Endogenous as well as synthetic cannabinoids have potent vasodilatory actions in a variety of preparations. Their precise mechanism of action is as yet unclear, but several studies point to an indirect mechanism not involving cannabinoid receptors. In some blood vessels, it has been proposed that these substances activate type 1 vanilloid (TRPV1) receptors on primary afferent perivascular nerves, stimulating the release of vasodilatory neuropeptides such as calcitonin gene related peptide (CGRP). In earlier experiments we found a discrepancy between the type of K⁺ channel that is activated by exogenous CGRP. Vasorelaxation to CGRP was sensitive to BK_Ca channel blockers whereas a hyperpolarization to CGRP was sensitive to K_ATP channel blockers. In the present study the influence of the cannabinoid methanandamide and of exogenous CGRP (10^-8M) on the macroscopic potassium currents of rat mesenteric artery myocytes was investigated. Whole-cell membrane currents of isolated small mesenteric smooth muscle cells of Wistar female rats were recorded at room temperature using the conventional and perforated patch-clamp technique. Membrane currents were evoked by stepping the membrane potential from a holding potential of -70 mV for 200 ms to various test potentials between -110 and +60 mV, in 10 mV increments. Methanandamide (10^-5M) was ineffective at influencing I_K. CGRP activated a whole-cell current that was blocked by TEA (1 mM) and iberiotoxin (10 mM) and not blocked by glibenclamide (100 mM). However when we reduced the concentration of intracellular calcium and intracellular ATP in the pipette solution, CGRP had no significant effect on the macroscopic potassium current. In the perforated patch configuration no significant effect of CGRP on the current was seen. Our results show no direct effect of methanandamide on macroscopic potassium currents in mesenteric smooth muscle cells, corroborating earlier studies that the substance acts indirectly. CGRP activates BK_Ca channels, but does not seem to activate K_ATP channels in these cells in the present conditions.