Certain ergolines are potent and selective 5-hydroxytryptamine (5-HT)2 receptor antagonists. Previous studies with two ergoline esters, LY53857 and sergolexole, documented their potency as 5-HT2 receptor antagonists and their metabolism in rats to a less active metabolite, 1-isopropyl dihydrolysergic acid. LY215840, an ergoline amide, has been identified as a potent 5-HT2 receptor antagonist that is not hydrolyzed to 1-isopropyl dihydrolysergic acid. In the rat jugular vein, LY215840 (3 x 109-10) to 10(-8) M) blocked 5-HT2 receptors mediating contraction to 5-HT in vitro. After i.v. and p.o. administration to rats, LY215840 was a potent 5-HT2 receptor antagonist, documented by its ability to block the pressor response to 5-HT administered i.v. Furthermore, after i.v. and p.o. administration of LY215840, blockade of vascular 5-HT2 receptors persisted in excess of 2 and 6 hr, respectively. LY215840 also blocked vascular 5-HT2 receptors in doses that did not affect alpha-1, beta-1 receptors or angiotensin II pressor responses, documenting the selectivity of LY215840 as an inhibitor of 5-HT2 and not other vascular receptors that modulate vasoconstriction. In addition to inhibiting vascular 5-HT2 receptors, LY215840 also inhibited 5-HT-amplified, ADP-induced aggregation (another 5-HT2 receptor-mediated response) in both rabbit and human platelets. Because of its ability to block both platelet and vascular 5-HT2 receptors, we studied the effectiveness of LY215840 in the rabbit carotid artery model of vascular occlusion. Low i.v. doses of LY215840 markedly prolonged time to vascular occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)