Alpha3beta4-nicotinic receptors mediate adrenergic nerve- and peptidergic (CGRP) nerve-dependent vasodilation induced by nicotine in rat mesenteric arteries.
OBJECTIVE
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.


METHODS
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.


RESULTS
Perfusion of nicotine (1-100 microM) 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 microM) (partial agonist for nicotinic beta2 subtype and full agonist for nicotinic beta4 subtype) induced vasodilation in a concentration-dependent manner. Vasodilation induced by nicotine, (-)-cytisine- and (+/-)-epibatidine was markedly attenuated by guanethidine (5 microM) and pretreatment with capsaicin (1 microM). Mecamylamine (relatively selective antagonist for alpha3beta4 subtype), but not dihydro-beta-erythroidine (selective antagonist for alpha4beta2 subtype) or alpha-bungarotoxin (selective antagonist for alpha7 subtype), markedly inhibited nicotine-induced vasodilation. Nicotine-induced vasodilation was inhibited by methyllycaconitine at high concentrations (>1 microM), which non-selectively antagonize nicotinic receptors, while a low concentration of 10 nM, which selectively antagonizes alpha7 subtype, had no effect. (-)-Cytisine and (+/-)-epibatidine-induced vasodilation were abolished by mecamylamine.


CONCLUSIONS
These results suggest that the nicotinic alpha3beta4 receptor subtype, but not the alpha7 and alpha4beta2 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.
Eguchi
S
S
Department of Clinical Pharmaceutical Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Miyashita
S
S
Kitamura
Y
Y
Kawasaki
H
H
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005731:Ganglionic Stimulants / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D017933:Peripheral Nervous System / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579165:Chrna7 protein, rat; D005731:Ganglionic Stimulants; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; D015740:Calcitonin Gene-Related Peptide