VASODILATION BY CALCITONIN GENE-RELATED PEPTIDE (CGRP) AND BY TRANSMURAL-STIMULATION OF THE METHOXAMINE-CONTRACTED RAT HEPATIC-ARTERY AFTER PRETREATMENT WITH GUANETHIDINE

Non-cholinergic, non-adrenergic vasodilation has been studied by transmural field stimulation of the isolated rat hepatic artery and compared with responses in the splenic artery. In the hepatic artery with rubbed endothelium, transmural stimulation caused a contracture that was blocked by phentolamine and potentiated after capsaicin. After pretreatment with guanethidine in order to deplete the neuronal stores of noradrenaline, the methoxamine-contracted hepatic artery was significantly relaxed by transmural stimulation; more efficiently than the splenic artery. This relaxation of the hepatic artery was attenuated following a 30 min exposure to capsaicin and largely blocked by tetrodotoxin (TTX). The relaxation by exogenous CGRP was independent of a functional endothelium. In contrast, vasodilation by substance P (SP) and neurokinin A (NKA), was completely dependent on an intact endothelium. Exogenous CGRP caused a near-complete relaxation of the methoxamine-contracted hepatic artery both before and after capsaicin treatment. CGRP was a more efficient relaxant of the hepatic than the splenic artery. These findings show that responses to transmural stimulation of the hepatic artery are modulated after pretreatment with capsaicin, indicating release of relaxing substances such as CGRP, presumably from capsaicin-sensitive neuronal stores. In conclusion, CGRP is a likely mediator of neuronal vasodilation in the rat liver, independent of the state of the endothelium.