Journal of Pharmacology and Experimental Therapeutics 1999-04-01

Mechanisms of delta-hexachlorocyclohexane toxicity: I. Relationship between altered ventricular myocyte contractility and ryanodine receptor function.

E D Buck, W G Lachnit, I N Pessah

Index: J. Pharmacol. Exp. Ther. 289(1) , 477-85, (1999)

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Abstract

Several isomers of hexachlorocyclohexanes (HCHs) have been shown to be toxic to mammals. Previous studies have revealed that the delta isomer (delta-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 delta and gamma 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 delta- but not gamma-HCH depressed the peak of intracellular Ca2+ transients and prolonged recovery time. These effects were correlated with the ability of delta-HCH to inhibit the binding of [3H]ryanodine, a conformationally sensitive probe for RyR2 function, to SR preparations (IC50 = 2 and 18 microM 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 delta-HCH. Results from these studies revealed that delta-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.