α3β4-Nicotinic receptors mediate adrenergic nerve- and peptidergic (CGRP) nerve-dependent vasodilation induced by nicotine in rat mesenteric arteries

Background and purpose: Previous studies demonstrated that nicotine-induced endothelium-independent vasodilation is mediated by perivascular adrenergic nerves and nerves releasing calcitonin gene-related peptide (CGRPergic nerves). We characterized the nicotinic acetylcholine (ACh) receptor subtype underlying the vasodilation in response to nicotine in rat mesenteric arteries. Experimental approach: Rat mesenteric vascular beds without endothelium were contracted by perfusion with Krebs solution containing methoxamine and the perfusion pressure was measured with a pressure transducer. Key results: Perfusion of nicotine (1-100 mu M) for 1 min caused a concentration-dependent decrease in perfusion pressure due to vasodilation. Perfusion of (+/-)-epibatidine (1-100 nM) (non-selective agonist) or (-)- cytisine (1-100 mu M) ( partial agonist for nicotinic beta 2 subtype and full agonist for nicotinic beta 4 subtype) induced vasodilation in a concentration-dependent manner. Vasodilation induced by nicotine, (-)-cytisine- and (+/-)- epibatidine was markedly attenuated by guanethidine (5 mu M) and pretreatment with capsaicin (1 mu M). Mecamylamine (relatively selective antagonist for alpha 3 beta 4 subtype), but not dihydro-berythroidine (selective antagonist for alpha 4 beta 2 subtype) or alpha-bungarotoxin (selective antagonist for alpha 7 subtype), markedly inhibited nicotine-induced vasodilation. Nicotine-induced vasodilation was inhibited by methyllycaconitine at high concentrations (> 1 mu M), which non-selectively antagonize nicotinic receptors, while a low concentration of 10 nM, which selectively antagonizes alpha 7 subtype, had no effect. (-)-Cytisine and (+/-)-epibatidine-induced vasodilation were abolished by mecamylamine Conclusion and implications: These results suggest that the nicotinic alpha 3 beta 4 receptor subtype, but not the alpha 7 and alpha 4 beta 2 subtypes, is responsible for the vasodilation in rat mesenteric arteries induced by nicotine-and nicotinic ACh receptor agonists through stimulation of adrenergic and CGRPergic perivascular nerves.