Rat mesenteric arteries are innervated by calcitonin gene-related peptide (CGRP)-containing vasodilator nerves (CGRP nerves). This study investigated the presence of presynaptic CGRP receptors on CGRP nerves and the receptors' role in the regulation of CGRP release from these nerves. The rat mesenteric vascular bed was perfused with Krebs' solution containing 7 microM methoxamine plus 5 microM guanethidine to produce active tone and block adrenergic neurotransmission. In this preparation, periarterial nerve stimulation (PNS;2 Hz) and bolus infusion of CGRP (50 pmol) caused a decrease in perfusion pressure caused by vasodilation. Vasodilator response to PNS was abolished by 0.3 microM tetrodotoxin and by 1 microM human CGRP[8-37] (CGRP[8-37]), a CGRP receptor antagonist, which also abolished the response to bolus infusion of CGRP. Perfusion of CGRP (0.03-0.5 nM) dose-dependently inhibited vasodilator response to PNS, whereas it did not affect the response to bolus infusion of CGRP. The inhibitory effect of CGRP (0.3 nM) was antagonized by CGRP[8-37] (3 and 10 nM). Lower concentrations of CGRP[8-37] (1-10 nM) potentiated the vasodilator response to PNS, but higher concentrations (100 nM-1 microM) inhibited the response. The vasodilator response to bolus infusion of CGRP was dose-dependently inhibited by CGRP[8-37]. Eel calcitonin (5 and 50 microM), forskolin (0.01 and 0.1 microM), 3-isobutyl-1-methylxanthine (0.3 and 1 microM) and cyclic 8-bromo-adenosine 3':5'-monophosphate (10 and 100 microM) had no effect on the PNS-induced vasodilation. These results suggest that CGRP nerves are endowed with presynaptic CGRP receptors, which regulate CGRP release from the nerves via a negative feedback mechanism.