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Research ArticleCARDIOVASCULAR

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 R. Triggle and William C. Cole
Journal of Pharmacology and Experimental Therapeutics August 2001, 298 (2) 718-728;
Mircea Iftinca
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Gareth J. Waldron
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Christopher R. Triggle
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William C. Cole
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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 KDRactivation; and 3) mean open time of RPV Kv1.5 channels in inside-out patches was decreased significantly. Ketoconazole reduced KDR current amplitude with a Kdvalue 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.

Footnotes

  • This study was supported by a grant from the Canadian Institutes for Health Research (CIHR, MT-13505). W.C.C. is a Senior Scholar of the Alberta Heritage Foundation for Medical Research, M.I. was supported by a CIHR Graduate Studentship, and G.J.W. was a Medical Research Council-Hypertension Society of Canada Postdoctoral Fellow.

  • Abbreviations:
    BKCa
    large conductance Ca2+-activated K+ channel
    KATP
    ATP-sensitive K+ channel
    KDR
    delayed rectifier K+ channel
    EDHF
    endothelium-derived hyperpolarizing factor
    EET
    epoxyeicosatrienoic acid
    IKCa
    intermediate conductance Ca2+-activated K+ channel
    Kv
    voltage-gated K+ channel
    I-O
    inside-out
    1-ABT
    1-aminobenzotriazole
    RPV
    rabbit portal vein
    RPV Kv1.5
    rabbit portal vein Kv1.5
    HEK
    human embryonic kidney
    I-V
    current-voltage
    • Received January 16, 2001.
    • Accepted April 19, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 2
1 Aug 2001
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Research ArticleCARDIOVASCULAR

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 R. Triggle and William C. Cole
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 718-728;

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Research ArticleCARDIOVASCULAR

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 R. Triggle and William C. Cole
Journal of Pharmacology and Experimental Therapeutics August 1, 2001, 298 (2) 718-728;
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