Cardiohemodynamic and electrophysiological effects of a selective EP4 receptor agonist ONO­-AE1­-329 in the halothane-anesthetized dogs

Cardiovascular effects of a highly selective prostaglandin E2 type 4 (EP4) receptor agonist ONO-AE1-329 were assessed with the halothane-anesthetized dogs (n=6). ONO-AE1-329 was intravenously infused in three escalating doses of 0.3, 1 and 3 ng/kg/min for 10 min with a pause of 20 min between the doses. The low dose of 0.3 ng/kg/min significantly increased maximum upstroke velocity of left ventricular pressure by 18% at 20 min, indicating increase of ventricular contractility. The middle dose of 1 ng/kg/min significantly decreased total peripheral resistance by 24% and left ventricular end-diastolic pressure by 32% at 10 min, indicating dilation of arteriolar resistance vessels and venous capacitance ones, respectively; and increased cardiac output by 25% at 10 min in addition to the change induced by the low dose. The high dose of 3 ng/kg/min increased heart rate by 34% at 10 min; decreased mean blood pressure by 14% at 10 min and atrioventricular nodal conduction time by 13% at 5 min; and shortened left ventricular systolic period by 8% at 10 min and electromechanical coupling defined as an interval from completion of repolarization to the start of ventricular diastole by 39% at 10 min in addition to the changes induced by the middle dose. No significant change was detected in a ventricular repolarization period. These results indicate that ONO-AE1-329 may possess a similar cardiovascular profile to typical phosphodiesterase 3 inhibitors as an inodilator, and suggest that EP4 receptor stimulation can become an alternative strategy for the treatment of congestive heart failure.