Pituitary adenylate cyclase-activating polypeptide-27 causes a biphasic chronotropic effect and atrial fibrillation...

We investigated the effects of a neuropeptide, pituitary adenylate cyclase-activating polypeptide- (PACAP) 27, on the sinoatrial nodal pacemaker activity and the mechanisms for the cardiac effects of PACAP-27 in the autonomically decentralized heart of the anesthetized dog. PACAP-27 (0.01-0.3 nmol) injected into the sinus node artery increased followed by decreased sinus rate. PACAP-27 (0.1 and 0.3 nmol) caused atrial fibrillation spontaneously. After atropine, PACAP-27 never decreased but only increased sinus rate as did vasoactive intestinal peptide. However, propranolol did not affect the negative and positive chronotropic effects. Tetrodotoxin but not hexamethonium abolished the negative chronotropic response to PACAP-27 in atropine nontreated dogs, and tetrodotoxin also inhibited the positive chronotropic response by 34% in atropine-treated dogs. In atropine- and propranolol-treated dogs, positive chronotropic responses to PACAP-27 were inhibited by PACAP-(6-27), a PACAP receptor antagonist but not by vasoactive intestinal peptide (10-28), a vasoactive intestinal peptide receptor antagonist. These results indicate that PACAP-27 causes the negative chronotropic effect through the postganglionic parasympathetic nerve activation and it produces the positive chronotropic effect mediated by PACAP receptors with an activation of non-adrenergic, nonvasoactive intestinal peptide-ergic nerves at least in part in the dog heart. Atropine and tetrodotoxin abolished atrial fibrillation induced by PACAP-27 but other blockers did not. These results suggest that neurally released acetylcholine induced by PACAP-27 participates in the induction of atrial fibrillation.