endothelin-1 and ridogrel

This study compares the effects of threshold concentrations of endothelin-1 in isolated rat basilar arteries with those in mesenteric arterial branches and investigates the mechanisms of inhibitory and potentiating endothelin-1-effects. In basilar arteries, endothelin-1 reduces the contractions induced by 5-hydroxytryptamine (5-HT), by the thromboxane A2 agonist U46619, and by vasopressin. The inhibitory effect of endothelin-1 on the contraction induced by 5-HT is abolished by deendothelialization, by the endothelin ET(B) receptor antagonist RES 701-1, by indomethacin, or by glibenclamide. In mesenteric arteries, endothelin-1 potentiates the contractile effects of 5-HT, U46619, and vasopressin. The potentiation of the contractile effect induced by 5-HT is only somewhat modified by deendothelialization, but abolished by the thromboxane A2 receptor antagonists GR32191 and ridogrel. U46619 potentiates the 5-HT-effect in mesenteric arteries. Thus, though the contractile endothelin ET(A) receptors were not blocked, threshold concentrations of endothelin-1 inhibited contractile effects in the rat basilar artery via activation of endothelial ET(B) receptors. Prostaglandins and ATP-sensitive K+ channels are involved in this inhibitory action. In contrast, endothelin-1 potentiates contractile actions in mesenteric arteries via the release of endogeneous thromboxane A2 from non-endothelial cells. The study points out the completely different role of the endothelium in combined effects of endothelin-1 between cerebral and mesenteric arteries.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Basilar Artery; Biphenyl Compounds; Drug Synergism; Endothelin Receptor Antagonists; Endothelin-1; Glyburide; Heptanoic Acids; Indomethacin; Male; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth, Vascular; Pentanoic Acids; Peptides, Cyclic; Pyridines; Rats; Rats, Sprague-Dawley; Serotonin; Vasoconstriction; Vasopressins

To determine the role of endothelium-derived contracting factor (EDCF) in the response to endothelin-1 in arteries with regenerated endothelium.. 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.. 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.. 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.

Topics: Animals; Coronary Vessels; Cyclooxygenase Inhibitors; Endothelin-1; Endothelium, Vascular; Imidazoles; Indomethacin; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroarginine; Pentanoic Acids; Pyridines; Swine; Thromboxane A2; Thromboxane-A Synthase