Abstract
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 ≧ 5- HT > sumatriptan > α- 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-HT 1A/1B (propranolol), 5-HT 1C (mesulergine), 5-HT 2 (ketanserin, mianserin) and 5-HT 3 (MDL 72222) sites were inactive to block the 5-HT-induced contraction. In contrast, the 5-HT 1/5-HT 2 receptor antagonists methiothepin and metergoline inhibited the 5-HT-induced response with relatively high affinity (pA 2 = 8.16 ± 0.26 and 6.73 ± 0.05, respectively). Overall, this pharmacological profile indicated clearly that a 5-HT 1 receptor, must closely related to the 5-HT 1D 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=0.0051). Analyses of the correlation between the agonist and antagonist potencies at bovine cerebrovascular receptors and their published affinities at the cloned human 5-HT 1Dα and 5-HT 1Dβ (or human 5-HT 1B) receptors showed a highly significant correlstion only with the 5-HT 1Dβ (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-HT 1D receptor and that bovine pial arteries appear to be the best available pharmacological model for the human cerebrovascular 5-HT 1D receptor. Further, the results suggest that bovine cerebrovascular 5-HT 1D receptors resemble the cloned human 5-HT 1Dβ (or human 5-HT 1B) receptor subtype.
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