Effects of the Diuretic Agent Indapamide on Na⁺, Transient Outward, and Delayed Rectifier Currents in Canine Atrial Myocytes

From the Department of Medicine (Z.W., S.N.), University of Montreal; the Research Center (Y.L., L.Y., Z.W., S.N.), Montreal Heart Institute; and the Department of Pharmacology and Therapeutics (L.Y., S.N.), McGill University, Montreal, Quebec, Canada.

Correspondence to Stanley Nattel, MD, Research Center, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec H1T 1C8, Canada. E-mail nattel{at}icm.umontreal.ca

Abstract—The diuretic agent indapamide has been reported to block the slow component of the delayed rectifier K⁺ current (I_Ks) without altering the rapid component (I_Kr) or the inward rectifier current and has been used as a pharmacological probe for I_Ks; however, the effects of indapamide on Na⁺ (I_Na), L-type Ca²⁺ (I_Ca), and transient outward K⁺ (I_to) currents have not been determined. We applied tight-seal, whole-cell, patch-clamp techniques to assess the effects of indapamide on I_Na, I_to, I_Ca, and I_Ks in canine atrial myocytes. Indapamide inhibited I_Na, I_to, and I_Ks in a concentration-dependent and reversible way, without altering I_Ca. Block increased with depolarization, with the 50% blocking concentration (EC₅₀) decreasing from 129±26 µmol/L (at -60 mV) to 79±17 µmol/L (at -10 mV) for I_Na, from 174±19 µmol/L (at +10 mV) to 98±7 µmol/L (at +60 mV) for I_to, and from 148±28 µmol/L (at +10 mV) to 86±18 µmol/L (at +60 mV) for I_Ks. Significant inhibition was seen at concentrations as low as 10 µmol/L for all 3 currents. In addition, indapamide effectively inhibited the ultrarapid delayed rectifier current in a voltage-independent way, with an EC₅₀ of 138±7 µmol/L at +10 mV. Standard microelectrode experiments showed the effects of indapamide on the action potential to be consistent with the ionic actions seen. We conclude that in addition to its well-recognized I_Ks-blocking action, indapamide also inhibits I_Na and I_to effectively and with similar potency. Thus, indapamide is not a reliable pharmacological probe with which to study the specific effects of I_Ks blockade, and I_Na and I_to block may contribute to the potential profile of cardiac actions of the compound.

Key Words: ion channel blocker • ECG • cardiac antiarrhythmic drug • heart electrophysiology

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