PACAP-38 activates parasympathetic nerves in isolated, blood-perfused dog atria

A pituitary adenylate cyclase-activating polypeptide (PACAP) activates PACAP and vasoactive intestinal peptide (VIP) receptors. We investigated the effects of PACAP-38 on the sinus rate and atrial contractile force in isolated, blood-perfused dog heart preparations and the stimulation by PACAP-38 of the parasympathetic nerve fibers. PACAP-38 (3-1000 pmol) caused positive and/or negative chronotropic responses and it dose dependently increased atrial and ventricular contractile force. The positive cardiac responses to PACAP-38 unlike those to VIP were much less than the positive responses to norepinephrine. Atropine inhibited the negative chronotropic responses to PACAP-38 and augmented the positive chronotropic and inotropic responses. Physostigmine potentiated the negative cardiac responses to PACAP-38 and acetylcholine. After physostigmine treatment, additionally, tetrodotoxin blocked the negative cardiac responses to PACAP-38 and intracardiac parasympathetic nerve stimulation. Propranolol did not inhibit the positive cardiac responses to PACAP-38 in atropine-treated atria. PACAP-(6-38) (1 and 3 nmol), an antagonist of PACAP-38, did not affect the cardiac responses to 100 pmol of PACAP-38. These results suggest that (1) PACAP-38 directly increases sinus rate and atrial contractile force and (2) PACAP-38 activates parasympathetic nerves and causes negative chronotropic and inotropic responses in the dog heart.