title: Insurmountable antagonism of AT-1015, a 5-HT2 antagonist, on serotonin-induced endothelium-dependent relaxation in porcine coronary artery.
abstract: The purpose of this study was to examine the inhibitory effects of AT-1015, a newly synthesized 5-HT(2) receptor antagonist, on serotonin-induced endothelium-dependent relaxation in U 46619 (5 x 10(-9)M)-precontracted porcine coronary artery pre-incubated with ketanserin (3 x 10(-6)M), and then compare its effects with another potent 5-HT(2) antagonist, ritanserin. The investigation showed that AT-1015 (10(-8)-10(-6)M) caused rightward shift with significant inhibition of maximum relaxation response induced by serotonin in porcine coronary artery with endothelium. Ritanserin caused a rightward shift of serotonin-induced relaxation without decreasing maximum response at 10(-9) and 10(-8)M, but it inhibited the maximum relaxation response at 10(-7)M. The study showed that AT-1015 and ritanserin had no inhibitory effect on bradykinin-induced relaxation in porcine coronary artery with endothelium. Thus, these findings suggested that AT-1015 at concentrations of 10(-8)-10(-6)M caused noncompetitive blockade of serotonin-induced endothelium-dependent relaxation in porcine coronary artery. The antagonistic effects of AT-1015 on serotonin-induced relaxation were different from that of ritanserin, except at 10(-7)M ritanserin. The variation of inhibitory effects between these two 5-HT(2) antagonists may be due to the different chemical structure and/or interaction sites at the receptor.
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, 5-13-2 Kamishinei-cho, Niigata 950-2081, Japan.
authors.forename: Mamunur
authors.initials: M
authors.lastname: Rashid
authors.forename: Mikio
authors.initials: M
authors.lastname: Nakazawa
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nagatomo
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000187:drug effects*; D007540:Isonipecotic Acids / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D016713:Ritanserin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D007540:Isonipecotic Acids; C411870:N-(2-(4-(5H-dibenzo(a,d)cyclohepten-5-yliden)piperidino)ethyl)-1-formyl-4-piperidinecarboxamide; D012702:Serotonin Antagonists; D014662:Vasoconstrictor Agents; D016713:Ritanserin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001920:Bradykinin