Focaccio A, Peeters G, Movsesian M, Roden R, Eki Y, Krall J, Bristow M R
Department of Cardiology, University of Naples, Italy.
Circulation. 1996 Feb 15;93(4):817-25. doi: 10.1161/01.cir.93.4.817.
The quinolinone compounds OPC-8212 (vesnarinone), OPC-18790, and OPC-8490 are members of a family of unique positive inotropic compounds that have no positive chronotropic effects. In subjects with heart failure, the prototypic compound OPC-8212 may reduce morbidity and mortality at low doses but increase mortality at high doses.
To further characterize the inotropic mechanism(s) of action of these compounds, we investigated the effects of OPC-8490, a water-soluble quinolinone, on the inotropic response, inhibition of phosphodiesterase (PDE), and action potential in human ventricular myocardial preparations. In isolated right ventricular trabeculae and membranes prepared from left ventricular myocardium, OPC-8490 produced dose-related positive inotropic effects, inhibited type III PDE activity, and prolonged action potential. Comparative experiments with other PDE inhibitors, sodium channel agonists, and potassium channel antagonists indicated that the positive inotropic effects are due to PDE inhibition, whereas the action potential effects of OPC-8490 are due to effects on ion channels.
We conclude that OPC-8490 produces selective positive inotropic effects because of type III PDE inhibition combined with ion channel effects, with the latter property inhibiting the positive chronotropic response usually associated with agents that increase intracellular cAMP concentrations.
喹啉酮化合物OPC - 8212（维司力农）、OPC - 18790和OPC - 8490是一类独特的正性肌力化合物家族成员，它们没有正性变时作用。在心力衰竭患者中，原型化合物OPC - 8212在低剂量时可能降低发病率和死亡率，但在高剂量时会增加死亡率。
为了进一步阐明这些化合物的正性肌力作用机制，我们研究了水溶性喹啉酮OPC - 8490对人心室肌标本的正性肌力反应、磷酸二酯酶（PDE）抑制作用及动作电位的影响。在分离的右心室小梁和左心室心肌制备的膜片中，OPC - 8490产生剂量相关的正性肌力作用，抑制III型PDE活性，并延长动作电位。与其他PDE抑制剂、钠通道激动剂和钾通道拮抗剂的对比实验表明，正性肌力作用是由于PDE抑制，而OPC - 8490对动作电位的影响是由于对离子通道的作用。
我们得出结论，OPC - 8490产生选择性正性肌力作用是因为III型PDE抑制与离子通道作用相结合，后一特性抑制了通常与增加细胞内cAMP浓度的药物相关的正性变时反应。
