Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel - Open-channel block by methanesulfonanilides

We recently reported that mutations in HERG, a potassium channel gene, cause long QT syndrome. Heterologous expression of HERG in Xenopus oocytes revealed that this channel had biophysical properties nearly identical to a cardiac delayed rectifier K+ current, I-Kr, but had dissimilar pharmacological properties. Class III antiarrhythmic drugs such as E-4031 and MK-499 are potent and specific blockers of I-Kr in cardiac myocytes. Our initial studies indicated that these compounds did not block HERG at a concentration of 1 mu mol/L. In the present study, we used standard two-microelectrode voltage-clamp techniques to further characterize the effects of these drugs on HERO channels expressed in oocytes. Consistent with initial findings, 1 mu mol/L MK-499 and E-4031 had no effect on HERO when oocytes were voltage clamped at a negative potential and not pulsed during equilibration with the drug. However, MK-499 did block HERG current if oocytes were repetitively pulsed, or clamped at a voltage positive to the threshold potential for channel activation. This finding is in contrast to previous studies that showed significant block of I-Kr in isolated myocytes by similar drugs, even in the absence of pulsing. This apparent discrepancy may be due to differences in channel characteristics (HERG versus guinea pig and mouse I-Kr), tissue (oocytes versus myocytes), or specific drugs. Under steady state conditions, block of HERO by MK-499 was half maximal at 123+/-12 nmol/L at a test potential of -20 mV. MK-499 (150 nmol/L) did not affect the voltage dependence of activation and rectification nor the kinetics of activation and deactivation of HERG. These data indicate that MK-499 preferentially blocks open HERG channels and further support the conclusion that HERG subunits form I-Kr channels in cardiac myocytes.