In the present study, selective calcitonin gene-related peptide (CGRP) and neurokinin (NK) agonists and antagonists were used to characterize the receptors mediating the nerve-induced arterial vasodilation and venous vasoconstriction in the rat mesenteric vasculature. In guanethidine-pretreated preparations, perivascular nerve stimulation (PNS) induced a frequency-dependent vasodilation in the arterial vasculature (precontracted with methoxamine), yet only induced an atropine-resistant contraction in the venous mesenteric vasculature (precontracted with U46619) of the rat. hCGRP alpha induced a marked dose-dependent relaxation of the arterial side, whereas only a slight vasodilation was seen at a high dose on the precontracted venous side. The PNS or hCGRP alpha-induced arterial dilatation was markedly reduced by the antagonist hCGRP8-37, whereas the venoconstrictive response to PNS was not. Furthermore, [acetamidomethyl-Cys2,7]hCGRP was inactive on either side of the rat mesenteric vasculature. A selective NK-1 nonpeptidic antagonist (CP-96,345) reduced the response of the venous vasculature to PNS by 70% without affecting the response of the arterial side to the same stimulus. Furthermore, a selective NK-3 receptor antagonist ([Trp7,beta-Ala8]-NKA (4-10)) did not affect the venoconstriction induced by PNS, yet markedly reduced the pressor response induced by a selective NK-3 receptor agonist, [MePhe7]-NKB. Hence, PNS induces the release of CGRP which activates specifically CGRP1 receptors and induces relaxation on the arterial vasculature. On the venous side, the nerve stimulation activates transmural NK-1 receptors and evokes a venoconstriction.