A CALCITONIN GENE-RELATED PEPTIDE (CGRP) ANTAGONIST (CGRP8-37) INHIBITS MICROVASCULAR RESPONSES INDUCED BY CGRP AND CAPSAICIN IN SKIN

1 The effect of the calcitonin gene-related peptide (CGRP) antagonist CGRP8-37 on responses to CGRP and other mediators was investigated in rabbit dorsal skin. 2 Blood flow changes at intradermally-injected sites were measured by a multiple site 133xenon clearance technique. CGRP8-37 had little effect on blood flow at doses up to 0.3 nmol/site, when injected alone, although a significant increase in blood flow was observed at the highest dose tested (1 nmol/site). 3 CGRP8-37 dose-dependently inhibited the increased blood flow induced by human alpha-CGRP and human beta-CGRP, but had no effect on equivalent vasodilator responses induced by vasoactive intestinal peptide (VIP) and prostaglandin E1 (PGE1). CGRP8-37 showed a preferential ability to inhibit alpha-CGRP (IC50 0.04 nmol), when compared with beta-CGRP (IC50 greater-than-or-equal-to 0.3 nmol). 4 Capsaicin, which selectively activates sensory nerves, caused a dose-dependent increase in blood flow when injected intradermally into rabbit skin. The effects of capsaicin (0.01-0.1-mu-mol/site) were inhibited by CGRP8-37 (0.3 nmol/site), with a partial but significant attenuation of blood flow induced by the highest dose of capsaicin. 5 Oedema formation, induced by intradermal histamine injection (3 nmol/site), was measured in rabbit skin by the local accumulation of intravenously-injected I-125-labelled albumin. Vasodilator doses of CGRP, PGE1 and capsaicin potentiated, in a synergistic manner, oedema formation induced by histamine. CGRP8-37 totally inhibited the potentiating effect of CGRP, partially inhibited the synergistic effect of capsaicin, but did not affect PGE1-induced responses. 6 The results suggest that capsaicin acts to release a rabbit form of CGRP in skin and that CGRP8-37 is a useful antagonist for investigating the potential of CGRP as a neurogenic mediator of inflammation.