The contribution of calcitonin gene-related peptide (CGRP) to neurogenic vasodilator responses

Abstract

The neuropeptide calcitonin gene-related peptide (CGRP) is a potent vasodilator in the microcirculation of many tissues including the skin and joint. In order to elucidate the mechanism of endogenous CGRP release, we have used a multiple site 133Xe clearance technique to measure local blood flow changes in response to agents injected intradermally in the rabbit. Capsaicin (100 nmol/site) and human alpha CGRP (3 pmol/site) stimulated similar increases in blood flow and, in both cases, the effect was totally abolished by the CGRP antagonist, CGRP8-37 (1 nmol/site). By contrast, the nitric oxide synthase inhibitor L-nitro arginine methyl ester (L-NAME, 30 nmol/site) had little effect on human alpha CGRP-induced vasodilation, but caused significant inhibition of the response to capsaicin (p < 0.05). These results show that increased blood flow in rabbit skin caused by exogenous CGRP is independent of nitric oxide. In addition, however, they suggest that nitric oxide is required for either the release of endogenous CGRP from capsaicin-sensitive nerves or its subsequent activity.

Nitric oxide mediates the amplification by interleukin-1β of neurogenic vasodilatation in the rat skin

“…The residual vasodilatation seen in capsaicin-pretreated rats is likely to be a reaction to the injection per se, since it was not higher than the vasodilatation caused by intraplantar injection of saline alone. These findings are consistent with the notion that the capsaicin-induced rise of cutaneous blood flow is mediated by stimulation of fine afferent nerve fibres (Holzer, 1992) and release of the vasodilator transmitter CGRP (Hughes and Brain, 1991;Brain et al, 1993). Hence, the absence of any effect of interleukin-lß in capsaicin-pretreated rats implies that the cytokine augments the neurogenic component in the vasodilator response to capsaicin by sensitizing afferent nerve fibres to noxious stimuli.…”

“…The use of s.c. N°-nitro-L-arginine methyl ester was regarded as impractible, therefore, given that local N°-nitro-L-arginine methyl ester could inhibit vasodilator responses solely by virtue of its vasoconstrictor effect. Such a functional antagonism might be responsible for the inhibitory effect of topical N°-nitro-L-arginine methyl ester on capsaicin-induced vasodilatation (Brain et al, 1993), an effect that was not observed after i.v. administration of the drug.…”

“…We have previously shown that the inflammatory cytokine interleukin-lß enhances the hyperaemia evoked by injection of capsaicin into the rat plantar hindpaw skin in a prostaglandin-dependent manner (Herbert and Holzer, 1994). Since the vasodilator effect of calcitonin gene-related peptide (CGRP), the major neuragenie mediator of the capsaicin-induced vasodilatation (Hughes and Brain, 1991;Brain et al, 1993), was not altered by interleukin-1ß it was concluded that the effect of the cytokine was brought about by sensitization of afferent neiVe endings to capsaicin (Herbert and Holzer, 1994).This inference was further tested here by examining the effect of interleukin-1/3 in rats in which thin afferent neurones bad been defunctionalized by systemic …”

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

“…Macmillan Press Ltd, 1994 Preliminary findings of this study have been published in the proceedings of the European Workshop on Inflammation Meeting, London, 1992 (Brain et al, 1993).…”

Cutaneous Vasodilation during Local Heating: Role of Local Cutaneous Thermosensation

“…Of specific interest is that a portion of the skin blood flow response to innocuous heating is blunted by blocking the TRPV1 ion channel with capsazepine (Wong and Fieger, 2010). The increase in skin blood flow via TRPV1 ion channels is consistent with the activation of an axon-reflex and the release of vasoactive neuropeptides, presumably calcitonin gene-related peptide (CGRP) and Substance P (Brain and Williams, 1988; Brain et al, 1993). Both TRPV1 and TRPM3, when activated by a ligand (capsaicin and neurosteriod pregnenolone, respectively) produce an axon reflex mediated release of CGRP (Brain et al, 1986; Holzer, 1991; Tominaga and Caterina, 2004; Held et al, 2015).…”