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Research ArticleCardiovascular

Penitrem A as a Tool for Understanding the Role of Large Conductance Ca2+/Voltage-Sensitive K+ Channels in Vascular Function

Shinichi Asano, Ian N. Bratz, Zachary C. Berwick, Ibra S. Fancher, Johnathan D. Tune and Gregory M. Dick
Journal of Pharmacology and Experimental Therapeutics August 2012, 342 (2) 453-460; DOI: https://doi.org/10.1124/jpet.111.191072
Shinichi Asano
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Ian N. Bratz
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Zachary C. Berwick
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Ibra S. Fancher
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Johnathan D. Tune
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Gregory M. Dick
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Abstract

Large conductance, Ca2+/voltage-sensitive K+ channels (BK channels) are well characterized, but their physiological roles, often determined through pharmacological manipulation, are less clear. Iberiotoxin is considered the “gold standard” antagonist, but cost and membrane-impermeability limit its usefulness. Economical and membrane-permeable alternatives could facilitate the study of BK channels. Thus, we characterized the effect of penitrem A, a tremorigenic mycotoxin, on BK channels and demonstrate its utility for studying vascular function in vitro and in vivo. Whole-cell currents from human embryonic kidney 293 cells transfected with hSlo α or α + β1 were blocked >95% by penitrem A (IC50 6.4 versus 64.4 nM; p < 0.05). Furthermore, penitrem A inhibited BK channels in inside-out and cell-attached patches, whereas iberiotoxin could not. Inhibitory effects of penitrem A on whole-cell K+ currents were equivalent to iberiotoxin in canine coronary smooth muscle cells. As for specificity, penitrem A had no effect on native delayed rectifier K+ currents, cloned voltage-dependent Kv1.5 channels, or native ATP-dependent KATP current. Penitrem A enhanced the sensitivity to K+-induced contraction in canine coronary arteries by 23 ± 5% (p < 0.05) and increased the blood pressure response to phenylephrine in anesthetized mice by 36 ± 11% (p < 0.05). Our data indicate that penitrem A is a useful tool for studying the role of BK channels in vascular function and is practical for cell and tissue (in vitro) studies as well as anesthetized animal (in vivo) experiments.

Footnotes

  • This work was supported by a Research Funds Development Grant from West Virginia University [Grant RDG 1] and the National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL092245, T32-HL090610].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.111.191072.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    BK channel
    large conductance Ca2+/voltage-sensitive K+ channel
    KV channel
    voltage-dependent K+ channel
    KATP channel
    ATP-dependent K+ channel
    ANOVA
    analysis of variance
    HEK
    human embryonic kidney
    NPo
    total open probability.

  • Received December 15, 2011.
  • Accepted May 9, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 2
1 Aug 2012
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Research ArticleCardiovascular

Penitrem A and Vascular Reactivity

Shinichi Asano, Ian N. Bratz, Zachary C. Berwick, Ibra S. Fancher, Johnathan D. Tune and Gregory M. Dick
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 453-460; DOI: https://doi.org/10.1124/jpet.111.191072

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Research ArticleCardiovascular

Penitrem A and Vascular Reactivity

Shinichi Asano, Ian N. Bratz, Zachary C. Berwick, Ibra S. Fancher, Johnathan D. Tune and Gregory M. Dick
Journal of Pharmacology and Experimental Therapeutics August 1, 2012, 342 (2) 453-460; DOI: https://doi.org/10.1124/jpet.111.191072
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