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

1 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. 2 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. 3 Perfusion of nicotine (1-100 muM) for 1 min caused concentration-dependent vasodilation. Capsazepine (vanilloid receptor-1 antagonist; 1-10 muM) and ruthenium red (inhibitor of vanilloid response; 1-30 muM) concentration-dependently inhibited the nicotine-induced vasodilation without affecting the vasodilator response to exogenous CGRP. 4 Nicotine-induced vasodilation was not inhibited by treatment with 3,4-dihydroxyphenylalanine (DOPA) receptor antagonist (L-DOPA cyclohexyl ester; 0.001- 10 muM), dopamine D1 receptor-selective antagonist (SCH23390; 1-10 muM), dopamine D2 receptor antagonist (haloperidol; 0.1-0.5 muM), ATP P2x receptor-desensitizing agonist (alpha,beta-methylene ATP; 1-10 muM), adenosine A(2) receptor antagonist (8(p-sulfophenyl) theophylline; 10-50 muM) or neuropeptide Y (NPY)-Y1 receptor antagonist (BIBP3226; 0.1-0.5 muM). 5 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. 6 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.