Published Online
on February 3, 2003

A more recent version of this article appeared on February 18, 2003

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Submitted on July 30, 2002
Revised on October 30, 2002
Accepted on October 30, 2002

Spironolactone and Its Main Metabolite, Canrenoic Acid, Block Human Ether-a-Go-Go-Related Gene Channels

Ricardo Caballero BPharm, PhD, Ignacio Moreno BPharm, Teresa González BSc, Cristina Arias BSc, Carmen Valenzuela BSc, PhD, Eva Delpón BPharm, PhD^*, and Juan Tamargo MD, PhD, FESC

From the Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.

^* To whom correspondence should be addressed. E-mail: edelpon{at}med.ucm.es.

Background--It has been demonstrated that spironolactone (SP) decreases the QT dispersion in chronic heart failure. In this study, the effects of SP and its metabolite, canrenoic acid (CA), on human ether-a-go-go-related gene (HERG) currents were analyzed.

Methods and Results--HERG currents elicited in stably transfected Chinese hamster ovary cells were measured with the whole-cell patch-clamp technique. SP decreased HERG currents in a concentration-dependent manner (IC₅₀=23.0±1.5 µmol/L) and shifted the midpoint of the activation curve to more negative potentials (Vh=-13.1±3.4 versus -18.9±3.6 mV, P<0.05) without modifying the activation and deactivation kinetics. SP-induced block (1 µmol/L) appeared at the range of membrane potentials coinciding with that of channel activation, and thereafter, it remained constant, reaching 24.7±3.8% at +60 mV (n=6, P<0.05). CA (0.01 nmol/L to 500 µmol/L) blocked HERG channels in a voltage- and frequency-independent manner. CA at 1 nmol/L shifted the midpoint of the activation curve to -19.9±1.8 mV and accelerated the time course of channel activation (=1064±125 versus 820±93 ms, n=11, P<0.01). The envelope of the tail test demonstrated that at the very beginning of the pulses to +40 mV (25 ms), a certain amount of block was apparent (31.3±9.9%). CA did not modify the voltage-dependence of HERG channel inactivation (Vh=-60.8±5.6 versus -62.9±3.1 mV, n=6, P>0.05) or the kinetics of the reactivation process at any potential tested. CA and aldosterone also blocked the native I_Kr in guinea-pig ventricular myocytes.

Conclusions--At concentrations reached after administration of therapeutic doses of SP, CA blocked the HERG channels by binding to both the closed and open states of the channel.

Key words: ion channels • potassium channels • patch-clamp techniques • spironolactone

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