Methanandamide hyperpolarizes gastric arteries by stimulation of TRPV1 receptors on perivascular CGRP containing nerves

Endogenous as well as synthetic cannabinoids have potent vasodilatory actions in a variety of vascular preparations. Their precise mechanism of action is as yet unclear, but several Studies point to the activation of type 1 vanilloid (TRPV1) receptors oil primary afferent perivascular nerves, stimulating the release of calcitonin gene related peptide (CGRP). Given the documented gastroprotective Function of these nerves, and the various gastrointestinal effects reported for cannabinoids, we explored a possible link between these systems in the gastric circulation by comparing responses of small gastric arteries to cannabinoids and to calcitonin gene related peptide using conventional microelectrode techniques. Exposure of small gastric arteries to the stable endocannabinoid a analogue methanandamide caused a hyperpolarization of the vascular smooth muscle cells, which was completely abolished by the vanilloid receptor antagonist capsazepine (P < 0.01). Exposure to exogenous calcitonin gene related peptide evoked fully reproducible (P > 0.05) hyperpolarizations with similar time Course, unaffected by capsazepine. Preincubation with glibenclamide, an inhibitor of ATP-sensitive potassium (K-ATP) channels, reversed both responses to methanandaamide (P < 0.01) and calcitonin gene related peptide (P < 0.05). Similar results Were Found in rat mesenteric arteries. These findings show that cannabinoids stimulate TPPV1 receptors, presumably causing the release of calcitonin gene related peptide, which hyperpolarizes the smooth muscle cells by activation of K-ATP channels. Because membrane hyperpolarization is a powerful mediator of vasorelaxation, this novel pathway might prove to be,in important mechanism affording gastroprotection.