Drug design for cardiac treatment by control of K channel

The delayed rectifier K - D1+ d - D1 current （I - D2K - D2）是最重要的currents之一responsible for repolarization of cardiac action potential. I D2K D2 is composed of twodistinctive组件：a rapidly activating component, I D2Kr D2, and a slowly activating component，I - D2Ks D2. Most of the Class III drugs currently used, such as d-sotalol, dofetilide，sematilide and MS-551 preferentially block I I D2Kr D2. Potassium channel genes which encodeI - D2Kr D2 and I - D2Ks D2, are HERG and KVLQT1/minK, respectively. In this study，我们examined the modulation of various class III antiarrhythmic drugs on HERG and KVLQT1/minKcurrents.We have previously shown that vesnarinone, a cardiotonic agentproduced a frequency-dependent prolongation of action potential duration (APD) in rabbit ventricularmyocytes. This favorable property as a class III antiarrhythmic agent未在前报告其他class III drugs. To elucidate the underlying mechanisms，we studied the effects of vesnarinone on HERG channels，KVLQT1/minK channels in Xenopus oocytes. Vesnarinone provided a concentration-dependentinhibition on HERG current with an IC D250 D2 of 58.7±9.3 μM + 50mv (n=5). The onset of HERG blockby 100μM vesnarinone at +10mV developed with a time constant of 178±15 msec (n=3). vesnarinone at300m produced a minimal reduction in KVLQT1/minK current. These results suggest that 1) theprolongation in APD by vesnarinone is caused by block of HERG, but not KVLQT1/minK channels，2) frequency-dependent prolongation of APD by vesnarinone results from the voltage-dependent bindingand unbinding of the drug to HERG channels with moderate time constants3) inactivation gate may not interfere neither the drug binding nor unbinding when membrane voltagewas altered。

The delayed rectifier KィイD1+ィエD1 current (IィイD2KィエD2) is one of the most important currents responsible for repolarization of cardiac action potential. IィイD2KィエD2 is composed of two distinctive components : a rapidly activating component, IィイD2KrィエD2, and a slowly activating component, IィイD2KsィエD2. Most of the Class III drugs currently used, such as d-sotalol, dofetilide, sematilide and MS-551 preferentially block IィイD2KrィエD2. Potassium channel genes which encode IィイD2KrィエD2 and IィイD2KsィエD2, are HERG and KVLQT1/minK, respectively. In this study, we examined the modulation of various class III antiarrhythmic drugs on HERG and KVLQT1/minK currents.We have previously shown that vesnarinone, a cardiotonic agent, produced a frequency-dependent prolongation of action potential duration (APD) in rabbit ventricular myocytes. This favorable property as a class III antiarrhythmic agent has not been reported with other class III drugs. To elucidate the underlying mechanisms, we studied the effects of vesnarinone on HERG channels, and KVLQT1/minK channels in Xenopus oocytes. Vesnarinone provided a concentration-dependent inhibition on HERG current with an ICィイD250ィエD2 of 58.7±9.3 μM + 50mV (n=5). The onset of HERG block by 100μM vesnarinone at +10mV developed with a time constant of 178±15 msec (n=3). Vesnarinone at 300 M produced a minimal reduction in KVLQT1/minK current. These results suggest that 1) the prolongation in APD by vesnarinone is caused by block of HERG, but not KVLQT1/minK channels, 2) frequency-dependent prolongation of APD by vesnarinone results from the voltage-dependent binding and unbinding of the drug to HERG channels with moderate time constants, 3) inactivation gate may not interfere neither the drug binding nor unbinding when membrane voltage was altered.