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Paul M Vanhoutte - One of the best experts on this subject based on the ideXlab platform.
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endothelial dysfunction the first step toward coronary arteriosclerosis
Circulation, 2009Co-Authors: Paul M VanhoutteAbstract:: The Endothelium causes relaxations of the underlying vascular smooth muscle, by releasing nitric oxide (NO). The endothelial cells also can evoke hyperpolarization of the vascular smooth muscle cells (Endothelium-dependent hyperpolarizations, Endothelium-derived hyperpolarizing factors-mediated responses). Endothelium-dependent relaxations involve both pertussis toxin-sensitive Gi and pertussis toxin-insensitive Gq coupling proteins. The endothelial release of NO is reduced in diabetes and hypertension. Arteries covered with regenerated Endothelium lose the pertussis-toxin sensitive pathway for NO-release. This dysfunction favors vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. Endothelial cells also release Endothelium-derived contracting factors (EDCF). Most Endothelium-dependent contractions are mediated by vasoconstrictor prostanoids (endoperoxides and prostacyclin), which activate thromboxane-prostanoid (TP)-receptors of the underlying vascular smooth muscle cells. EDCF-mediated responses are augmented by aging, hypertension and diabetes. Thus, endothelial dysfunction is the first step toward coronary arteriosclerosis.
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Endothelin-1 releases Endothelium-derived endoperoxides and thromboxane A2 in porcine coronary arteries with regenerated Endothelium.
Acta Pharmacologica Sinica, 1999Co-Authors: Seung-jung Park, John J. Lee, Paul M VanhoutteAbstract:AIM: To determine the role of Endothelium-derived contracting factor (EDCF) in the response to endothelin-1 in arteries with regenerated Endothelium. METHODS: Rings of porcine coronary arteries, with and without Endothelium of previously deendothelialized left anterior descending coronary arteries and native left circumflex coronary arteries, were suspended in conventional organ chambers for the measurement of isometric force. RESULTS: In quiescent rings of the previously deendothelialized left anterior descending coronary artery treated with the NO-synthase inhibitor nitro-L-arginine, endothelin-1 caused contractions which were larger in rings with than that in those without Endothelium. Under the same experimental conditions, in the left circumflex coronary artery, the contractions to endothelin-1 were augmented markedly by the removal of the Endothelium. In rings with Endothelium of the previously deendothelialized left anterior descending coronary artery, indometacin (inhibitor of cyclooxygenase) and ridogrel (thromboxane A2 receptor antagonist and inhibitor of thromboxane synthase) inhibited contractions to endothelin-1. Dazoxiben (inhibitor of thromboxane synthase) inhibited, to the same extent as indometacin and ridogel, the response to higher concentrations of endothelin-1. The Endothelium-dependent component of the response to lower concentrations of endothelin-1 was inhibited by indometacin and ridogrel, but not by dazoxiben. In rings without Endothelium of both previously deendothelialized left anterior descending and native left circumflex coronary arteries, indometacin and ridogrel did not affect the contractions to endothelin-1. CONCLUSION: These findings suggest that in regenerated Endothelium, high concentrations of endothelin-1 stimulate the release of thromboxane A2. Endoperoxides generated by activation of endothelial cyclooxygenase may be the Endothelium-derived contracting factor(s) released in regenerated Endothelium by lower concentrations of the peptide.
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Alteration of Endothelium-Dependent Hyperpolarizations in Porcine Coronary Arteries With Regenerated Endothelium
Circulation Research, 1999Co-Authors: Catherine Thollon, Paul M Vanhoutte, Jean P. Bidouard, Christine Cambarrat, Isabelle Delescluse, Nicole Villeneuve, Jean Paul VilaineAbstract:Abstract—The present study was designed to test the ability of regenerated Endothelium to evoke Endothelium-dependent hyperpolarizations. Hyperpolarizations induced by serotonin and bradykinin were compared in isolated porcine coronary arteries with native or regenerated Endothelium, 4 weeks after balloon endothelial denudation. The experiments were performed in the presence of inhibitors of nitric oxide synthase (Nω-nitro-l-arginine) and cyclooxygenase (indomethacin). The transmembrane potential was measured using conventional glass microelectrodes. Smooth muscle cells from coronary arteries with regenerated Endothelium were depolarized in comparison with control coronary arteries from the same hearts. Spontaneous membrane potential oscillations of small amplitude or spikes were observed in some of these arteries but never in arteries with native Endothelium. In coronary arteries from control pigs, both serotonin and bradykinin induced concentration-dependent hyperpolarizations. In the presence of ketans...
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Vascular Endothelium: Vasoactive mediators
Progress in Cardiovascular Diseases, 1996Co-Authors: Paul M Vanhoutte, Jean-vivien MombouliAbstract:Abstract In most blood vessels, the Endothelium generates both vasodilator and growth-stabilizing mediators under normal physiological circumstances. The vasodilator influence of the Endothelium modulates the vasoconstriction induced by adrenergic nerves, blood-borne substances, and local autacoids. Nitric oxide (NO) is a major Endothelium-derived vasodilator, along with protacyclin. A third substance called Endothelium-derived hyperpolarizing factors (EDHF) mediates vasodilatation in certain conduit arteries and in most resistance vessels. EDHF may be a cytochrome P-450 metabolite of arachidonic acid. NO acts mostly through an elevation of cyclic guanosine monophosphate in vascular smooth muscle, whereas prostacyclin stimulates adenylate cyclase. The model of action of EDHF involves the activation of K+ channels. The multiplicity of the factors released by the Endothelium, as well as the complexity of the interactions among these factors and those with other nonendothelial mediators, determine the extent of vasomotor control exerted locally by the Endothelium.
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Vascular Endothelium : Vasoactive mediators
Progress in Cardiovascular Diseases, 1996Co-Authors: Paul M Vanhoutte, Jean-vivien MombouliAbstract:In most blood vessels, the Endothelium generates both vasodilator and growth-stabilizing mediators under normal physiological circumstances. The vasodilator influence of the Endothelium modulates the vasoconstriction induced by adrenergic nerves, bloodborne substances, and local autacoids. Nitric oxide (NO) is a major Endothelium-derived vasodilator, along with prostacyclin. A third substance called Endothelium-derived hyperpolarizing factors (EDHF) mediates vasodilatation in certain conduit arteries and in most resistance vessels. EDHF may be a cytochrome P-450 metabolite of arachidonic acid. NO acts mostly through an elevation of cyclic guanosine monophosphate in vascular smooth muscle, whereas prostacyclin stimulates adenylate cyclase. The mode of action of EDHF involves the activation of K+ channels. The multiplicity of the factors released by the Endothelium, as well as the complexity of the interactions among these factors and those with other nonendothelial mediators, determine the extent of vasomotor control exerted locally by the Endothelium.
K Laustiola - One of the best experts on this subject based on the ideXlab platform.
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Endothelium dependent and independent effects of exogenous atp adenosine gtp and guanosine on vascular tone and cyclic nucleotide accumulation of rat mesenteric artery
British Journal of Pharmacology, 1992Co-Authors: Pauli Vuorinen, Ilkka Porsti, T Metsaketela, Vesa Manninen, H Vapaatalo, K LaustiolaAbstract:Summary 1 . The effects of exogenous guanosine 5′-triphosphate (GTP) and guanosine on vascular tone and cyclic nucleotide accumulation of noradrenaline-precontracted Endothelium-intact and Endothelium-denuded rat mesenteric artery rings were compared with the effects of the known purinoceptor agonists adenosine 5′-triphosphate (ATP) and adenosine. 2 . GTP (10 μm−1 mm) dose-dependently relaxed Endothelium-intact mesenteric artery rings by producing a rapid initial response followed by sustained relaxation resembling the relaxant response to acetylcholine. GTP also slightly relaxed Endothelium-denuded artery rings. The acetylcholine- and GTP-induced relaxations of Endothelium-intact rings were attenuated by NG-nitro l-arginine methyl ester (l-NAME, 330 μm) which attenuation was reversed with l-arginine (1 mm). 3 . Guanosine (10 μm−1 mm) relaxed both Endothelium-intact and -denuded artery rings in a dose-dependent manner. The relaxations were more pronounced in Endothelium-intact preparations and were only slightly attenuated by l-NAME (330 μm). 4 . ATP (1 μm−1 mm) and adenosine (10 μm−1 mm) dose-dependently relaxed Endothelium-intact and -denuded artery rings. The responses were more pronounced in Endothelium-intact vascular preparations. 5 . GTP (100 μm) and guanosine (100 μm) increased guanosine 3′:5′-cyclic monophosphate (cyclic GMP) accumulation in both Endothelium-intact and -denuded artery rings corresponding to the relaxations observed. The concentrations of adenosine 3′:5′-cyclic monophosphate (cyclic AMP) were not affected. 6 . ATP (100 μm) increased cyclic GMP concentration of Endothelium-intact artery rings. The concentrations of cyclic AMP were not affected by ATP (100 μm) and adenosine (100 μm) in Endothelium-intact and -denuded vascular preparations. 7 . These results provide evidence that exogenous GTP and guanosine relax precontracted Endothelium-intact and -denuded rat mesenteric artery rings by increasing cyclic GMP accumulation. The response to GTP of Endothelium-intact rings can mainly be explained by the release of Endothelium-derived relaxing factor (EDRF), but that of guanosine is only partly due to EDRF, and is a combination of Endothelium-dependent and -independent effects. The Endothelium-independent response of GTP and guanosine is a direct, unknown effect on smooth muscle and guanylate cyclase.
Kyu-tae Kang - One of the best experts on this subject based on the ideXlab platform.
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Endothelium-derived Relaxing Factors of Small Resistance Arteries in Hypertension
Toxicological Research, 2014Co-Authors: Kyu-tae KangAbstract:Endothelium-derived relaxing factors (EDRFs), including nitric oxide (NO), prostacyclin (PGI_2), and Endothelium-derived hyperpolarizing factor (EDHF), play pivotal roles in regulating vascular tone. Reduced EDRFs cause impaired Endothelium-dependent vasorelaxation, or endothelial dysfunction. Impaired Endothelium-dependent vasorelaxation in response to acetylcholine (ACh) is consistently observed in conduit vessels in human patients and experimental animal models of hypertension. Because small resistance arteries are known to produce more than one type of EDRF, the mechanism(s) mediating Endothelium-dependent vasorelaxation in small resistance arteries may be different from that observed in conduit vessels under hypertensive conditions, where vasorelaxation is mainly dependent on NO. EDHF has been described as one of the principal mediators of Endothelium-dependent vasorelaxation in small resistance arteries in normotensive animals. Furthermore, EDHF appears to become the predominant Endothelium-dependent vasorelaxation pathway when the endothelial NO synthase (NOS3)/NO pathway is absent, as in NOS3-knockout mice, whereas some studies have shown that the EDHF pathway is dysfunctional in experimental models of hypertension. This article reviews our current knowledge regarding EDRFs in small arteries under normotensive and hypertensive conditions.
William Martin - One of the best experts on this subject based on the ideXlab platform.
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Effects of metabolic inhibitors on Endothelium-dependent and Endothelium-independent vasodilatation of rat and rabbit aorta.
British Journal of Pharmacology, 2012Co-Authors: Cameron J. Weir, Ian F. Gibson, William MartinAbstract:1 Basal release of Endothelium-derived relaxing factor (EDRF) rendered Endothelium-containing rings of rat aorta 4.7 fold less sensitive to the contractile actions of phenylephrine and depressed the maximum response when compared with Endothelium-denuded rings. The responsiveness and maximum response to phenylephrine was, however, similar in rings of rabbit aorta with or without Endothelium. 2 Rotenone (1 nm-0.1 μm), an inhibitor of oxidative phosphorylation, induced a profound, irreversible blockade of phenylephrine-induced tone in Endothelium-containing and Endothelium-denuded rings of rat aorta, but induced only slight inhibition of tone in rings of rabbit aorta. 3 2-Deoxy glucose (10 mm), an inhibitor of glycolysis, had no effect on phenylephrine-induced contraction in Endothelium-denuded rings of rat aorta, but inhibited reversibly the Endothelium-dependent depression of contraction in Endothelium containing rings. 2-Deoxy glucose had no effect on phenylephrine-induced contraction in rings of rabbit aorta with or without Endothelium. 4 Rotenone (0.1 μm) inhibited acetylcholine-induced, Endothelium-dependent relaxation of phenylephrine-contracted rings or rat and rabbit aorta. In Endothelium-denuded rings of rat aorta, relaxation induced by glyceryl trinitrate of isoprenaline was also inhibited, but relaxation induced by 8-bromo cyclic GMP or dibutyryl cyclic AMP was not. Relaxation induced by verapamil on KCl-contracted, Endothelium-denuded rings of rat aorta was also unaffected. 5 2-Deoxy glucose (10 mm) inhibited acetylcholine-induced, Endothelium-dependent relaxation of phenylephrine-contracted rings of rat and rabbit aorta. In Endothelium-denuded rings of rat aorta, relaxation induced by glyceryl trinitrate and by isoprenaline was also inhibited, but relaxation induced by 8-bromo cyclic GMP or dibutyryl cyclic AMP was not. Relaxation induced by verapamil on KCl-contracted, Endothelium-denuded rings of rat aorta was also unaffected. 6 These data suggest that in rabbit and in rat aorta, rotenone inhibits acetylcholine-induced relaxation by inhibiting EDRF production, and by depressing smooth muscle sensitivity to EDRF, respectively. They further suggest that 2-deoxy glucose inhibits acetylcholine-induced relaxation in both tissues by depressing the sensitivity to EDRF, probably as a result of reduced synthesis of cyclic GMP. The additional possibility that 2-deoxy glucose inhibits EDRF production warrants further investigation. 7 The blockade by 2-deoxy glucose of the Endothelium-dependent depression of phenylephrine-induced tone in rat aorta probably reflects blockade of the actions of spontaneously released EDRF.
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conditions permitting suppression of stretch induced and vasoconstrictor tone by basal nitric oxide activity in porcine cerebral artery
British Journal of Pharmacology, 2000Co-Authors: Sarah J Wallis, William MartinAbstract:This study examined the ability of basal nitric oxide activity to suppress intrinsic and vasoconstrictor tone in isolated rings of porcine cerebral artery. Following stretch of approximately 1 g, NG-nitro-L-arginine methyl ester (L-NAME, 100 μM) produced a rise in tone in Endothelium-containing but not Endothelium-denuded rings. Thus, intrinsic tone was present and was powerfully suppressed by basal nitric oxide activity. Nevertheless, when concentration-response curves were constructed to U46619 and 5-hydroxytryptamine (5-HT), no Endothelium-dependent depression of vasoconstriction was observed. It therefore appeared that basal nitric oxide activity was able to suppress intrinsic but not vasoconstrictor tone in these vessels. Stretch-tension curves generated following the application of stretch over the range 0–5.5 g on Endothelium-denuded rings showed that tension was stretch-induced. Experiments conducted in the presence of L-NAME (100 μM) revealed that the level of tone present in Endothelium-containing rings was substantially higher than in Endothelium-denuded rings across the entire range of stretch. When Endothelium-containing and Endothelium-denuded rings were set at similar levels of stretch-induced tone, rather than similar levels of stretch, the presence of the Endothelium now depressed significantly vasoconstrictor responses to U46619 and 5-HT. Thus, when Endothelium-containing and Endothelium-denuded rings of porcine cerebral artery are set at similar points along their respective stretch-tension curves, rather than at similar levels of stretch, basal nitric oxide activity can be seen to inhibit both stretch-induced and vasoconstrictor tone. British Journal of Pharmacology (2000) 130, 567–574; doi:10.1038/sj.bjp.0703351
Hideyuki Yamawaki - One of the best experts on this subject based on the ideXlab platform.
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mechanisms underlying impairment of Endothelium dependent relaxation by fetal bovine serum in organ cultured rat mesenteric artery
European Journal of Pharmacology, 2011Co-Authors: Tomoka Morita, Muneyoshi Okada, Yukio Hara, Hideyuki YamawakiAbstract:Abstract Organ culture of blood vessels provides a useful technique to investigate long-term effects of drugs because tissue architecture and function are well preserved. Various growth factors are responsible for structural and functional changes during vascular diseases. We investigated long-term effects of fetal bovine serum (FBS) which contains such factors on Endothelium-dependent relaxation using organ-culture method. Rat isolated mesenteric arteries with Endothelium were cultured for 3 days without or with 10% FBS (FBS). Acetylcholine- and bradykinin-induced Endothelium-dependent relaxations were significantly impaired in FBS, whereas sodium nitroprusside-induced relaxation of Endothelium-removed artery was unchanged. Morphological examination revealed that Endothelium was intact in FBS. Acetylcholine-induced nitric oxide (NO) release as detected by 4, 5-diaminofluorescein significantly decreased in FBS, whereas endothelial NO synthase expression was unchanged. A Ca2+ ionophore, A23187-induced relaxation was unchanged in FBS. A phospholipase C activator, m-3M3FBS-induced relaxation of FBS was unchanged in either Ca2+-containing or -free solution. Total expressions of transient receptor potential canonical channels (TRPCs: TRPC-1, -4, -5) were similar in FBS. These data suggest that FBS impairs Endothelium-dependent relaxation by inhibiting events upstream of phospholipase C activation including phospholipase C, G-protein, and receptors in Endothelium.