Altered serotonin receptor subtypes mediate coronary microvascular hyperreactivity in pigs with chronic inhibition of nitric oxide synthesis

Background: We previously reported that chronic inhibition of nitric oxide synthesis by administration of N(ω)-nitro-L-arginine methyl ester (L- NAME) causes microvascular hyperreactivity to 5-hydroxytryptamine (5-HT) and vascular structural changes in pigs in vivo. In the present study, we investigated the relative contributions of 5-HT receptor subtypes to microvascular hyperreactivity in this animal model. Methods and Results: Coronary vasomotor response was studied in 16 pigs treated with oral L-NAME for 4 weeks (L group) and in 11 control pigs (C group). Intracoronary administration of 5-HT at 30 μg/kg decreased coronary blood flow (CBF) in the two groups. The decrease in CBF by 5-HT was greater (P<.01) in the L group than in the C group. The decrease in CBF by 5-HT in the C group was blocked completely by pretreatment with ketanserin, a 5-HT₂ antagonist. In contrast, the augmented decrease in CBF by 5-HT in the L group was only partly inhibited by ketanserin alone and was blocked completely by ketanserin and methiothepin, a 5-HT₁/5-HT₂ antagonist. The decrease in CBF caused by prostaglandin F(2α) and the increase in CBF caused by nitroglycerin were comparable between the two groups and were not affected by the 5-HT antagonists. Conclusions: These results suggest that the 5-HT-induced microvascular hyperreactivity may be mediated by relative changes in affinity for 5-HT receptors or de novo expression of 5-HT₁ receptors in microvascular smooth muscle cells in our animal model.