SOLUBLE GUANYLYL CYCLASE ACTIVATOR BAY 41-2272 IMPROVES VASCULAR ACTIVITY OF THORACIC AORTA ISOLATED FROM DOCA HYPERTENSIVE MALE WISTAR RATS (original) (raw)
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BAY 41-2272 Treatment Improves Acetylcholine-Induced Aortic Relaxation in L-NAME Hypertensive Rats
International Journal of Angiology, 2016
Hypertension is one of the most common emerging chronic diseases of developed and developing countries. There is a correlation between hypertension and cardiovascular diseases. Delayed in treatment proceed to stroke, congestive heart failure, chronic kidney disease, and premature death. 1,2 Several pathophysiological factors are participating in pathogenesis of hypertension. 3 Nitric oxide (NO) is a signaling molecule of biological system and produces vascular relaxation through Keywords ► hypertension ► L-NAME ► mean arterial pressure ► BAY 41-2272 ► thoracic aorta ► improves acetylcholine relaxation ► Wistar rats
General Pharmacology: The Vascular System, 2000
The contribution of endothelial factors and mechanisms underlying decreased acetylcholine-induced relaxation and endothelial inhibitory action on phenylephrine-induced contraction were evaluated in aortas of two-kidney, one-clip hypertensive (2K-1C) and normotensive (2K) rats. Relaxation induced by acetylcholine in 2K-1C precontracted by phenylephrine was lower [Maximum Effect (ME): 71.33 ± 3.36%; pD 2 : 7.050 ± 0.03] than in 2K (ME: 95.26 ± 1.59%; pD 2 : 7.31 ± 0.07). This response was abolished by N G-nitro-L-arginine (L-NNA) in 2K-1C, but was only reduced in 2K (ME: 29.21 ± 9.28%). Indomethacin had no effect in 2K-1C, and slightly attenuated acetylcholine-induced relaxation in 2K. The combination of L-NNA and indomethacin almost abolished acetylcholine-induced relaxation in 2K-1C, while in 2K, the inhibition (ME: 56.61 ± 8.95%) was lower than the effect of L-NNA alone. During the KCl-induced precontraction, 2K and 2K-1C aortas showed similar acetylcholine-induced relaxation (43.50 ± 5.64% vs. 41.60 ± 4.36%), which was abolished by L-NNA. The levels of cGMP produced in response to acetylcholine were not different between 2K and 2K-1C. The sensitivity to sodium nitroprusside was lower in phenylephrine-precontracted aortas from 2K-1C than 2K, as showed by the pD 2 values (7.72 ± 0.20 vs. 8.59 ± 0.17), and this difference was abolished in aortas precontracted by KCl. The membrane potential was less negative in 2K-1C than in 2K (À 41.57 ± 1.19 vs. À 51.00 ± 1.13 mV) and hyperpolarization induced by acetylcholine was lower in 2K-1C than in 2K aortas (6.00 ± 0.66 vs. 13.27 ± 1.61 mV). Phenylephrineinduced contraction in aortas with endothelium was similar in both groups, and increased by the endothelium removal. This increase was lower in 2K-1C (from 1.32 ± 0.06 to 1.90 ± 0.21 g) than 2K (from 1.49 ± 0.07 to 2.83 ± 0.18 g). L-NNA and the endothelium removal had similar effect in 2K-1C (1.85 ± 0.18 g) and were lower in 2K (2.18 ± 0.20 g). Indomethacin decreased phenylephrine-induced contraction only in 2K. In conclusion, our major finding was a selective defect in smooth muscle membrane hyperpolarization, which could explain the decreased relaxation to acetylcholine and the attenuated inhibitory effect of endothelium on the contractile function in 2K-1C aortas.
European journal of …, 2010
The present study was designed to investigate the contribution of endothelial cell caveolae to vascular relaxation in aortas from a normotensive (2K) and renal hypertensive (2K-1C) rat. For that purpose, concentration-effect curves to acetylcholine were constructed in 2K and 2K-1C intact endothelium aortic rings, in the absence or in the presence of the caveolae disassembler methyl-β-ciclodextrin. The potency (pD 2 ) and the maximum relaxant effect to acetylcholine were greater in 2K than in 2K-1C aortas. Methyl-β-ciclodextrin reduced the pD 2 in 2K and the maximum relaxant effect in both 2K and 2K-1C. The quantification of the caveolae number by electronic microscopy has shown a larger number of caveolae in 2K than in 2K-1C endothelial cells, which was reduced by methyl-β-ciclodextrin in both 2K and 2K-1C. The production of NO stimulated with acetylcholine was greater in 2K than in 2K-1C endothelial cells, and this effect was impaired by methyl-β-ciclodextrin in both 2K and 2K-1C. The cytosolic Ca 2+ concentration ([Ca 2+ ]c) was simultaneously measured in endothelial and smooth muscle cells stimulated with acetylcholine by confocal image of aortic slices. Acetylcholine produced a greater [Ca 2+ ]c increase in 2K than in 2K-1C endothelial cells, which response was inhibited by methyl-β-ciclodextrin only in 2K cells. In smooth muscle cells the reduction of [Ca 2+ ]c was higher in 2K than in 2K-1C. This effect was inhibited by methyl-β-ciclodextrin only in 2K cells. Taken together, our results suggest that the decreased number of caveolae in the endothelial cells from 2K-1C rat aortas is involved in the impaired effect of acetylcholine on [Ca 2+ ]c and NO.
American Journal of Hypertension, 2019
Background Acetylcholinesterase inhibition prevents autonomic imbalance, reduces inflammation, and attenuates the development of hypertension. Considering that vascular dysfunction is a crucial feature of arterial hypertension, we investigated the effects of chronic administration of acetylcholinesterase inhibitors—pyridostigmine or donepezil—on vascular reactivity of spontaneously hypertensive rats (SHR). Methods Endothelium-dependent relaxant responses to acetylcholine (ACh) and contractile responses induced by electric field stimulation (EFS) and alpha-adrenergic agonist were studied in mesenteric resistance arteries from SHR and Wistar Kyoto rats. SHR were treated for 16 weeks with vehicle, pyridostigmine (1.5 mg/kg/day) or donepezil (1.4 mg/kg/day). Results Pyridostigmine and donepezil decreased the vasoconstrictor responses to EFS, which were increased in vehicle-treated SHR. Acetylcholinesterase inhibition increased the modulatory effects of nitric oxide (NO) on SHR vascular ...
Journal of Ethnopharmacology, 2011
Ethnopharmacological relevance The fruits of Cocos nucifera Linn. (Arecaceae) have long been used in traditional medicine for the treatment of cardio-metabolic disorders. Aim of the study To evaluate the ethanolic extract of Cocos nucifera Linn. endocarp (CNE) for its vasorelaxant activity on isolated rat aortic rings and antihypertensive effects in deoxycorticosterone acetate (DOCA) salt-induced hypertensive rats. Materials and methods Cocos nucifera Linn. endocarp was extracted with ethanol and characterized by HPLC. CNE was examined for its in vitro vascular relaxant effects in isolated norepinephrine, phenylephrine or potassium chloride pre-contracted aortic rings (both intact endothelium and denuded). In vivo anti-hypertensive studies were conducted in DOCA salt-induced uninephrectomized male Wistar rats. Results Removal of endothelium or pretreatment of aortic rings (intact endothelium) with l-NNA (10 μM) or ODQ (10 μM) followed by addition of contractile agonists prior to CNE significantly blocked the CNE-induced relaxation. Indomethacin (10 μM) and atropine (1 μM) partially blocked the relaxation, whereas glibenclamide (10 μM) did not alter it. CNE significantly reduced the mean systolic blood pressure in DOCA salt-induced hypertensive rats (from 185.3 ± 4.7 mmHg to 145.6 ± 6.1 mmHg). The activities observed were supported by the polyphenols, viz. chlorogenic acid, vanillic acid and ferulic acid identified in the extract. Conclusions These findings reveal that the vasorelaxant and antihypertensive effects of CNE, through nitric oxide production in a concentration and endothelium-dependent manner, is due to direct activation of nitric oxide/guanylate cyclase pathway, stimulation of muscarinic receptors and/or via cyclooxygenase pathway.
Mechanisms of Relaxation Induced by Flavonoid Ayanin In Isolated Aorta Rings From Wistar Rats
Colomb. …, 2010
Introduction: This study shows the relaxant effect induced by ayanin in aorta rings from Wistar rats linked to nitric oxide/ cyclic-GMP pathway. This flavonoid is the prevalent compound obtained from Croton schiedeanus Schlecht (Euphorbiaceae), specie used in Colombian folk medicine for the treatment of arterial hypertension. Objectives: To identify possible action mechanisms of vascular relaxation induced by ayanin (quercetin 3,4',7-trimethyl ether). Methodology: Isolated aorta rings from Wistar rats obtained at the Animal House of the University of Salamanca were contracted with KCl (80 mM) or phenylephrine (PE, 10-6 M) and exposed to ayanin (10-6-10-4 M). Then, the effect of ayanin was assessed in deendothelized rings contracted with PE and in intact rings contracted with PE previously incubated with: ODQ (10-6 M), L-NAME (10-4 M), L-NAME plus D-and L-arginine (10-4 M), indomethacin (5x10-6 M), dipyridamole (3x10-7 M), glibenclamide (10-6 M), propranolol (10-6 M), verapamil (10-7 M) or atropine (3x10-5 M). In addition, the relaxant effect of acetylcholine (Ach, 10-8-3x10-4 M), and sodium nitroprusside (SNP, 10-9-3x10-5 M) was assessed in the presence and absence of ayanin (10-6 M). Results: Ayanin induced a greater concentration-dependent relaxation in vessels contracted with phenylephrine (pEC 50 : 5.84±0.05), an effect significantly reduced by deendothelization and by both ODQ and L-NAME. L-arginine was able to reverse the effect of L-NAME. Indomethacin weakly inhibited ayanin response. Dipyridamole, glibenclamide, propranolol, verapamil, and atropine did not affect ayanin relaxation. Ayanin did not have any effect on the relaxation elicited by acetylcholine (ACh), while weakly decreasing the relaxation induced by sodium nitroprusside (SNP). Conclusion: Ayanin induces endothelium-dependent relaxation in the rat aorta mainly related to nitric oxide/cGMP pathway, according to the response observed in the presence of L-NAME, L-arginine and ODQ.
European Journal of Pharmacology, 1999
The contribution of tyrosine kinase activity to vasoreactivity in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats was investigated on isolated aortic preparations by the use of two tyrosine kinase inhibitors: methyl-2,5-dihydroxycinnamate (30 microM) and genistein (30 microM). The pretreatment of endothelium denuded aorta with methyl-2,5-dihydroxycinnamate reduced the sensitivity of the rings to noradrenaline to a larger extent in SHR than in WKY. The relaxing effects evoked by methyl-2,5-dihydroxycinnamate and genistein on the sustained contraction induced by endothelin-1 were also more pronounced in SHR denuded rings. Furthermore, in presence of methyl-2,5-dihydroxycinnamate, the endothelium-independent contractile responses to equipotent doses of cyclopiazonic acid were more depressed in SHR than in WKY. In WKY and SHR endothelium-intact aortas contracted with either phenylephrine or endothelin-1, carbachol and cyclopiazonic acid evoked endothelium derived relaxing factor (EDRF)/nitric oxide (NO)-dependent relaxations which were reduced by pretreatment of the rings with methyl-2,5-dihydroxycinnamate or genistein. These inhibitory effects were larger in WKY rings and more important on the cyclopiazonic acid response. In addition, sodium orthovanadate (30 microM) potentiated the noradrenaline-mediated contractions of endothelium-denuded SHR rings and reduced the cyclopiazonic acid-induced relaxation of endothelium-intact WKY rings. The present study suggests a regulatory role for tyrosine kinase in the smooth muscle contraction and the endothelium-dependent relaxation in WKY and SHR aortas and demonstrates the existence of a different relationship in the effect of tyrosine kinase inhibitors on vasoreactivity between SHR and WKY. We propose that an increase in the tyrosine kinase activity in SHR could lead to an enhanced reactivity of Ca2+-linked contractile mechanisms. In addition, our results suggest a link between the loss of tyrosine kinase activity and the altered endothelium-dependent relaxation associated with hypertension.