Effects of rat calcitonin gene-related peptide (rCGRP) on the longitudinal muscle-myenteric plexus (lm-mp) have been investigated in the present study. rCGRP was shown to have a biphasic effect on the nonstimulated lm-mp, i.e., a transient contraction followed by a longer lasting relaxation. This biphasic action was dose-dependent over the concentration range of 10(-10) to 10(-5) M. Tetrodotoxin (1 microM), atropine (1 microM), 2-chloroadenosine (1 microM) and clonidine (1 microM) inhibited the stimulatory effect. Tetrodotoxin and clonidine also partially inhibited the relaxing effect of rCGRP. This biphasic action of rCGRP was also seen on the contraction of the lm-mp elicited by electrical field stimulation. rCGRP showed only a relaxing effect on the nonstimulated plexus-free longitudinal muscle. rCGRP (2.6 x 10(-10) to 2.6 x 10(-7) M) inhibited both the phasic and tonic contractions induced by histamine in a competitive way and showed a more potent effect on the tonic contraction than that on the phasic contraction. rCGRP at the same dose range also inhibited the tonic but not phasic contraction evoked by membrane depolarization with the maximal stimulation of KCl (30 mM). rCGRP inhibited KCl-, but not histamine-induced, extracellular calcium-dependent contraction. The peptide did not affect the dose-response curve of oxotremorine. These results suggest that rCGRP may exert its stimulatory actions on the lm-mp via actions on the plexus nerves, whereas the depressant actions may be mediated via the nerves, as well as directly on the smooth muscle.