1 The mechanisms underlying vasodilator eect of nicotine on mesenteric resistance blood vessels and the role of calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves were studied in the rat. 2 Mesenteric vascular beds isolated from Wistar rats were perfused with Krebs solution, and perfusion pressure was measured with a pressure transducer. 3 In preparations with intact endothelium and contracted by perfusion with Krebs solution containing methoxamine, perfusion of nicotine (1 ± 100 mM) for 1 min caused a concentrationdependent vasodilator response without vasoconstriction. 4 The nicotine-induced vasodilation was markedly inhibited by hexamethonium (nicotinic cholinoceptor antagonist, 10 mM) and blocked by guanethidine (adrenergic neuron blocker, 5 mM). 5 Either denervation by cold storage (48C for 72 h) or adrenergic denervation by 6-hydroxydopamine (toxin for adrenergic neurons, 2 mM for 20 min incubation, twice) blocked the nicotine-induced vasodilation. 6 Neither endothelium removal with perfusion of sodium deoxycholate (1.80 mg ml 71 , for 30 s) nor treatment with N o -nitro-L-arginine (nitric oxide synthase inhibitor, 100 mM), atropine (muscarinic cholinoceptor antagonist, 10 nM) or propranolol (b-adrenoceptor antagonist, 100 nM) aected the nicotine-induced vasodilation. 7 In preparations without endothelium, treatment with capsaicin (depleting CGRP-containing sensory nerves, 1 mM) or human CGRP[8 ± 37] (CGRP receptor antagonist, 0.5 mM) markedly inhibited the nicotine-induced vasodilation. 8 These results suggest that, in the mesenteric resistance artery of the rat, nicotine induces vasodilation, which is independent of the function of the endothelium and is involved in activation of CGRPergic nerves. It is also suggested that nicotine stimulates presynaptic nicotinic cholinoceptors on adrenergic nerves to release adrenergic neurotransmitters, which then act on CGRPergic nerves to release endogenous CGRP from the nerve.

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 mM) for 1 min caused concentration-dependent vasodilation. Capsazepine (vanilloid receptor-1 antagonist; 1-10 mM) and ruthenium red (inhibitor of vanilloid response; 1-30 mM) 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 mM), dopamine D1 receptorselective antagonist (SCH23390; 1-10 mM), dopamine D2 receptor antagonist (haloperidol; 0.1-0.5 mM), ATP P2x receptor-desensitizing agonist (a,b-methylene ATP; 1-10 mM), adenosine A 2 receptor antagonist (8(p-sulfophenyl)theophylline; 10-50 mM) or neuropeptide Y (NPY)-Y1 receptor antagonist (BIBP3226; 0.1-0.5 mM). 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.

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