Vanilloid receptors mediate adrenergic nerve- and CGRP-containing nerve-dependent vasodilation induced by nicotine in rat mesenteric resistance arteries.

ABSTRACT

Previous studies showed that nicotine induces adrenergic nerve-dependent vasodilation that is mediated by endogenous calcitonin gene-related peptide (CGRP) released from CGRP-containing (CGRPergic) nerves. The mechanisms underlying the nicotine-induced vasodilation were further studied. 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. Perfusion of nicotine (1-100 microm) for 1 min caused concentration-dependent vasodilation. Capsazepine (vanilloid receptor-1 antagonist; 1-10 microm) and ruthenium red (inhibitor of vanilloid response; 1-30 microm) concentration-dependently inhibited the nicotine-induced vasodilation without affecting the vasodilator response to exogenous CGRP. Nicotine-induced vasodilation was not inhibited by treatment with 3,4-dihydroxyphenylalanine (DOPA) receptor antagonist (l-DOPA cyclohexyl ester; 0.001-10 microm), dopamine D1 receptor-selective antagonist (SCH23390; 1-10 microm), dopamine D2 receptor antagonist (haloperidol; 0.1-0.5 microm), ATP P2x receptor-desensitizing agonist (alpha,beta-methylene ATP; 1-10 microm), adenosine A2 receptor antagonist (8(p-sulfophenyl)theophylline; 10-50 microm) or neuropeptide Y (NPY)-Y1 receptor antagonist (BIBP3226; 0.1-0.5 microm). Immunohistochemical staining of the mesenteric artery showed dense innervation of CGRP- and vanilloid receptor-1-positive nerves, with both immunostainings appearing in the same neuron. The mesenteric artery was also densely innervated by NPY-positive nerves. Double immunostainings showed that both NPY and CGRP immunoreactivities appeared in the same neuron of the artery. These results suggest that nicotine acts on presynaptic nicotinic receptors to release adrenergic neurotransmitter(s) or related substance(s), which then stimulate vanilloid receptor-1 on CGRPergic nerves, resulting in CGRP release and vasodilation.