CALCITONIN-GENE-RELATED PEPTIDE MEDIATED NEUROGENIC VASORELAXATION INTHE ISOLATED CANINE LINGUAL ARTERY

The nature of neurogenic relaxation was investigated in ring preparati ons of canine lingual artery. In all experiments, the preparations wer e previously treated with guanethidine (5 x 10(-6) M) to block neuroge nic constrictor responses. In the presence of norepinephrine (10(-5) M ) to induce tone, electrical stimulation (10 V, 4 to 16 Hz, for 45 sec ) produced relaxation of the rings in an endothelium-independent fashi on. The relaxant response in endothelium-denuded rings was not changed by propranolol (10(-5) M), and atropine (10(-5) M) did not affect the relaxation elicited by electrical stimulation in endothelium-intact r ings. N-G-monomethyl-L-arginine (10(-4) M) or N-G-nitro-L-arginine met hyl ester (10(-4) M), a nitric oxide (NO) synthase inhibitor, had no e ffect on the electrical stimulation-induced relaxation of endothelium- denuded rings. Human calcitonin gene-related peptide (CGRP)-(8 -37) (2 x 10(-8) M), a CGRP(1)-receptor antagonist, inhibited neurogenic rela xation of endothelium-denuded rings; substance P (10(-6) M) failed to mimic the observed effect of electrical stimulation. The demonstrated effect of electrical stimulation was inhibited by glibenclamide (10(-5 ) M), but not tetraethylammonium (2 x 10(-4) M); glibenclamide abolish ed the relaxation in response to exogenous CGRP or the ATP-sensitive K + channel opener cromakalim (10(-6) M) in endothelium-denuded rings. M oreover, tetrodotoxin (3.13 x 10(-6) M) inhibited the relaxation of en dothelium-denuded rings induced by electrical stimulation. The relaxat ion was selectively inhibited when endogenous CGRP had been depleted f rom perivascular nerves by capsaicin (10(-6) M). These results suggest that CGRP, but not NO, released from non-adrenergic non-cholinergic n erves by electrical stimulation produces relaxation of canine lingual artery that is mediated by activation of CGRP(1) receptors.