Endogenous calcitonin gene‐related peptide (CGRP) mediates adrenergic‐dependent vasodilation induced by nicotine in mesenteric resistance arteries of the rat

Abstract

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.

Pharmacology and Physiology of Perivascular Nerves Regulating Vascular Function

“…This finding may provide an explanation for the reported observations that electrical stimulation of the sympathetic nerves to cerebral circulation in normal experimental animals in general results in a very weak effect or no response in cerebral vascular tone and cerebral blood flow (2,42,43). This sympathetic innervation-dependent neurogenic vasodilation also has been demonstrated in the mesenteric vascular beds (44). This concept of presynaptic modulation of nitrergic nerves in the cerebral arteries (33) and peptidergic nerves in the mesenteric vascular bed (44) by sympathetic adrenergic nerves appears to be supported by reports from some in vivo experimentation that the functional consequence of neuronal NO and NE interaction may play a role in blood pressure regulation (45).…”

Altered function of nitrergic nerves inhibiting sympathetic neurotransmission in mesenteric vascular beds of renovascular hypertensive rats

“…4,19 The preparations were then rinsed with a sodium deoxycholate-free Krebs solution containing a selective a 1 -adrenoceptor agonist, methoxamine (1-2 mM, Nippon Shinyaku, Kyoto, Japan), and chemical removal of the endothelium was assessed by the lack of a relaxant effect in active tone after a bolus injection of 1 nmol acetylcholine, which was directly injected into the perfusate proximal to the arterial cannula with an infusion pump (model 975, Harvard Apparatus, Holliston, MA, USA). A volume of 100 ml was injected over a period of 12 s.…”

“…1,2 Nitric oxide (NO), a potent vasodilator, is synthesized from L-arginine by NO synthase (NOS) in various cells. NOS is present not only in vascular endothelial cells (endothelial NOS), but also in perivascular nerves (neuronal NOS; nNOS), 3,4 and the NO synthesized by nNOS has been shown to act as a neurotransmitter to produce strong vasodilation. 2 Thus, perivascular NO-containing nerves (nitrergic nerves) have been shown to distribute in various blood vessels as nonadrenergic noncholinergic nerves.…”

Effect of Adrenomedullin on Adrenergic Vasoconstriction in Mesenteric Resistance Arteries of the Rat

“…This caused a transient increase (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) in perfusion pressure. The preparations were then rinsed with SD-free Krebs solution for 1 h.…”

“…To remove the vascular endothelium, the preparations with resting tone were perfused with 1.80 mg / ml sodium deoxycholate (SD) in saline for 30 s as described previously (17,20). This caused a transient increase (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) in perfusion pressure.…”