Cutaneous vasodilatation induced by nitric oxide‐evoked stimulation of afferent nerves in the rat

Abstract

1 The site of action at which nitric oxide (NO) may contribute to neurogenic vasodilatation in the hindpaw skin of urethane-anaesthetized rats was examined by the use of N0-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase. 2 Skin blood flow was measured by laser Doppler flowmetry, and neurogenic vasodilatation was evoked either by topical application of mustard oil (5%) or antidromic electrical stimulation of the saphenous nerve (antidromic vasodilatation).3 L-NAME (60 lmol kg-', i.v.) attenuated the hyperaemia evoked by mustard oil in an enantiomerspecific manner but failed to reduce antidromic vasodilatation and the vasodilatation due to i.v. injected calcitonin gene-related peptide (CGRP) and substance P (0.1-1 nmol kg-each), two proposed mediators of neurogenic vasodilatation. 4 Pretreatment of rats with capsaicin (125 mg kg', s.c. 2 weeks beforehand), to defunctionalize afferent neurones, reduced the hyperaemic response to mustard oil and prevented L-NAME from further decreasing the vasodilatation evoked by mustard oil. 5 Intraplantar infusion of sodium nitroprusside (SNP, 0.15 nmol in 1 min), a donor of NO, induced hyperaemia which was significantly diminished by the CGRP antagonist i.v.) and by capsaicin pretreatment. The ability of CGRP8-37 to inhibit the vasodilator response to SNP was lost in capsaicin-pretreated rats. 6 Taken together, these data indicate that NO does not play a vasorelaxant messenger role in neurogenic vasodilatation but can contribute to activation of, and/or transmitter release from, afferent nerve fibres in response to irritant chemicals.

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).…”

The Pharmacology of Nitric Oxide in the Peripheral Nervous System of Blood Vessels

“…In the skin, the vasodilator response induced by axon reflexes or antidromic electrical stimulation seems to be mediated mostly by CGRP (Brain and Williams, 1989;Holzer, 1992). NO is unlikely to be involved in the rat skin microvasculature since NOS inhibitors do not affect the response (Ralevic et al, 1992;Holzer and Jocic, 1994). It is suggested that release of NO is involved in edema formation in rat paw skin induced by electrical stimulation of the saphenous nerve, but the vasodilator action of NO is unimportant in this context (Kajekar et al, 1995).…”

Mediation by prostaglandins of the nitric oxide‐induced neurogenic vasodilatation in rat skin

“…Together with the observation that the CGRP8-37-sensitive component of the vasodilator response to SNP is abolished by capsaicin-induced defunctionalization of afferent, neurones (Holzer & Jocic, 1994), this finding provides strong evidence that part of the SNP-evoked rise in cutaneous blood flow is due to release of CGRP from afferent nerves fibres. A similar conclusion holds true for the ability of SNP to dilate cerebral arterioles in the cat (Wei et al, 1992).…”

“…Effect of L-NAME and methylene blue on the cutaneous hyperaemia induced by SNP The inhibitor of NO synthase, N0-nitro-L-arginine methyl ester (L-NAME, 15 mg kg-l; Holzer & Jocic, 1994), or its vehicle (saline, 1 ml kg-') was injected i.v. 15 min before the third intraplantar application of SNP (150 pmol).…”

“…However, since intraplantar application of methylene blue at the active dose of 3 yimol (Duarte et al, 1990) caused a marked and long-lasting hyperaemia of unknown mechanism, caution should be exercised in the pharmacological assessment of the actions of this compound. In additional experiments it was ruled out that the vasodilator activity of SNP depended on endogenous NO formed via the L-arginine; NO synthase pathway (Moncada et al, 1991), since the SNP-evoked hyperaemia remained unaltered by an effective dose of L-NAME (15 mg kg-'; Holzer & Jocic, 1994).…”