Contractile and coronary vascular effects of pituitary adenylate cyclase activating polypeptide in neonatal pig hearts

OBJECTIVE: The purpose was to investigate the influence of the 38-amino-acid neuropeptide, pituitary adenylate cyclase activating polypeptide (PACAP38), on contractile function and coronary vascular tone in neonatal hearts. METHODS: Isolated, paced (150 bpm), isovolumically-beating, piglet hearts (n = 19) underwent retrograde aortic perfusion at constant coronary flow (approximately 2.5 ml/min/gwet) with an erythrocyte-enriched (Hct 15-20%) solution (37 degrees C). Agonists were injected into the aortic root of hearts, and the changes in +dP/dtmax and -dP/dtmax (reflecting contractility), and coronary perfusion pressure (reflecting vascular tone) were determined. Responses to PAPCAP38 were compared to isoproterenol, and to the truncated peptide PACAP6-38. RESULTS: PACAP38 (0.1 and 0.5 nmol) increased +dP/dtmax from 1387.4 +/- 134.6 to 1619.0 +/- 118.7, and from 1296.2 +/- 93.4 to 1872.2 +/- 111.4 mmHg/s (P < 0.05); changed -dP/dtmax from -1087.6 +/- 107.5 to -1206.6 +/- 93.6, and from -1025.0 +/- 46.8 to -1375.4 +/- 80.9 mmHg/s (P < 0.05) and decreased coronary perfusion pressure from 61.8 +/- 2.5 to 51.0 +/- 3.8, and from 62.5 +/- 1.0 to 45.3 +/- 3.3 mmHg (P < 0.005), respectively. In comparison, isoproterenol (0.1 nmol) increased +dP/dtmax from 1313.6 +/- 62.8 to 1679.0 +/- 74.4 (P < 0.05), and -dP/dtmax from -1026.4 +/- 54.1 to -1222.6 +/- 57.4 mmHg/s (P < 0.05). PACAP6-38 reduced PACAP38's coronary vasodilatory, but not its contractile, effect. When compared to our previous studies of the 27-amino-acid neuropeptide PACAP27, PACAP38 had less potent contractile, but similar vasodilatory effects. CONCLUSIONS: PACAP38 enhanced contractility and produced coronary vasodilation in piglet hearts, which may make PACAP38 a promising cardiotonic agent for the treatment of neonates with heart failure.