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(Circulation. 1997;96:3696-3703.)
© 1997 American Heart Association, Inc.

Articles

Vesnarinone Prolongs Action Potential Duration Without Reverse Frequency Dependence in Rabbit Ventricular Muscle by Blocking the Delayed Rectifier K⁺ Current

Junji Toyama, MD; Kaichiro Kamiya, MD; Jianhua Cheng, MD, PhD; Jong-Kook Lee, MD; Ryoko Suzuki, BSc; ; Itsuo Kodama, MD

From the Department of Circulation (J.T., K.K., J.C., J.K.L.) and the Department of Humoral Regulation (R.S., I.K.), Research Institute of Environmental Medicine, Nagoya (Japan) University.

Correspondence to Kaichiro Kamiya, MD, Department of Circulation, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464–01 Japan.

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 a 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 depolarization (+10 mV) and its recovery process at hyperpolarization (-75 mV) were compared between vesnarinone and E-4031. The I_K block by vesnarinone (3 µmol/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 µmol/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 (twofold at 2 from 0.2 Hz), but that by E-4031 was unchanged. In rabbit papillary muscles, vesnarinone (10 µmol/L) prolonged APD at stimulation frequencies >0.2 Hz, whereas E-4031 (0.3 µmol/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_Kr 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.

Key Words: arrhythmia • potassium channels • action potentials

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