{"id":57216,"date":"2024-03-20T10:26:55","date_gmt":"2024-03-20T10:26:55","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=57216"},"modified":"2024-04-02T04:24:48","modified_gmt":"2024-04-02T04:24:48","slug":"the-protective-effect-of-indole-alkaloid-vincanine-against-hypoxia-induced-vasorelaxation-model-of-rat-aorta","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no1\/the-protective-effect-of-indole-alkaloid-vincanine-against-hypoxia-induced-vasorelaxation-model-of-rat-aorta\/","title":{"rendered":"The Protective Effect of Indole Alkaloid Vincanine Against Hypoxia-Induced Vasorelaxation Model of Rat Aorta"},"content":{"rendered":"\n

Introduction <\/strong><\/p>\n\n\n\n

The world’s top cause of death is still cardiovascular diseases (CVD),\nwith hypertension being the main factor contributing to this high death rate.1<\/sup>\nApproximately one-third of annual worldwide deaths can be attributed to CVD2<\/sup>.\nMoreover, elevated blood pressure, or hypertension, is closely associated with\nat least half or more of cases involving ischemic stroke, hemorrhagic stroke,\nischemic heart disease, cardiomyopathy, aortic aneurysms, and peripheral\nvascular disease3<\/sup>. Unfortunately, this burden is increasing, despite\nthe advancements in therapeutic treatments, particularly for elderly\nindividuals4,5,6<\/sup>.<\/p>\n\n\n\n

Accordingly, one of the most pressing issues facing contemporary\nmedicine is the creation of fresh strategies for the effective treatment of\narterial hypertension that are based on the most recent developments in\nmolecular pharmacology. In addition, knowledge regarding the pharmacological\ncharacteristics of blood vessel-specific targets is especially crucial as they\nhave a direct bearing on the aetiology of arterial hypertension. A specific\nfocus is on clarifying the mechanisms governing the modulation of smooth muscle\nCa2+<\/sup> transporting systems, as their failure results in the emergence\nof pathogenic processes inside blood vessels. Disturbances in the contractile\nactivity of SMC-which is controlled by the intracellular Ca2+<\/sup> ion\nlevel upheld by the sarcoplasmic reticulum (SR) and plasmalemma-play a pivotal\nrole in this instance(Jackson, 2000). It is well known that abnormalities in\nthe contractile activity of SMCs associated with arterial hypertension are\ndirectly linked to their Ca2+<\/sup> transport system malfunction7<\/sup>.\nSimultaneously, particular focus is placed on naturally occurring biologically\nactive chemicals derived from plants. These compounds exhibit a broad spectrum\nof pharmacological effects and specifically interact with different kinds of\nion channels.<\/p>\n\n\n\n

The study focused on Vinca erecta Regel & Schmalh,\na plant primarily found in Central Asia’s mountainous region of Uzbekistan.\nThrough analyzing the roots and aerial parts of Vinca erecta, it was discovered\nthat the plant contains a high concentration of indole alkaloids. These\nspecific alkaloids, known as Vinca erecta, have gained significant recognition\nin the medical field for their effectiveness in treating cancer, malaria, and\ncardiac arrhythmia8<\/sup>. Researchers have recently explored the\nmodification of these alkaloids to generate new bioactive compounds. One\nparticularly promising compound is norfluorocurarine (vincanine), which was\nextracted from Vinca erecta. By synthesizing new quaternary halide derivatives\nof vincanine, researchers have expanded the scope of organic synthesis\npossibilities. Additionally, it is important to note that the quaternary base\nof norfluorocurarine, fluorocurarine, and its natural derivatives exhibit\nzwitterionic properties of various natures9<\/sup>. Recently we found that\nvincanine effectively protects rat aorta against hypoxia- induced\nvasorelaxation. In the present study, we aim to explore the mechanism by which\nvincanine protects rat aorta against hypoxia-induced vasorelaxation. This\nshould help to gain novel insight into the mechanisms involved in the\ncardioprotective effect of vincanine10<\/sup>.<\/p>\n\n\n\n

Materials\nand Methods<\/strong><\/p>\n\n\n\n

Chemicals <\/strong><\/p>\n\n\n\n

All chemicals were of analytical\ngrade commercially available. Phenylephrine, L-NAME, methylene blue,\nindomethacin, glibenclamide, TEA and, BaCl2<\/sub> were obtained from Sigma\nLtd Co., (St. Louis, MO, USA). Vincanine hydrochloride has been isolated as a\nVincanine from the roots of Vinca erecta (fam. Apocynaceae) at the Institute of\nthe Chemistry of Plant Substances of Academy of Sciences of Uzbekistan and was\nkindly provided by Shahobiddin Adizov.<\/strong><\/p>\n\n\n\n

Tissue Preparation<\/strong><\/p>\n\n\n\n

Our\ninstitution’s animal use committee authorized all experimental procedures and\npreoperative care guidelines. After being given sodium pentobarbital\nanesthesia, adult male Wistar rats weighing 200\u2013250 g had their thorax opened,\nthe thoracic aorta was swiftly removed, and the rats were then placed in Krebs\nsolution, which contained the following concentrations of salt (in mmol\/l): 118\nmM NaCl, 5 mM KCl, 25 mM NaHCO3<\/sub>, 1.2 mM MgSO4<\/sub>, 2 mM CaCl2<\/sub>,\n1.2 mM KH2<\/sub>PO4<\/sub>, and 11 mM glucose. The endothelium was\nhandled extremely carefully during the entire dissection process to prevent\naccidental injury. After being cleared of fat and connective tissue, the aorta\nwas divided into rings that measured 2-3 mm in length1<\/sup>1<\/sup>.<\/p>\n\n\n\n

Aortic-ring contraction studies<\/strong><\/p>\n\n\n\n

Two stainless hooks were used to mount the aortic\nrings; one was fastened to the organ bath’s bottom (Radnoti Glass, NSW, AUS),\nand the other was attached to a force transducer. Krebs solution was superfused\ninto the organ bath, which was kept at 37 oC and bubbled with a gas mixture\nconsisting of 95% O2<\/sub> and 5% \u0421\u041e2<\/sub>.\nFor 60 minutes, the Krebs solution was changed at least twice while the aortic\nrings were equilibrated in the solution with a tension of 1 g. A force\ntransducer (FT-03; Grass Instrument Company, USA) attached to a computer-based\ndata acquisition system (PowerLab, ADInstruments) connected to a chart recorder\nEndim 621-02 (Germany) was used to record the aortic ring contraction\nisometrically.<\/p>\n\n\n\n

Experimental Protocols<\/strong><\/p>\n\n\n\n

The effect of vincamine on hypoxia-induced\nvasorelaxation was assessed using aortic rings incubated in a glucose-free\nKrebs solution with a constant supply of 95% N2 <\/sub>\/ 5% CO2<\/sub>. After a 60-minute period of hypoxia which is\ncommonly used in these studies, aortic rings were precontracted with 50 mm KCl or 1\u00b5M phenylephrine (PE). The\nreduction in force upon hypoxia was described as a percentage of the\ncontraction force caused by 50 mM KCl or 1\u00b5M PE just before aeration with 95% N2\n<\/sub>\/ 5% CO2<\/sub>. This maximum hypoxic vasorelaxation occurred at around\n60 minutes.<\/p>\n\n\n\n

To examine the involvement of the\nvoltage-gated Ca2+<\/sup>-channels (VGCCs) in the effect of vincanineon hypoxia-induced\nvasorelaxation its effects in the presence of\nverapamil (0.1-1\n\u00b5M), an L-type Ca2+<\/sup>–\nchannel inhibitor, were studied.<\/p>\n\n\n\n

The effects of vincanine on hypoxia-induced\nvasorelaxation were examined in relation to its role in Ca2+<\/sup> release\nfrom the sarcoplasmic reticulum (SR). Specifically, the effects were examined\nin relation to PE-induced contraction of endothelium-denuded aortic rings in Ca2+<\/sup>-free\nbuffer containing EGTA (1 mM). In the second series of experiments, the effects\nof vincanine on hypoxia-induced vasorelaxation and its effects on\ncaffeine-induced contraction were investigated in order to investigate the role\nof Ca2+<\/sup> release from the SR in these processes.<\/p>\n\n\n\n

Tetraethylammonium chloride (TEA), a nonspecific inhibitor of the\ncalcium-activated large conductance K+<\/sup> channel (BKCa<\/sub>),\nglibenclamide, a specific inhibitor of the ATP-sensitive K+<\/sup> channel\n(KATP<\/sub>), and BaCl2<\/sub>, a specific inhibitor of the inward\nrectifying K+<\/sup> channels (KIR<\/sub>), were studied in conjunction\nwith vincanine to assess the contribution of the K+<\/sup>-channels to the\neffect of the drug on hypoxia-induced vasorelaxation. Since the action of\nmedicines on K+<\/sup>-channels is more effective in endothelium-intact\naortic rings, these investigations were conducted on these rings after they had\nbeen precontracted with 30 mM KCl to depolarize the membrane and activate K+<\/sup>-channels12<\/sup>. <\/p>\n\n\n\n

After removing the endothelium from ring specimens by\nrubbing the intimal surface with a cotton ball, the absence of ACh-induced\nrelaxation was considered as evidence of successful denudation. This allowed\nresearchers to evaluate the involvement of the endothelium in the effect of\nvincanine on hypoxia-induced vasorelaxation. The effects of PE-induced\ncontraction of endothelium-intact aortic rings preincubated with L-NAME\n(nitro-L-arginine methyl ester, an inhibitor of NO synthase), methylene blue (a\nguanylyl cyclase inhibitor), and indomethacin (a cyclooxygenase inhibitor) were\ninvestigated in order to better understand the role of the endothelium in the\neffect of vincanine on hypoxia-induced vasorelaxation.<\/strong><\/p>\n\n\n\n

Statistics<\/strong><\/p>\n\n\n\n

This article uses the mean \u00b1 standard error of the\nmean (s.e.m.) of n observations to represent all data. To conduct statistical\nanalysis, an unpaired Student’s t-test was employed. The concentration-response\ncurve was used to get the EC50<\/sub> and IC50<\/sub> values, or the\ndrug concentrations that cause a 50% contraction or relaxation of the maximal\nresponse (EMax). The sigmoidal curve fitting method in Origin 7.0 (Microcal,\nNorthampton, MA, U.S.A.) was used to generate these values. When P < 0.05\nwas reached, the differences between the experimental and control values were\ndeemed significant.<\/p>\n\n\n\n

Results and\nDiscussion<\/strong><\/p>\n\n\n\n

Impact of vincanine on vasorelaxation produced by hypoxia<\/strong><\/em><\/p>\n\n\n\n

In control experiments, exposure of endothelium-intact aortic rings to\nKrebs solution gassed with 95% N2 <\/sub>\/\n5% CO2<\/sub> for 60 minutes significantly reduced contractile response to KCl\nor PE. As shown in Fig. 1, the response of aortic rings to KCl (50 mM) and\nPE (1\u00b5M) was decreased by 55.3\u00b14.1% and\n51.2\u00b14.4%, respectively, of the control response in\nnormoxia. These results show\nthat stimulated hypoxia-induced vasorelaxation which was more potent in aortic\nrings precontracted with PE than KCl indicating that the contractile\nresponse to PE is more sensitive to hypoxia than is that to KCl. It\nwas found that the pretreatment of the endothelium-intact aortic rings with vincanine\nsignificantly reduced the vasorelaxation induced by hypoxia in aortic\nrings precontracted both with KCl and PE Fig.1. As demonstrated in Fig. 1, A the vincanine maximally\ninhibited hypoxia-induced vasorelaxation in the aortic rings precontracted with\nKCl (50 mM) from 44.7\u00b14.1% to 17.4\u00b13.7% at the concentration of 15 \u00b5M.\nSimilarly, on the aortic rings precontracted with PE (1 \u00b5M) vincanine maximally\ninhibited hypoxia-induced vasorelaxation from 48.8\u00b14.4% to 11.5\u00b13.2% at the\nconcentration of 10 \u00b5M Fig. 1, B.<\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1<\/strong>: Effect of vincaine on endothelium-induced vasorelaxation generated by hypoxia:<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

These results show that the effect of vincanine on the vasorelaxation induced by hypoxia is more potent in aortic rings precontracted with PE than with KCl. It was reported that vasorelaxation induced by hypoxia is mainly due to a reduction [Ca2+<\/sup>]i<\/sub><\/em> in the smooth muscle cells resulting from the\ninhibition of Ca2+<\/sup> influx through VDCCs and calcium release\nfrom the SR via IP3<\/sub>Rs13,14<\/sup>.To\nexamine the involvement of the VDCCs in\nthe inhibitory effect of vincanine on hypoxia-induced vasorelaxation its effects in the\npresence of verapamil, an inhibitor of L-type Ca2+\n<\/sup>channels, were studied. In these studies, was found that in\naortic rings preincubated with verapamil (0.1 \u00b5M) and precontracted with KCl the inhibitory effect of\nvincanine on the vasorelaxation\ninduced by hypoxia reduced from 27.3\u00b13.7% to\n17.4\u00b13.7%\n<\/strong>Fig. 2. This result suggests that L-type\nVDCCs may be involved in the inhibitory effect of vincanine on\nhypoxia-induced vasorelaxation. <\/p>\n\n\n\n\n\n
\"\"<\/td>\nFigure 2:<\/strong> Influence of verapamil on the hypoxia-induced vasorelaxation in endothelium in intact rat aortic rings precontracted with KCl was observed. <\/strong>

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

Vincanine also inhibited the\nhypoxia-induced vasorelaxation in the aortic rings\nprecontracted with PE in the Ca2+<\/sup>-free buffer. In\nthese experimental conditions, PE-induced aortic ring contraction is mainly due\nto the release of Ca2+<\/sup> from SR through inositol\n1,4,5-trisphosphate receptors (IP3<\/sub>Rs)15<\/sup>. Findings displayed in Fig.\n3 demonstrate the impact of vincanine on the vasorelaxation induced by\nhypoxia in these conditions reduced from 24.8\u00b14.1% to 10.8\u00b14.2%.\nThese results indicate that the modulation of calcium release from the SRalso may be associated with the\ninhibitory effect of vincanine\non the vasorelaxation induced by hypoxia.<\/p>\n\n\n\n\n\n
\"\"<\/td>\nFigure 3:<\/strong> Effect of vincanine on endothelium-induced vasorelaxation in Ca2+<\/sup>-free Krebs solution with intact rat aortic rings precontracted by phenylephrine. <\/strong>

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

This suggestion was confirmed in experiments that examined the effect of\nvincanine on caffeine-induced contraction in a Ca2+<\/sup>-free buffer which is mediated by Ca2+<\/sup> released from the SR by\nthe mechanism of Ca2+<\/sup>-induced Ca2+<\/sup>-release\n(CICR)16,17,18<\/sup>. According to these studies, vincanine decreased the\nvasorelaxation brought on by hypoxia in intact aortic rings precontracted with\ncaffeine (10 mM) in the Ca2+<\/sup>-free buffer from 12.8\u00b13.2% to 7.8\u00b14.3%.\nFig. 4. All of these findings point to the possibility that the modulation of\nL-type VDCC and the Ca2+-<\/sup>induced Ca2+<\/sup>-release pathway may\nbe the mechanism by which vincanine inhibits hypoxia-induced vasorelaxation.<\/p>\n\n\n\n\n\n
\"\"<\/td>\nFigure 4:<\/strong> Effect of the vincanine on the hypoxia – induced vasorelaxation in endothelium – intact rat aortic rings precontracted with caffeine in Ca2+<\/sup>-free Krebs solution. <\/strong>

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The involvement of the K+<\/sup> – channels in the inhibitory effect of vincanine on hypoxia-induced vasorelaxation<\/strong><\/p>\n\n\n\n

Numerous studies have demonstrated that the mechanism underlying vasorelaxant response to hypoxia may\ninvolve the activation of various types of K+<\/sup>-channels, resulting in\nvascular hyperpolarization and relaxation. In particular,\nit was reported that the inward rectifier K+<\/sup>-channels\n(KIR <\/sub>2.1) which modulate basal tone in small-diameter coronary and\ncerebral arteries participated in their hypoxic vasorelaxation19<\/sup>.\nAlso was shown that voltage-gated K+<\/sup>-channels (KV <\/sub>7)\nwhich control the tone of pulmonary and cerebral arteries may also be involved\nin hypoxic vasorelaxation20<\/sup>. Furthermore, it has been proposed that\nhypoxia may partially cause vasorelaxation by directly activating ATP-sensitive\nK+<\/sup>-channels (KATP<\/sub>)21<\/sup>. KATP<\/sub>-channels\nare essential for vasodilation in response to metabolic demand and for\nmaintaining resting blood flow in a number of vascular beds, most notably the\ncoronary circulation22<\/sup>.<\/p>\n\n\n\n

Thus, we investigate in this work if various K+<\/sup>-channel types\nare involved in the (inhibitory) action of vincamine on hypoxia-induced\nvasorelaxation. For this purpose, the inhibitory\neffect of vincamine on hypoxia-induced vasorelaxation was studied in the presence of specific inhibitors of KATP<\/sub>,\nBKCa <\/sub>and KIR<\/sub>-channels,\nglibenclamide (GLI), TEA, and BaCl2<\/sub>,\nrespectively. These studies were performed in the aortic rings\nprecontracted with 30 mM KCl since in this\ncondition effect of drugs on K+<\/sup>\nchannels is more potent23<\/sup>. As shown in Fig. 5 in the intact aortic\nring preincubated with glibenclamide (50 \u03bcM) and precontracted with KCl (30 mM) the inhibitory effect of vincanine on hypoxia-induced vasorelaxation reduced from 27.2\u00b14.1% to 15.1\u00b14.2%.\nSimilarly, in the presence of TEA (10 mM) the inhibitory effect of vincanine on\nhypoxia-induced vasorelaxation was reduced from 26.6\u00b13.6%\nto 9.1\u00b13.6%.By contrast, in the\npresence ofBaCl2 <\/sub>(100 \u03bcM), the effect of vincanine on hypoxia-induced\nvasorelaxation reduced not significantly (Fig. 5). These results demonstrate that preincubation\nof aortic rings with glibenclamide\nsignificantly abolished the effect of vincanine on hypoxia-induced\nvasorelaxation suggesting that KATP <\/sub>-channels could be\ninvolved in this effect. <\/p>\n\n\n\n\n\n
\"\"<\/td>\nFigure 5:<\/strong> Effect of K+<\/sup> channel blockers on hypoxia-induced vasorelaxation in intact aortic rings when vincanine is present. <\/strong>

<\/p>\n

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The involvement of the endothelium in the inhibitory effect of vincanine on hypoxia-induced vasorelaxation<\/strong><\/p>\n\n\n\n

It was shown that a critical role\nin hypoxia-induced vasorelaxation plays changes in the\nmechanisms of endothelium-dependent contraction and relaxation mediated by several vasoactive factors24,25<\/sup>. Vasoconstrictors like thromboxane (TXA2<\/sub>) and endothelin-1\n(ET-1)26<\/sup>, or vasodilators like nitric oxide (NO), prostacyclin (PGI2<\/sub>),\nand endothelium-derived hyperpolarizing factor (EDHF), are the most significant\namong them. Thus, the aortic rings with endothelium removed were used to assess\nthe impact of vincanine on hypoxia-induced vasorelaxation in order to examine\nthe participation of endothelium. The vasorelaxation caused by hypoxia in\naortic rings precontracted with KCl (50 mM) and PE (1 \u00b5M) increased by 5.7\u00b12.4%\nand 9.1\u00b13.7%, respectively, when the endothelium was removed by rubbing the\nintimal surface with a cotton ball (Fig. 6). These findings demonstrate that in\naortic rings precontracted by PE, the ablation of the endothelium more\ndramatically increases the vasorelaxation brought on by hypoxia.<\/p>\n\n\n\n

In similar experiments in\nthe endothelium-denuded aortic rings\nprecontracted with KCl (50 mM) and PE (1 \u00b5M) the effect of vincanine on hypoxia-induced\nvsorelaxation reduced from 27.2\u00b13.7% to 9.2\u00b13.6%\nand from 37.3\u00b13.2% to 13.2\u00b13.9%,\nrespectively Fig. 6. These results indicate that removal of endothelium\nsignificantly reduced the effect of vincanine on\nhypoxia-induced vasorelaxation suggesting that\nthis effect of vincanine is endothelium-dependent.<\/p>\n\n\n\n\n\n
\"\"<\/td>\nFigure 6:<\/strong> Effect of vincanine on hypoxia-induced vasorelaxation in the endothelium – aortic rings precontracted with KCl (A) and phenylephrine (B), both intact and endothelium denuded. <\/strong>

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The\neffect of vincanine on endothelium-intact aortic rings preincubated with NOS\ninhibitors (L-NAME), guanylate cyclase-methylene blue, and\ncyclooxygenase-indomethacin was investigated in order to shed more light on the\nendothelium’s role in hypoxia-induced vasorelaxation. As shown in Fig. 7,A in the intact\naortic ring preincubated with L-NAME (100\n\u00b5M) and methylene blue (10 \u00b5M)\nand precontracted\nwith KCl (50 mM) the inhibitory effect\nof vincanine on hypoxia-induced vasorelaxation reduced from 27.3\u00b13.7% to 19.2\u00b13.6% and from 27.3\u00b13.7% to 22.4\u00b14.2%, respectively.At these time in intact aortic ring preincubated with L-NAME (100 \u00b5M) and methylene blue (10\n\u00b5M) and precontracted with PE (1 \u00b5M) the\ninhibitory effect of vincanine on\nhypoxia-induced vasorelaxation was reduced from 37.3\u00b13.2%\nto 25.4\u00b14.1% and from 37.3\u00b13.2% to 30.2\u00b13.9% arespectively Fig. 7, B. In contrast preincubation of the\nintact aortic ring with indomethacine, a\ncyclooxygenase inhibitor, not\nsignificantly inhibited the effect\nof vincanine on hypoxia-induced vasorelaxation Fig.7. These results demonstrate that L-NAME\nand methylene blue significantly reduced the\neffect of vincamine on hypoxia-induced vasorelaxation suggesting that this effect of vincanine is endothelium-dependent and likely is\nassociated with modulation\nof NO\/sGC\/cGMP\/PKG pathway.<\/p>\n\n\n\n\n\n
\"\"<\/td>\nFigure 7: Effect of vincanine on hypoxia – induced vasorelaxation in the endothelium – intact aortic rings preincubated with L- NAME, methylene blue, and indomethacin  and precontracted with KCl (A) and phenylephrine (B). <\/strong>

<\/p>\n

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Conclusion<\/strong><\/p>\n\n\n\n

According to the current research, the hypoxia-induced vasorelaxation in the rat aorta was greatly reduced by the alkaloid vincanine that was extracted from Vinca minor H. leaves. Vincanine may shield the rat aorta from hypoxic damage to the vasculature, according to the acquired results. This endothelium-dependent protective effect of vincanine is probably achieved by suppression of L-type VDCC and Ca2+<\/sup> release from SR in addition to modifying the NO\/sGC\/cGMP\/PKG pathway. New therapeutic approaches for the prevention and treatment of a variety of cardiovascular disorders linked to ischemia\/hypoxia may result from further research into the processes behind vincanine’s protective action.<\/p>\n\n\n\n

Acknowledgement<\/strong><\/p>\n\n\n\n

This work was\nsupported by the Science and Technology Development Coordination Committee.<\/p>\n\n\n\n

Conflict of interest <\/strong><\/p>\n\n\n\n

The authors have declared that no conflict of interest exists.<\/p>\n\n\n\n

Funding source<\/strong> <\/p>\n\n\n\n

This work was financed by the grant F-OT-2021-154 of the Science and Technology Development Coordination Committee under the Cabinet of Ministers of the Republic of Uzbekistan. <\/p>\n\n\n\n

Ethics approval<\/strong><\/p>\n\n\n\n

The experimental protocols complied with the standards and requirements for\nthe humane treatment of animals and the provisions of the Ethical Commission of\nthe IBB at the National University of Uzbekistan. (Protocol No. 7 of\n04\/07\/2022) on the use of laboratory animals. Preparations of isolated aortic\nsegments were obtained using a known method.<\/p>\n\n\n\n

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