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

<jats:p><jats:italic>Background</jats:italic>Methanesulfonanilide derivatives, selective inhibitors of the rapidly activating component (<jats:italic>I</jats:italic><jats:sub>Kr</jats:sub>) of the delayed rectifier potassium current (<jats:italic>I</jats:italic><jats:sub>K</jats:sub>), 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<jats:italic>I</jats:italic><jats:sub>K</jats:sub>reduction. Therefore, we investigated the mode of<jats:italic>I</jats:italic><jats:sub>K</jats:sub>block by vesnarinone.</jats:p><jats:p><jats:italic>Methods and Results</jats:italic><jats:italic>I</jats:italic><jats:sub>K</jats:sub>of the rabbit ventricular myocyte was activated by voltage-clamp steps applied from a holding potential to various depolarizing levels. The development of<jats:italic>I</jats:italic><jats:sub>K</jats:sub>block at depolarization (+10 mV) and its recovery process at hyperpolarization (−75 mV) were compared between vesnarinone and E-4031. The<jats:italic>I</jats:italic><jats:sub>K</jats:sub>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.<jats:italic>I</jats:italic><jats:sub>K</jats:sub>block by E-4031 (0.3 μmol/L) developed instantaneously, with no recovery from the block at hyperpolarization. The<jats:italic>I</jats:italic><jats:sub>K</jats:sub>block by vesnarinone, estimated by<jats:italic>I</jats:italic><jats:sub>K</jats:sub>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.</jats:p><jats:p><jats:italic>Conclusions</jats:italic>Vesnarinone may prolong the repolarization of human cardiac muscle without reverse frequency dependence, because<jats:italic>I</jats:italic><jats:sub>Kr</jats:sub>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.</jats:p>