Effect of a calcitonin gene‐related peptide antagonist (CGRP_8–37) on skin vasodilatation and oedema induced by stimulation of the rat saphenous nerve

Abstract

1 The effect of the calcitonin gene-related peptide antagonist (CGRP837, 400 nmol kg-', i.v.) on the increased blood flow induced by calcitonin gene related peptide (CGRP), vasodilator prostaglandins, and topical capsaicin was measured with a laser Doppler blood flow meter in rat abdominal skin.2 The saphenous nerve was electrically stimulated and the effect of CGRP8-37 (400 nmol kg-', i.v.) on the increased blood flow (measured by laser Doppler flowmetry) and oedema formation (measured by the extravascular accumulation of ['25f]-albumin) was investigated in the rat hind paw.3 CGRP8-37 (400 nmol kg-', i.v.) had no effect on basal cutaneous blood flow at uninjected sites and sites injected with Tyrode buffer, but acted selectively to inhibit the increased blood flow induced by intradermal CGRP (10 pmol/site, P< 0.05), but not that induced by prostaglandin E2 (PGE2, 300 pmol/ site) or carba-prostacyclin (cPGI2, 100 pmol/site). 4 Capsaicin (0.1-33 mM), applied topically, acted in a dose-related manner to increase blood flow. CGRP837 (400 nmol kg-', i.v.) almost totally inhibited blood flow induced by capsaicin (10 mM; P <0.05) but did not significantly inhibit blood flow induced by a higher dose of capsaicin (33 mM). 5 The increased blood flow induced by short stimulation of the saphenous nerve (10 V, 1 ms, 2 Hz for 30 s) was inhibited by 76%, 5 min after i.v. CGRP837 (400 nmol kg-', i.v., P<0.05). 6 A longer (5 min) electrical stimulation of the saphenous nerve caused oedema formation, in addition to increased blood flow. The oedema formation was significantly inhibited by CGRP8-37 (400 nmol kg-', i.v., P<0.05). 7 The results suggest that the potent microvascular vasodilator neuropeptide, CGRP, is responsible for the increased blood flow observed after short stimulation of the saphenous nerve and that endogenous CGRP contributes in a pro-inflammatory manner to neurogenic oedema formation in the rat hind paw.

Interaction of human adrenomedullin 13–52 with calcitonin gene‐related peptide receptors in the microvasculature of the rat and hamster

“…These results with the CGRP receptor antagonist CGRP8-37 are consistent with an interaction of ADM13 52 with CGRPI receptors. The doses of CGRP837 we used to show inhibition of vasodilatation, 100 nmol kg-' and 300 nmol kg-' in the rat skin and hamster cheek pouch, respectively, are comparable with those used previously to exhibit a selective inhibition of CGRP-induced vasodilator responses (Escott & Brain, 1993 (Nuki et al, 1993;Eguchi et al, 1993); however, our study is the first demonstration of inhibition of ADM13-52-evoked vasodilator responses in the microvasculature in vivo by CGRP8-37. Further evidence also suggests that ADM, or an ADM-related peptide, can interact with the same receptor sites as CGRP.…”

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

“…Antidromic stimulation of the saphenous nerve Antidromic stimulation of the cut saphenous nerve was performed as described previously (Lembeck & Holzer, 1979;Delay-Goyet et al, 1992;Escott & Brain, 1993). Briefly, the right saphenous nerve was carefully dissected in the leg and cut, and the peripheral stump placed on bipolar platinum electrodes and immersed in paraffin oil.…”

“…Briefly, the right saphenous nerve was carefully dissected in the leg and cut, and the peripheral stump placed on bipolar platinum electrodes and immersed in paraffin oil. Electrical stimulation was performed with pulses of 15 V strength and 1 ms duration delivered at 2 Hz for a period fo 30 s (Delay-Goyet et al, 1992;Escott & Brain, 1993 (Escott & Brain, 1993) D-NAME (N0-nitro-D-arginine methyl ester) and L-NAME (N0-nitro-L-arginine methyl ester) were obtained from Bachem (Bubendorf, Switzerland) and dissolved in saline to give solutions of 60 mM which were injected i.v. at a volume of 1 ml kg-'.…”

“…The precise role of NO remains enigmatic. In view of the reports that NO does not participate in the hyperaemic effect of CGRP (Ralevic et al, 1992;Hughes & Brain, 1994) which is the chief mediator of antidromic and capsaicin-evoked vasodilatation (Delay-Goyet et al, 1992;Escott & Brain, 1993;Hughes & Brain, 1994) the present study was under- ' Author for correspondence. taken to examine systematically a possible participation of NO in the hyperaemic responses to antidromic nerve stimulation and to application of mustard oil, CGRP and substance P. The possible site of action of NO has also been evaluated.…”

Tissue-Specific Regulation of Microvascular Diameter: Opposite Functional Roles of Neuronal and Smooth Muscle Located Vanilloid Receptor-1

“…The time constant was set to 1 s. During the experiment, the exposed skeletal muscle was kept moist by a wet chamber placed around the probe. Blood flow changes were recorded continuously throughout the experiment and were expressed as arbitrary units of flux (Escott and Brain, 1993;Pórszá sz and Szolcsá nyi, 1994). The zero level was verified at the end of the experiment.…”