Nitric oxide‐dependent release of vasodilator quantities of calcitonin gene‐related peptide from capsaicin‐sensitive nerves in rabbit skin

Abstract

1 Calcitonin gene-related peptide (CGRP) is a potent and long lasting vasodilator in the cutaneous microvasculature of many species including the rabbit. In this study we have investigated the role of nitric oxide in the release of endogenous CGRP, in response to capsaicin, in rabbit skin.2 Cutaneous blood flow was measured in response to intradermally-injected agents by a multiple site '33Xenon clearance technique. 3 The increased blood flow induced by capsaicin (100 nmol/site) and CGRP (3 pmol/site) was totally inhibited by the CGRP antagonist CGRP(837 (1 nmol/site), whilst the increased blood flow induced by sodium nitroprusside (0.3, 1 and 3 nmol/site) was unaffected by CGRP(g-3s,. 4 The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 30 nmol/site) had no effect the vasodilator response induced by CGRP, but significantly inhibited capsaicin-induced blood flow. The inhibitory effect of L-NAME on capsaicin-induced blood flow was reversed by intradermal L-arginine (300 nmol/site), whilst the inactive enantiomer D-NAME (30 nmol/site) and the a-adrenoceptor agonist phenylephrine (10 pmol/site), at a dose which had a similar effect to L-NAME on basal blood flow, had no effect on capsaicin-induced blood flow. 5These results suggest that CGRP is the important vasodilator which is released from capsaicinsensitive sensory nerves in rabbit skin and that the release of CGRP, but not its mechanism of vasodilator action, is nitric oxide-dependent in the rabbit cutaneous microvasculature.

Rapid nitric oxide‐ and prostaglandin‐dependent release of calcitonin gene‐related peptide (CGRP) triggered by endotoxin in rat mesenteric arterial bed

“…In vivo experiments using a rat model of endotoxicosis have shown that the early hypotension and the loss of vascular responsiveness to noradrenaline occurring within the first 1 h of shock was dependent on NO production and apparently involved the activation of cNOS in either endothelial or neural cells (Wright et al, 1992;Szabo et al, 1993). Some studies have shown that NO appears to increase CGRP release from perivascular nerves in cerebral arteries (Wei et al, 1992), and microvessels in skin (Holzer & Jocic, 1994;Hughes & Brain, 1994;Kajekar et al, 1995) by observation of blood flow in response to a CGRP receptor blocker. On the other hand, several studies have indicated that CGRP does not account for vasodilatation in response to NO (Ralevic et al, 1992;Ayajiki et al, 1994;Faraci & Breese, 1994;Brian et al, 1995).…”

Role of nitric oxide (NO) in ocular inflammation

“…Hence, our results suggest that NO plays an important role in ocular inflammation and that in fact NO may have dual effects: first, NO is involved in the activation of C-fibres, causing release of transmitters such as CGRP; secondly, NO mediates the effects of CGRP (see also Andersson, 1992). Recently it was reported that L-NAME inhibited the capsaicin-induced (and C-fibre-mediated) increase in blood flow in rabbit skin, suggesting a role for NO in the activation of C-fibres (Hughes & Brain, 1994). Interestingly, NO has been found to accelerate the synthesis of prostaglandins which in turn may cooperate with NO in activating C-fibres (Sautebin et al, 1995).…”

Calcitonin Gene-Related Peptide8-37 Antagonizes Capsaicin-Induced Vasodilation in the Skin: Evaluation of a Human in Vivo Pharmacodynamic Model

“…This finding is particularly interesting because there is much debate surrounding the role of NO in the vasodilator mechanism of CGRP. If one considers endogenous CGRP release from capsaicin-sensitive nociceptors in the skin pivotal for the capsaicin-induced DBF response and one takes into account that the vasodilator effect of CGRP in humans is partly mediated by the release of NO (de Hoon et al, 2003), one Hughes and Brain (1994) demonstrated that in the rabbit cutaneous microvasculature, NO synthase inhibition had no effect on the subjects ϭ 11; number of observations after capsaicin/placebo per arm ϭ 22) during intra-arterial infusion of indomethacin (5 g ⅐ min Ϫ1 ⅐ dl Ϫ1 forearm). DBF increase was similar in the indomethacin IA and the NIA after application of 1000 g of capsaicin.…”