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Open Access item Spironolactone and its main metabolite, canrenoic acid, block human ether-a-go-go–related gene channels

Authors:Caballero, Ricardo
Moreno de Alborán, Ignacio
González, Teresa
Arias, Cristina
Valenzuela, Carmen
Delpón, Eva
Tamargo, Juan
Keywords:Ion channels, Potassium channels, Patch-clamp techniques, Spironolactone
Issue Date:18-Feb-2003
Publisher:American Heart Association
Citation:Circulation 107(6): 889-895 (2003)
Abstract: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 ({tau}=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 IKr in guinea-pig ventricular myocytes.
Description:8 pages, 6 figures.
Publisher version (URL):http://dx.doi.org/10.1161/01.CIR.0000048189.58449.F7
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