CLASS-III ANTIARRHYTHMIC DRUGS BLOCK HERG, A HUMAN CARDIAC DELAYED RECTIFIER K- OPEN-CHANNEL BLOCK BY METHANESULFONANILIDES( CHANNEL )

We recently reported that mutations in HERG, a potassium channel gene, cause long QT syndrome. Heterologous expression of HERG in Xenopus oo cytes revealed that this channel had biophysical properties nearly ide ntical to a cardiac delayed rectifier K+ current, I-Kr, but had dissim ilar pharmacological properties. Class III antiarrhythmic drugs such a s E-4031 and MK-499 are potent and specific blockers of I-Kr in cardia c 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-403 1 had no effect on HERO when oocytes were voltage clamped at a negativ e potential and not pulsed during equilibration with the drug. However , MK-499 did block HERG current if oocytes were repetitively pulsed, o r clamped at a voltage positive to the threshold potential for channel activation. This finding is in contrast to previous studies that show ed significant block of I-Kr in isolated myocytes by similar drugs, ev en in the absence of pulsing. This apparent discrepancy may be due to differences in channel characteristics (HERG versus guinea pig and mou se I-Kr), tissue (oocytes versus myocytes), or specific drugs. Under s teady state conditions, block of HERO by MK-499 was half maximal at 12 3+/-12 nmol/L at a test potential of -20 mV. MK-499 (150 nmol/L) did n ot affect the voltage dependence of activation and rectification nor t he kinetics of activation and deactivation of HERG. These data indicat e that MK-499 preferentially blocks open HERG channels and further sup port the conclusion that HERG subunits form I-Kr channels in cardiac m yocytes.