Cardiohemodynamic and electrophysiological effects of a selective EP4 receptor agonist ONO-AE1-329 in the halothane-anesthetized dogs
Cardiohemodynamic and electrophysiological effects of a selective EP4 receptor agonist ONO-AE1-329 in the halothane-anesthetized dogs
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选择性 EP4 受体激动剂 ONO-AE1-329 对氟烷麻醉犬的心脏血流动力学和电生理学影响
DOI：
10.1016/j.ejphar.2015.06.012
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发表时间：
2015
期刊：
影响因子：
5
通讯作者：
Sugiyama A
中科院分区：
文献类型：
--
作者：
Nomura H;Nakamura Y;Cao X;Honda A;Katagi J;Ohara H;Izumi-Nakaseko H;Satoh Y;Ando K;Sugiyama A
使用氟烷麻醉的狗 (n=6) 评估高选择性前列腺素 E2 型 4 (EP4) 受体激动剂 ONO-AE1-329 的心血管作用。 ONO-AE1-329 以 0.3、1 和 3 ng/kg/min 的三种递增剂量静脉输注，持续 10 分钟，剂量之间暂停 20 分钟。 0.3 ng/kg/min 的低剂量使 20 分钟时左心室压力的最大上冲速度显着增加 18%，表明心室收缩力增加。中剂量1ng/kg/min在10分钟时显着降低总外周阻力24%和左心室舒张末压32%，分别表明小动脉阻力血管和静脉电容血管扩张；除了低剂量引起的变化外，10 分钟时心输出量增加了 25%。 3 ng/kg/min 的高剂量在 10 分钟时心率增加了 34%； 10 分钟时平均血压降低 14%，5 分钟时房室结传导时间降低 13%；除了中等剂量引起的变化外，10 分钟时左心室收缩期缩短了 8%，机电耦合（定义为从复极完成到心室舒张开始的时间间隔）在 10 分钟时缩短了 39%。在心室复极期间没有检测到显着变化。这些结果表明，ONO-AE1-329 作为膨胀剂可能具有与典型磷酸二酯酶 3 抑制剂相似的心血管特征，并表明 EP4 受体刺激可以成为治疗充血性心力衰竭的替代策略。
Cardiovascular effects of a highly selective prostaglandin E2type 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 EP4receptor stimulation can become an alternative strategy for the treatment of congestive heart failure.