EXCITATORY AND INHIBITORY ACTIONS OF PITUITARY ADENYLATE CYCLASE-ACTIVATING PEPTIDE (PACAP) IN THE INTERNAL ANAL-SPHINCTER SMOOTH-MUSCLE - SITES OF ACTIONS

Unlike its effects on the rest of the GI tract, the effects of pituita ry adenylate cyclase-activating peptide (PACAP) on the internal anal s phincter (IAS) are not known. We examined the actions of PACAP-38 (her e PACAP) and PACAP-27 on the basal IAS tone of circular smooth muscle strips before and after the administration of different neurohumoral a ntagonists. PACAP caused a concentration-dependent fall in the basal t one of the IAS. Interestingly, however, at higher concentrations, PACA P caused a biphasic response: an initial contraction followed by a rel axation. Both the contractile and the relaxant responses were insensit ive to atropine, guanethidine, apamin or tetrodotoxin. Both the contra ctile and the relaxant effects were inhibited by PACAP 6-38 (a selecti ve antagonist of PACAP), vasoactive intestinal polypeptide 10-28 (a va soactive intestinal polypeptide antagonist) and PACAP tachyphylaxis. T he nitric oxide synthase inhibitor N-omega-nitro-L-arginine attenuated the inhibitory but not the excitatory effect of PACAP. Conversely, th e contractile but not the relaxant effect of PACAP on the IAS was near ly obliterated by the substance P antagonist spantide. The N-type Ca+-channel blocker omega-conotoxin caused significant suppression of bot h the contractile and the inhibitory actions of PACAP. We conclude tha t in the IAS, PACAP has a dual effect: a contraction followed by a rel axation. The contraction of IAS by PACAP is speculated to occur via th e activation of PACAP receptor at the substance P-containing nerve ter minals. PACAP-induced IAS relaxation, on the other hand, appears to be mediated in large part by its direct action at the smooth muscle cell s and in part by its action at the nerve terminals of the myenteric in hibitory neurons.