PACAP INDUCES BRADYCARDIA IN GUINEA-PIG HEART BY STIMULATION OF ATRIAL CHOLINERGIC NEURONS

Based on previous studies which indicated that pituitary adenylate cyc lase activating peptide (PACAP) acts as a positive inotropic and chron otropic substance in different species via the cAMP signal transductio n pathway, the objective of the present work was to investigate cAMP-r egulated myocardial key proteins in response to PACAP in isolated vent ricular cells of the guinea pig. Surprisingly, the two molecular forms of PACAP, PACAP(1-27) and PACAP(1-38), showed no effect on intracellu lar cAMP-levels, L-type Ca(2+)channel current or phosphorylation of tr oponin inhibitor (TnI) and phospholamban (PLB), Additionally, inotropy of isolated guinea-pig ventricular strips was not affected by the neu ropeptide. However, in isolated spontaneously beating guinea-pig atria , PACAP(1-27) and PACAP(1-38), but not VIP induced severe bradycardia in a dose-dependent manner, This effect could be prevented by preincub ation with the PACAP receptor antagonist PACAP(6-38), by atropine and by omega-conotoxin, a blocker of neuronal N-type Ca(2+)channels. PACAP stimulates release of [H-3]-labelled acetylcholine. Only preparations showing an increase in [H-3]acetylcholine release developed bradycard ia, indicating a causal relationship between both phenomena. It was co ncluded that PACAP exerts no influence on guinea-pig ventricular tissu e, but induces negative chronotropic effects in isolated guinea-pig at ria by stimulation of acetylcholine release from parasympathetic neuro ns via PACAP type 1 receptors.