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Research ArticleArticle

Mechanisms of δ-Hexachlorocyclohexane Toxicity: I. Relationship Between Altered Ventricular Myocyte Contractility and Ryanodine Receptor Function

Edmond D. Buck, Wilhelm G. Lachnit and Isaac N. Pessah
Journal of Pharmacology and Experimental Therapeutics April 1999, 289 (1) 477-485;
Edmond D. Buck
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Wilhelm G. Lachnit
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Isaac N. Pessah
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Abstract

Several isomers of hexachlorocyclohexanes (HCHs) have been shown to be toxic to mammals. Previous studies have revealed that the δ isomer (δ-HCH) was particularly potent toward disrupting Ca2+homeostasis in a variety of excitable and nonexcitable cells and altering contractility of cardiac muscle. The effects of the δ and γ isomers of HCH were further investigated on isolated ventricular myocytes from guinea pig and on single cardiac ryanodine receptor (RyR2) Ca2+-release channels from cardiac SR vesicles. Intracellular Ca2+ transients were examined in electrically stimulated cells using the fluorescent dye indo-1, and twitch contractions of myocytes were analyzed using a video-based edge motion detection system. Exposure of myocytes to δ- but not γ-HCH depressed the peak of intracellular Ca2+ transients and prolonged recovery time. These effects were correlated with the ability of δ-HCH to inhibit the binding of [3H]ryanodine, a conformationally sensitive probe for RyR2 function, to SR preparations (IC50 = 2 and 18 μM for high- and low-affinity interactions, respectively). Measurements of single-channel gating kinetics under voltage-clamp provided direct evidence of a potent isoform-selective activation of RyR2 by δ-HCH. Results from these studies revealed that δ-HCH alters Ca2+ homeostasis and contractility in cardiac myocytes and that the mechanism can be ascribed, at least in part, to a direct interaction with the RyR2 channel complex.

Footnotes

  • Send reprint requests to: Isaac N. Pessah, Ph.D., Department of Molecular Biosciences, School of Veterinary Medicine, University of California, 1 Shields Ave., Davis, CA 95616. E-mail:inpessah{at}ucdavis.edu

  • ↵1 This work was supported by National Institute for Environmental Health Sciences Grants ES05002 and ES05707 (to I.N.P.) and an American Heart Association, Western States Affiliate, grant (to E.D.B.).

  • Abbreviations:
    HCH
    hexachlorocyclohexane
    IP3,inositol-1
    4,5-trisphosphate
    SR
    sarcoplasmic reticulum
    [Ca2+]i
    intracellular Ca2+concentration
    ER
    endoplasmic reticulum
    RyR
    ryanodine receptor
    RyR2
    cardiac isoform of the ryanodine receptor
    Po
    open probability
    • Received August 3, 1998.
    • Accepted November 13, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 1
1 Apr 1999
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Research ArticleArticle

Mechanisms of δ-Hexachlorocyclohexane Toxicity: I. Relationship Between Altered Ventricular Myocyte Contractility and Ryanodine Receptor Function

Edmond D. Buck, Wilhelm G. Lachnit and Isaac N. Pessah
Journal of Pharmacology and Experimental Therapeutics April 1, 1999, 289 (1) 477-485;

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Research ArticleArticle

Mechanisms of δ-Hexachlorocyclohexane Toxicity: I. Relationship Between Altered Ventricular Myocyte Contractility and Ryanodine Receptor Function

Edmond D. Buck, Wilhelm G. Lachnit and Isaac N. Pessah
Journal of Pharmacology and Experimental Therapeutics April 1, 1999, 289 (1) 477-485;
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