LY215840, A HIGH-AFFINITY 5-HT7 RECEPTOR-LIGAND, BLOCKS SEROTONIN-INDUCED RELAXATION IN CANINE CORONARY-ARTERY

The canine coronary artery possesses a smooth muscle relaxant serotoni n (5-HT) receptor distinct from previously characterized 5-HT receptor s. On the basis of the ability of LY53857 to block weakly coronary smo oth muscle relaxation to 5-HT, we examined several structurally relate d ergolines in endothelium denuded rings of canine coronary artery pre contracted with PGF(2 alpha) (10 mu M) 5-HT (10 nM-100 mu M)-induced r elaxation was antagonized competitively by the ergoline esters LY53857 (-log K-B = 6.5) and sergolexole (-log K-B = 6.4) and by the ergoline amide amersergide, (-log K-B = 6.7). In contrast to the relatively lo w affinity of these ergolines, LY215840, another ergoline amide, antag onized 5-HT-induced relaxation in a competitive manner with the highes t affinity (-log K-B = 8.3). This effect was independent of the 5-HT2 receptor affinity of these ergolines, because LY2158401 LY53857T sergo lexole and amesergide all possessed similar 5-HT2 receptor affinity. F urther, all four ergolines possessed affinity for the human 5-HT7 rece ptor, and LY215840 had the highest 5-HT7 receptor affinity (K-i = 14.7 nM). Finally, in vascular smooth muscle under basal tone, LY215840 (1 mu M) blocked the relaxant response to high concentrations of 5-HT an d 5-MeOT without altering their contractile potency. LY215840 (1 mu M) did not alter contraction to sumatriptan, an agent that lacks relaxan t activity. In contrast, LY215840 (1 mu M) markedly potentiated contra ction to 5-carboxamidotryptamine, the most potent coronary relaxant ag onist and the agonist with the highest 5-HT7 receptor affinity. The ab ility of LY215840 to block the relaxant 5-HT receptor in canine corona ry artery may reflect its 5-HT7 receptor antagonist activity and make it a useful tool to probe the relationship between the 5-HT7 receptor and the coronary vasoactive properties of 5-HT.