State-dependent block of rabbit vascular smooth muscle delayed rectifier and Kv1.5 channels by inhibitors of cytochrome P450-dependent enzymes

Mircea Iftinca, Gareth J. Waldron, Christopher Triggle, William C. Cole

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12 Citations (Scopus)

Abstract

The effects of the cytochrome P450 inhibitors clotrimazole, ketoconazole, and 1-aminobenzotriazole (1-ABT) on native delayed rectifier (KDR) and cloned Kv1.5 (RPV Kv1.5) K+ channels of rabbit portal vein (RPV) myocytes were determined using whole-cell and single channel patch-clamp analysis. Clotrimazole reduced KDR and RPV Kv1.5 whole-cell current with respective Kd values of 1.15 ± 0.39 and 1.99 ± 0.6 μM. Clotrimazole acted via an open state blocking mechanism based on the following: 1) the early time course of KDR current activation was not affected, but inhibition developed with time during depolarizing steps and increased the rate of decay in current amplitude; 2) the inhibition was voltage-dependent, increasing steeply over the voltage range of KDR activation; and 3) mean open time of RPV Kv1.5 channels in inside-out patches was decreased significantly. Ketoconazole reduced KDR current amplitude with a Kd value of 38 ± 3.2 μM. However, ketoconazole acted via a closed (resting) state blocking mechanism: 1) KDR amplitude was reduced throughout the duration of depolarizing steps and the rate of decay of current was unaffected, 2) there was no voltage dependence to the block by ketoconazole over the KDR activation range, and 3) ketoconazole did not affect mean open time of RPV Kv1.5 channels in inside-out membrane patches. 1-ABT between 0.5 and 3 mM did not affect native KDR or RPV Kv1.5 current of rabbit portal vein myocytes. Clotrimazole and ketoconazole, but not 1-ABT, suppress vascular KDR channels by direct, state-dependent block mechanisms not involving the modulation of cytochrome P450 enzyme activity.

Original languageEnglish
Pages (from-to)718-728
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume298
Issue number2
Publication statusPublished - 2001
Externally publishedYes

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ASJC Scopus subject areas

  • Pharmacology

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