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Research ArticleArticle

Direct Effects of Candesartan and Eprosartan on Human Cloned Potassium Channels Involved in Cardiac Repolarization

Ricardo Caballero, Eva Delpón, Carmen Valenzuela, Mónica Longobardo, Teresa González and Juan Tamargo
Molecular Pharmacology April 2001, 59 (4) 825-836; DOI: https://doi.org/10.1124/mol.59.4.825
Ricardo Caballero
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain
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Eva Delpón
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain
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Carmen Valenzuela
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain
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Mónica Longobardo
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain
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Teresa González
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain
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Juan Tamargo
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain
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Abstract

In the present study, we analyzed the effects of two angiotensin II type 1 receptor antagonists, candesartan (0.1 μM) and eprosartan (1 μM), on hKv1.5, HERG, KvLQT1+minK, and Kv4.3 channels expressed onLtk − or Chinese hamster ovary cells using the patch-clamp technique. Candesartan and eprosartan produced a voltage-dependent block of hKv1.5 channels decreasing the current at +60 mV by 20.9 ± 2.3% and 14.3 ± 1.5%, respectively. The blockade was frequency-dependent, suggesting an open-channel interaction. Eprosartan inhibited the tail amplitude of HERG currents elicited on repolarization after pulses to +60 mV from 239 ± 78 to 179 ± 72 pA. Candesartan shifted the activation curve of HERG channels in the hyperpolarizing direction, thus increasing the current amplitude elicited by depolarizations to potentials between −50 and 0 mV. Candesartan reduced the KvLQT1+minK currents elicited by 2-s pulses to +60 mV (38.7 ± 6.3%). In contrast, eprosartan transiently increased (8.8 ± 2.7%) and thereafter reduced the KvLQT1+minK current amplitude by 17.7 ± 3.0%. Eprosartan, but not candesartan, blocked Kv4.3 channels in a voltage-dependent manner (22.2 ± 3.5% at +50 mV) without modifying the voltage-dependence of Kv4.3 channel inactivation. Candesartan slightly prolonged the action potential duration recorded in guinea pig papillary muscles at all driving rates. Eprosartan prolonged the action potential duration in muscles driven at 0.1 to 1 Hz, but it shortened this parameter at faster rates (2–3 Hz). All these results demonstrated that candesartan and eprosartan exert direct effects on Kv1.5, HERG, KvLQT1+minK, and Kv4.3 currents involved in human cardiac repolarization.

Footnotes

    • Received July 31, 2000.
    • Accepted December 22, 2000.
  • Send reprint requests to: Eva Delpón, BPharm, Ph.D., Department of Pharmacology, School of Medicine, Universidad Complutense, 28040-Madrid, Spain. E-mail:edelpon{at}eucmax.sim.ucm.es

  • Supported by Grants SAF-99-0069, CAM 08.4/0016/1998, and SAF98-0058.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 59 (4)
Molecular Pharmacology
Vol. 59, Issue 4
1 Apr 2001
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Research ArticleArticle

Direct Effects of Candesartan and Eprosartan on Human Cloned Potassium Channels Involved in Cardiac Repolarization

Ricardo Caballero, Eva Delpón, Carmen Valenzuela, Mónica Longobardo, Teresa González and Juan Tamargo
Molecular Pharmacology April 1, 2001, 59 (4) 825-836; DOI: https://doi.org/10.1124/mol.59.4.825

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Research ArticleArticle

Direct Effects of Candesartan and Eprosartan on Human Cloned Potassium Channels Involved in Cardiac Repolarization

Ricardo Caballero, Eva Delpón, Carmen Valenzuela, Mónica Longobardo, Teresa González and Juan Tamargo
Molecular Pharmacology April 1, 2001, 59 (4) 825-836; DOI: https://doi.org/10.1124/mol.59.4.825
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