BLOCK OF I-KS, THE SLOW COMPONENT OF THE DELAYED RECTIFIER K+ CURRENT, BY THE DIURETIC AGENT INDAPAMIDE IN GUINEA-PIG MYOCYTES

There is a high incidence of diuretic use among patients who develop exaggerated QT prolongation and polymorphic ventricular tachycardia (torsade de pointes) during treatment with action potential-prolonging agents. Diuretic-induced hypokalemia is thought to be the usual mechanism, but a direct effect of diuretic drugs on repolarizing currents is an additional possibility. Therefore, in this study, we examined the effects of the diuretic agents chlorthalidone and indapamide on the cardiac delayed rectifier current. In guinea pig ventricular myocytes, this current is made up of two components: I-Kr, a rapidly activating, inwardly rectifying current blocked by most action potential-prolonging antiarrhythmics, and I-Ks, a slowly activating component. In this preparation, indapamide blocked outward current in a time-, voltage- and concentration-dependent fashion, whereas chlorthalidone (1 mmol/L) was without effect. The following features of the effect of indapamide strongly suggest selective block of I-Ks: (1) Indapamide block was significantly greater with 5000-millisecond activating pulses (-43 +/- 5% at +50 mV [100 mu mol/L indapamide]) than with 225-millisecond ones (-20 +/- 5%; n = 5, P < .01), and the signature of the indapamide-sensitive current was a slowly activating delayed rectifier current. (2) The voltage dependence of indapamide block (EC(50), 101 mu mol/L at +50 mV and 196 mu mol/L at +10 mV) was consistent with preferential block of I-Ks relative to I-Kr. (3) In the presence of indapamide, an envelope-of-tails test for I-Kr was satisfied. The drug-insensitive current had rectifying properties similar to those described for I-Kr in these cells. In addition, under experimental conditions where only I-Kr was present, indapamide was without effect. When Xenopus oocytes were injected with minK, a cRNA encoding an I-Ks-like current, induced current was blocked by indapamide. These studies demonstrate that indapamide is a K+ channel blocker but, unlike most antiarrhythmics, targets I-Ks.