5-HT(1) RECEPTORS MEDIATING CONTRACTION IN BOVINE CEREBRAL-ARTERIES - A MODEL FOR HUMAN CEREBROVASCULAR 5-HT(1D-BETA) RECEPTORS

We report on the pharmacological profile of the 5-HT receptor which induces contraction of the bovine isolated cerebral arteries. Several 5-HT receptor agonists were tested for their ability to induce vasoconstriction in bovine pial arteries and their potencies were compared to that of 5-HT. The rank order of agonist potency can be summarized as 5-carboxamidotryptamine (5-CT) = RU 24969 greater-than-or-equal-to 5-HT > sumatriptan > alpha-methyl-5-HT > methysergide > 2-methyl-5-HT > ((+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene (8-OH-DPAT). Only methysergide induced a-contraction which was smaller than that elicited by 5-HT. Antagonists with selective affinity at 5-HT1A/1B (propranolol), 5-HT1C (mesulergine), 5-HT2 (ketanserin, mianserin) and 5-HT3 (MDL 72222) sites were inactive to block the 5-HT-induced contraction. In contrast, the 5-HT1/5-HT2 receptor antagonists methiothepin and metergoline inhibited the 5-HT-induced response with relatively high affinity (pA2 = 8.16 +/- 0.26 and 6.73 +/- 0.05, respectively). Overall, this pharmacological profile indicated clearly that a 5-HT1 receptor, most closely related to the 5-HT1D subtype, is responsible for the 5-HT-induced contraction of bovine cerebral arteries. Correlation analysis of the potencies of a series of 5-HT receptor agonists and antagonists in bovine and human cerebrovascular preparations showed a highly significant positive correlation (r = 0.94, P = 0.005 1). Analyses of the correlation between the agonist and antagonist potencies at bovine cerebrovascular receptors and their published affinities at the cloned human 5-HT1Dalpha and 5-HT1Dbeta (or human 5-HT1B) receptors showed a highly significant correlation only with the 5-HT1Dbeta (r = 0.82; P = 0.006) subtype. We conclude that cerebral vasoconstriction in bovine cerebral arteries is mediated by a receptor homologous to the human cerebrovascular 5-HT1D receptor and that bovine pial arteries appear to be the best available pharmacological model for the human cerebrovascular 5-HT1D receptor. Further, the results suggest that bovine cerebrovascular 5-HT1D receptors resemble the cloned human 5-HT1Dbeta (or human 5-HT1B) receptor subtype.