Abstract
The whole-cell patch-clamp technique was used in adult mouse ventricular myocytes at 22°C to study the transient outward current (Ito) and its sensitivity to the antimycotics miconazole and clotrimazole, as well as to glybenclamide. Ito elicited by depolarizing steps from a holding potential of −80 mV consisted of a fast inactivating component and a slowly inactivating component. In the presence of miconazole (IC50 of ≈8 μM) or clotrimazole, Ito peak amplitude was reduced and its inactivation accelerated, due to a selective suppression of the slow component, without an effect on the fast component or on the noninactivating current. The effect did not reverse upon washout, was not induced by intracellular drug application, and occurred without a change of the steady-state inactivation. In the presence of glybenclamide Ito peak amplitude was reduced and its inactivation accelerated. In contrast to the antimycotics, glybenclamide suppressed both the fast and the slow components (IC50 of ≈50 μM), its effect was reversible, and was associated with a negative shift of the steady-state inactivation. These data demonstrate a pharmacological separation of Itocomponents using antimycotic drugs but not glybenclamide.
Footnotes
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This study was supported by Grant 0299.98 for FWO, the Flemish Foundation for Science. Published abstracts on parts of this work are as follows: Hernandez MJ, Sipido KR and Mubagwa K (1999) High sensitivity to 4-aminopyridine of the transient outward current in mouse ventricular myocytes. Biophys J76:A88; Hernandez MJ, Sipido KR and Mubagwa K (1999) Outward currents in mouse cardiomyocytes. Pfluegers Arch437:R9; Hernandez MJ, Sipido KR and Mubagwa K (1999) Identification of two transient outward current components in mouse cardiomyocytes by the imidazole antimycotics clotrimazole and miconazole. Pfluegers Arch438:R31; and Macianskiene R, Moccia F, Sipido K and Mubagwa K (2001) Glybenclamide inhibits transient outward potassium currents in mouse ventricular myocytes. Pfluegers Arch, in press.
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1These authors contributed equally to this study.
- Abbreviations:
- 4-AP
- 4-aminopyridine
- Received December 11, 2000.
- Accepted April 26, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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