Published online before print February 3, 2003, doi: 10.1161/01.CIR.0000048189.58449.F7
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2003;107:889.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Spironolactone and Its Main Metabolite, Canrenoic Acid, Block Human Ether-a-Go-Go–Related Gene Channels
From the Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
Correspondence to Eva Delpón, Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. 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 IKr 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
This article has been cited by other articles:
 |
|
 |
|
  S. B. Ganapathi, M. Kester, and K. S. Elmslie State-dependent block of HERG potassium channels by R-roscovitine: implications for cancer therapy Am J Physiol Cell Physiol, April 1, 2009; 296(4): C701 - C710. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. S. Tutor, E. Delpon, R. Caballero, R. Gomez, L. Nunez, M. Vaquero, J. Tamargo, F. Mayor Jr., and P. Penela Association of 14-3-3 Proteins to beta1-Adrenergic Receptors Modulates Kv11.1 K+ Channel Activity in Recombinant Systems Mol. Biol. Cell, November 1, 2006; 17(11): 4666 - 4674. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Chai, I. M. Garrelds, R. de Vries, and A.H. Jan Danser Cardioprotective Effects of Eplerenone in the Rat Heart: Interaction With Locally Synthesized or Blood-Derived Aldosterone? Hypertension, April 1, 2006; 47(4): 665 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Barbato, S. Rashid, P. J. Mulrow, J. I. Shapiro, and R. Franco-Saenz Mechanisms for Aldosterone and Spironolactone-Induced Positive Inotropic Actions in the Rat Heart Hypertension, November 1, 2004; 44(5): 751 - 757. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Tamargo, R. Caballero, R. Gomez, C. Valenzuela, and E. Delpon Pharmacology of cardiac potassium channels Cardiovasc Res, April 1, 2004; 62(1): 9 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. C. White Aldosterone: Direct Effects on and Production by the Heart J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2376 - 2383. [Full Text] [PDF]
|
|