Vesnarinone prolongs action potential duration without reverse frequency dependence in rabbit ventricular muscle by blocking the delayed rectifier K+ current

Background Methanesulfonanilide derivatives, selective inhibitors of the rapidly activating component (I-Kr) of the delayed rectifier potassium current (I-K), prolong action potential duration (APD) of cardiac muscles with reverse frequency dependence, which limits their clinical use because of proarrhythmia. Vesnarinone, a quinolinone derivative developed as cardiotonic agent, has complex pharmacological properties, but its clinical efficacy is explained in part by I-K reduction. Therefore, we investigated the mode of I-K block by vesnarinone. Methods and Results I-K of the rabbit ventricular myocyte was activated by voltage-clamp steps applied from a holding potential to various depolarizing levels. The development of I-K block at depclarization (+10 mV) and its recovery process at hyperpolarization (-75 mV) were compared between vesnarinone and E-4031. The I-K block by vesnarinone (3 mu mol/L) developed and recovered monoexponentially, with time constants of 361 ms (n=5) and 1.87 seconds (n=4), respectively, I-K block by E-4031 (0.3 mu mol/L) developed instantaneously. with no recovery from the block at hyperpolarization. The I-K block by vesnarinone, estimated by I-K tail after a train of depolarizing pulses (for 30 seconds at 0.2. to 2 Hz), was increased with increasing frequency (two-fold at 2 from 0.2 Hz), but that by E-4031 was unchanged. In rabbit papillary muscles, vesnarinone (10 mu mol/L) prolonged APD at stimulation frequencies >0.2 Hz, whereas E-4031 (0.3 mu mol/L) prolonged that in a reverse frequency-dependent manner. Conclusions Vesnarinone may prolong the repolarization of human cardiac muscle without reverse frequency dependence, because I-K, is expressed in humans as well as in the rabbit, Thus, this drug may be a model for an ideal class III drug without the risk of proarrhythmia.