Both synthetic and endogenous cannabinoids have potent vasodilatory effects in a number of vascular preparations. Their precise mechanism of action, however, is still unclear. In the present study, the relaxant effect of the cannabinoid methanandamide was explored in rat gastric arteries using isometric tension measurements. Since in some vessels, cannabinoids have been shown to release CGRP from perivascular nerves, the influence of methanandamide was compared with that of exogenous CGRP. In our preparations, both methanandamide and exogenous CGRP elicited substantial concentration-dependent relaxations, which were endothelium-independent. Methanandamide-induced relaxations were only slightly inhibited after pre-treatment with capsaicin or capsazepine. Preincubation with 30 mM extracellular K⁺ or with 3 mM TEA significantly inhibited the responses elicited by CGRP, while having no effect on the methanandamide-induced relaxations. Furthermore, the responses to methanandamide were unaffected by the CB₁ receptor antagonist AM251 or the CB₂ receptor antagonists AM630 and SR144528. Abnormal-cannabidiol, a selective agonist of a recently described non-CB₁/non-CB₂ cannabinoid receptor, induced concentration-dependent relaxations comparable to those elicited by methanandamide. Taken together, this study demonstrates that methanandamide is a potent vasodilator in rat gastric arteries. Our results suggest that the major part of the vasorelaxing action of methanandamide is independent of stimulation of CGRP release from the perivascular nerves, but is probably due to activation of a not yet identified non-CB₁/non-CB₂ cannabinoid receptor on the smooth muscle cells.