Insurmountable antagonism of AT-1015, a 5-HT2 antagonist, on serotonin-induced endothelium-dependent relaxation in porcine coronary artery

Abstract

Abstract The purpose of this study was to examine the inhibitory effects of AT-1015, a newly synthesized 5-HT2 receptor antagonist, on serotonin-induced endothelium-dependent relaxation in U 46619 (5 times 10−9m)-precontracted porcine coronary artery pre-incubated with ketanserin (3 times 10−6m), and then compare its effects with another potent 5-HT2 antagonist, ritanserin. The investigation showed that AT-1015 (10−8−10−6m) 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 10−8m, but it inhibited the maximum relaxation response at 10−7m. 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 10−8−10−6m 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 10−7m ritanserin. The variation of inhibitory effects between these two 5-HT2 antagonists may be due to the different chemical structure and/or interaction sites at the receptor.