INTRACELLULAR [MG-III ANTIARRHYTHMIC DRUG(+] DETERMINES SPECIFICITY OF K+ CHANNEL BLOCK BY A CLASS)

E-4031 and related methanesulfonanilide class III antiarrhythmic drugs block I-Kr, a cardiac delayed rectifier K+ current. The current-volta ge relationship of I-Kr exhibits rectification; currents progressively decline in magnitude al test potentials >0 mV. Whole-cell voltage-cla mp techniques were used to determine whether rectification results fro m block of channels by intracellular Mg++. The properties of E-4031-se nsitive current were compared in guinea pig ventricular myocytes inter nally perfused with either a nominally Mg++-free solution or with a so lution containing 1 mM Mg++. Based on an envelope of tails test, we co nclude that inward rectification of guinea pig I-Kr is due to a voltag e-dependent gating mechanism and does not result from block of the cha nnel by intracellular Mg++. Under normal physiologic conditions, E-403 1 is a specific blocker of I-Kr. However, in the absence of intracellu lar Mg++, E-4031 also partially blocks I-Ks. Block of I-Ks is prevente d by prior treatment of cells with isoproterenol, which suggests that E-4031 only blocks unphosphorylated I-Ks channels in the absence of in tracellular Mg++.