J. Turgeon et al., BLOCK OF I-KS, THE SLOW COMPONENT OF THE DELAYED RECTIFIER K-PIG MYOCYTES( CURRENT, BY THE DIURETIC AGENT INDAPAMIDE IN GUINEA), Circulation research, 75(5), 1994, pp. 879-886
There is a high incidence of diuretic use among patients who develop e
xaggerated QT prolongation and polymorphic ventricular tachycardia (to
rsade de pointes) during treatment with action potential-prolonging ag
ents. Diuretic-induced hypokalemia is thought to be the usual mechanis
m, but a direct effect of diuretic drugs on repolarizing currents is a
n additional possibility. Therefore, in this study, we examined the ef
fects of the diuretic agents chlorthalidone and indapamide on the card
iac delayed rectifier current. In guinea pig ventricular myocytes, thi
s current is made up of two components: I-Kr, a rapidly activating, in
wardly rectifying current blocked by most action potential-prolonging
antiarrhythmics, and I-Ks, a slowly activating component. In this prep
aration, indapamide blocked outward current in a time-, voltage- and c
oncentration-dependent fashion, whereas chlorthalidone (1 mmol/L) was
without effect. The following features of the effect of indapamide str
ongly suggest selective block of I-Ks: (1) Indapamide block was signif
icantly 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-sensitiv
e current was a slowly activating delayed rectifier current. (2) The v
oltage 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 ce
lls. In addition, under experimental conditions where only I-Kr was pr
esent, indapamide was without effect. When Xenopus oocytes were inject
ed with minK, a cRNA encoding an I-Ks-like current, induced current wa
s blocked by indapamide. These studies demonstrate that indapamide is
a K+ channel blocker but, unlike most antiarrhythmics, targets I-Ks.