Although dense networks of adrenergic nerves are present and noradrenaline causes vasoconstriction, electrical field stimulation failed to elicit any constriction of the isolated ring preparation of the guinea pig mesenteric artery. In the presence of an active tone, a vasodilator response was elicited by electrical field stimulation in endothelium-removed tissues. Nonadrenergic, noncholinergic nerves mediate the electrical field stimulation-induced vasodilator response, since guanethidine and atropine did not affect while tetrodotoxin abolished it. Multiple mediators seem to participate in this vasodilatation. NADPH-diaphorase-positive nerves, calcitonin gene-related peptide (CGRP)- and vasoactive intestinal peptide (VIP)-immunoreactive nerves were present in the mesenteric artery. Nitro-L-arginine but not nitro-D-arginine suppressed the electrical field stimulation-induced vasodilator response with rapid onset and L-arginine restored it. VIP and CGRP relaxed the tissue in a dose-dependent manner. Pretreatment of the animals with capsaicin partly reduced the electrical field stimulation-induced vasodilator response. CGRP-(8-37), a CGRP antagonist, slightly attenuated the vasodilator response induced by both electrical field stimulation and CGRP. Glibenclamide, an inhibitor of ATP-sensitive K+ channels, decreased the nitro-L-arginine- and capsaicin-insensitive component of the electrical field stimulation-induced vasodilator response. Zinc protoporphyrin IX, an inhibitor of CO formation, did not affect the electrical field stimulation-induced response. In the presence of nitro-L-arginine without an active tone, electrical field stimulation induced a vasoconstrictor response that was sensitive to bunazosin and guanethidine. The results show that the electrical field stimulation-induced vasodilator response of the mesenteric artery of guinea pigs is mediated by nitric oxide (NO), CGRP and some yet unidentified substance(s). Elimination of the vasodilator response unmasked the adrenergic vasoconstrictor response to electrical field stimulation.