CGRP AND NITRIC-OXIDE OF NEURONAL ORIGIN AND THEIR INVOLVEMENT IN NEUROGENIC VASODILATATION IN RAT SKIN MICROVASCULATURE

1 Sensory nerves are important for the initiation of neurogenic inflam mation and tissue repair. Both calcitonin gene-related peptide (CGRP) and nitric oxide (NO) have been implicated in neurogenic vasodilatatio n and inflammatory responses. 2 A blister model in the rat hind footpa d was used as a site to induce neurogenic vasodilatation in response t o antidromic electrical stimulation of the sciatic nerve. Blood flux w as monitored with a laser Doppler flow monitor. 3 The quantitative con tributions of CGRP and NO to vasodilatation were examined by use of th e CGRP receptor antagonist CGRP(8-37) and NO synthase inhibitors 7-nit roindazole (7-NI), 3-bromo 7-NI and N-G-nitro L-arginine methyl ester (L-NAME). The potential modulatory role of endothelin was examined by use of the ETA receptor antagonist BQ-123. 4 CGRP(8-37) (10 mu M) was perfused over the blister base before nerve stimulation and continuous ly throughout the post-stimulation period, resulting in a significant reduction (41%) in the blood flux vascular response. 5 Pretreatment wi th the specific neuronal NO synthase inhibitors, 7-NI and 3-bromo 7-NI (10 mg kg(-1), i.v.), and of the non-specific L-NAME (100 mu M), resu lted in significant inhibition of the blood flux response (36%, 72% an d 57% decrease, respectively). In contrast, 7-NI treatment in young ra ts pretreated with capsaicin had no further effect on the vascular res ponse, suggesting that the source of NO is the sensory nerves. 6 BQ-12 3 (10 mu M) significantly enhanced the stimulation-induced blood Aux r esponse (61% increase). When 7-NI was co-administered with either CGRP (8-37) Or BQ-123, the drug actions were additive, suggesting that ther e was no interaction between NO and CGRP or endothelin. 7 These data s uggest that both NO and CGRP participate in neurogenic vasodilatation in rat skin microvasculature and that this response is modulated by en dogenous endothelin.