The effects of calcitonin gene-related peptide (CGRP) I(alpha) (human), CGRP II(beta) (human), CGRP (rat), and [Tyr0]-CGRP (rat) on the resting tone of opossum internal anal sphincter (IAS) were studied. Different CGRPs identified above produced a concentration-dependent fall in the resting tension of the IAS. CGRP II (human) was most potent, while [Tyr0]-CGRP (rat) was the least. The fall in IAS tension caused by CGRP II (human) was not modified by the neurotoxin tetrodotoxin, beta adrenoceptor antagonist propranolol and prostaglandin synthesis inhibitor indomethacin. In contrast to the other CGRP analogs, [Tyr0]-CGRP 28-37 (rat) produced no significant effects on the resting tension of the IAS. However, the fragment caused significant rightward shifts in the concentration-effect curves of different CGRP analogs examined on the IAS. [Tyr0]-CGRP 28-37 (rat) was found to be almost equipotent in antagonizing the inhibitory effects of CGRP (rat) and [Tyr0]-CGRP (rat), but was approximately 12 and 4 times more potent in antagonizing the responses of CGRP I (human) and CGRP II (human), respectively, as compared to that of CGRP (rat) and [Tyr0]-CGRP (rat). Calcitonin, on the other hand, caused a rise in the IAS tension by its action directly at the smooth muscle and this was not modified by [Tyr0]-CGRP 28-37. Thus, we conclude that: 1) CGRP causes a fall in the resting tension of IAS by its action directly at the smooth muscle; 2) [Tyr0]-CGRP 28-37 (rat) may serve as an antagonist of CGRP responses and 3) CGRP and calcitonin produce opposite actions on the resting IAS tension by the activation of their own receptors at the smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)