7,2',4'-pentahydroxyflavone in rats aortic ring. Eur J Pharmacol 2020;880:173123.
Katakia YT, Duddu S, Nithya S, Kumar P, Rahman F, Kumaramanickavel G, et al. Ex vivo
model for studying endothelial tip cells: Revisiting the classical aortic-ring assay. Microvasc Res 2020;128:103939.
Zhang F, Mi Y, Qi JL, Li JW, Si M, Guan BC, et al.
Modulation of K(v) 7 potassium channels by a novel opener pyrazolo[1,5-a] pyrimidin-7 (4H)-one compound QO-58. Br J Pharmacol 2013;168:1030-42.
Ye Y, Gao M, Feng L, Feng B, Ma X. Isoliquiritigenin-induced vasodilation by activating large-conductance Ca2+
channels in mouse mesenteric arteries. Clin Exp Pharmacol Physiol 2019;46:1044-52.
Baretella O, Chung SK, Xu A, Vanhoutte PM. Endothelial overexpression of endothelin-1 modulates aortic, carotid, iliac and renal arterial responses in obese mice. Acta Pharmacol Sin 2017;38:498-512.
Mulvany MJ. Resistance vessel growth and remodelling: Cause or consequence in cardiovascular disease. J Hum Hypertens 1995;9:479-85.
Mulvany MJ. Remodeling of resistance vessel structure in essential hypertension. Curr Opin Nephrol Hypertens 1993;2:77-81.
Delong C, Sharma S. Physiology, Peripheral Vascular Resistance. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2021.
Baumbach GL, Heistad DD. Remodeling of cerebral arterioles in chronic hypertension. Hypertension 1989;13:968-72.
Houghton JL, Davison CA, Kuhner PA, Torossov MT, Strogatz DS, Carr AA. Heterogeneous vasomotor responses of coronary conduit and resistance vessels in hypertension. J Am Coll Cardiol 1998;31:374-82.
Razali N, Dewa A, Asmawi MZ, Mohamed N, Manshor NM. Mechanisms underlying the vascular relaxation activities of Zingiber officinale
var. rubrum in thoracic aorta of spontaneously hypertensive rats. J Integr Med 2020;18:46-58.
Cechinel-Zanchett CC, da Silva RC, Tenfen A, Siebert DA, Micke G, Vitali L, et al. Bauhinia forficata
link, a Brazilian medicinal plant traditionally used to treat cardiovascular disorders, exerts endothelium-dependent and independent vasorelaxation in thoracic aorta of normotensive and hypertensive rats. J Ethnopharmacol 2019;243:112118.
Ginoza M, Fernandes GA, Corrêa MF, Fernandes JP. Novel potent vasodilating agents: Evaluation of the activity and potency of LINS01005 and derivatives in rat aorta. Eur J Pharm Sci 2020;143:105171.
Webb RC. Smooth muscle contraction and relaxation. Adv Physiol Educ 2003;27:201-6.
Kim B, Lee K, Chinannai KS, Ham I, Bu Y, Kim H, et al.
Endothelium-independent vasorelaxant effect of Ligusticum
jeholense root and rhizoma on rat thoracic aorta. Molecules 2015;20:10721-33.
Hussain MB, Marshall I. Characterization of alpha1-adrenoceptor subtypes mediating contractions to phenylephrine in rat thoracic aorta, mesenteric artery and pulmonary artery. Br J Pharmacol 1997;122:849-58.
Kim B, Kim KW, Lee S, Jo C, Lee K, Ham I, et al.
Endothelium-dependent vasorelaxant effect of Prunus Persica
branch on isolated rat thoracic aorta. Nutrients 2019;11:1816.
Quayle JM, Standen NB. KATP channels in vascular smooth muscle. Cardiovasc Res 1994;28:797-804.
Tennant BP, Cui Y, Tinker A, Clapp LH. Functional expression of inward rectifier potassium channels in cultured human pulmonary smooth muscle cells: Evidence for a major role of Kir2.4 subunits. J Membr Biol 2006;213:19-29.
Lasch M, Caballero Martinez A, Kumaraswami K, Ishikawa-Ankerhold H, Meister S, Deindl E. Contribution of the potassium channels KV
1.3 and KCa
3.1 to smooth muscle cell proliferation in growing collateral arteries. Cells 2020;9:913.
Cidad P, Jiménez-Pérez L, García-Arribas D, Miguel-Velado E, Tajada S, Ruiz-McDavitt C, et al.
Kv1.3 channels can modulate cell proliferation during phenotypic switch by an ion-flux independent mechanism. Arterioscler Thromb Vasc Biol 2012;32:1299-307.
Liu Y, Yin HL, Li C, Jiang F, Zhang SJ, Zhang XR, et al.
Sinapine thiocyanate ameliorates vascular endothelial dysfunction in hypertension by inhibiting activation of the NLRP3 inflammasome. Front Pharmacol 2020;11:620159.
Konukoglu D, Uzun H. Endothelial dysfunction and hypertension. Adv Exp Med Biol 2017;956:511-40.
Rosenthal JL, Jacob MS. Biomarkers in pulmonary arterial hypertension. Curr Heart Fail Rep 2014;11:477-84.
Guignabert C, Tu L, Girerd B, Ricard N, Huertas A, Montani D, et al.
New molecular targets of pulmonary vascular remodeling in pulmonary arterial hypertension: Importance of endothelial communication. Chest 2015;147:529-37.
Schmidt HH, Lohmann SM, Walter U. The nitric oxide and cGMP signal transduction system: Regulation and mechanism of action. Biochim Biophys Acta 1993;1178:153-75.
Lincoln TM, Cornwell TL. Intracellular cyclic GMP receptor proteins. FASEB J 1993;7:328-38.
Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochem J 1994;298:249-58.
Geraci MW, Gao B, Shepherd DC, Moore MD, Westcott JY, Fagan KA, et al.
Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J Clin Invest 1999;103:1509-15.
Clapp LH, Finney P, Turcato S, Tran S, Rubin LJ, Tinker A. Differential effects of stable prostacyclin analogs on smooth muscle proliferation and cyclic AMP generation in human pulmonary artery. Am J Respir Cell Mol Biol 2002;26:194-201.
Midgett C, Stitham J, Martin K, Hwa J. Prostacyclin receptor regulation – From transcription to trafficking. Curr Mol Med 2011;11:517-28.
Reid HM, Kinsella BT. Prostacyclin receptors: Transcriptional regulation and novel signalling mechanisms. Prostaglandins Other Lipid Mediat 2015;121:70-82.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]