Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5827056 | European Journal of Pharmacology | 2015 | 9 Pages |
Abstract
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 3Â ng/kg/min for 10Â min with a pause of 20Â min between the doses. The low dose of 0.3Â ng/kg/min significantly increased maximum upstroke velocity of left ventricular pressure by 18% at 20Â min, indicating increase of ventricular contractility. The middle dose of 1Â ng/kg/min significantly decreased total peripheral resistance by 24% and left ventricular end-diastolic pressure by 32% at 10Â min, indicating dilation of arteriolar resistance vessels and venous capacitance ones, respectively; and increased cardiac output by 25% at 10Â min in addition to the change induced by the low dose. The high dose of 3Â ng/kg/min increased heart rate by 34% at 10Â min; decreased mean blood pressure by 14% at 10Â min and atrioventricular nodal conduction time by 13% at 5Â min; and shortened left ventricular systolic period by 8% at 10Â min and electromechanical coupling defined as an interval from completion of repolarization to the start of ventricular diastole by 39% at 10Â 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.
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Authors
Hiroaki Nomura, Yuji Nakamura, Xin Cao, Atsushi Honda, Jun Katagi, Hiroshi Ohara, Hiroko Izumi-Nakaseko, Yoshioki Satoh, Kentaro Ando, Atsushi Sugiyama,