ici-192605 and ridogrel

Inhibition of nitric oxide (NO) synthesis induces vasoconstriction and reduction of the blood flow in the brain, indicating that basal release of NO provides a resting vasorelaxant tone in the cerebral circulation. In the present study, the contractile effect of the NO synthase blocker NG-nitro-L-arginine (100 mumol/L) in isolated rat middle cerebral arteries was attenuated markedly in the presence of the cyclooxygenase inhibitor indomethacin (5 mumol/L), the thromboxane A2 synthase inhibitor ridogrel (10 mumol/L), or the thromboxane receptor antagonist ICI 192605 (100 mumol/L). These results indicate that removal of the endogenous NO stimulates the release of thromboxane A2 in cerebral vessels and basal NO production regulates the resting cerebrovascular tone, at least in part, by suppressing thromboxane A2.

Topics: Animals; Cerebral Arteries; Cyclooxygenase Inhibitors; Dioxanes; Enzyme Inhibitors; Indomethacin; Male; Muscle Contraction; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Pentanoic Acids; Pyridines; Rats; Rats, Wistar; Thromboxane A2; Thromboxane-A Synthase

The goal of the present study was to characterize the role of the endothelium in the 5-hydroxytryptamine (5-HT)-induced contraction of the rat basilar artery. Rat basilar artery segments were mounted in myographs to study their isometric tension development. 5-HT caused dose-dependent contractions that were minimally affected by endothelium removal. The dose-response curve obtained with the 5-HT1 receptor agonist, 5-carboxamidotryptamine (5-CT), was biphasic in arteries with endothelium; removal of the endothelium eliminated the first phase of the contraction. The 5-HT2 receptor antagonist, ketanserin (30 nM), shifted the dose-response curve to 5-HT to the right; in arteries with endothelium, the curve became biphasic. Ketanserin inhibited the second phase of the dose-response curve to 5-CT. The mixed 5-HT1/5-HT2 receptor antagonist, metergoline (30 nM), shifted the dose-response curve to 5-HT non-competitively to the right and depressed both phases of the dose-response curve to 5-CT. In basilar arteries with endothelium and treated with ketanserin, the thromboxane A2 receptor antagonist, ICI 192605 (1 microM), significantly decreased the responsiveness to 5-HT and the dose-response curve for 5-HT became monophasic. ICI 192605 and the thromboxane A2 synthase inhibitor, ridogrel (10 microM), both suppressed the first phase of the dose-response curve to 5-CT. These data indicate that both endothelial 5-HT1 and smooth muscle 5-HT2 receptors participate in the contractions caused by 5-HT in the rat basilar artery.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Basilar Artery; Dioxanes; Endothelium, Vascular; In Vitro Techniques; Isometric Contraction; Ketanserin; Male; Metergoline; Muscle, Smooth, Vascular; Pentanoic Acids; Pyridines; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Thromboxane-A Synthase; Thromboxanes