Stereoselective modulation of ryanodine-sensitive calcium channels by the δ isomer of hexachlorocyclohexane (δ-HCH)

Isaac N Pessah, Frederick C Mohr, M. Schiedt, R. M. Joy

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

δ-Hexachlorocyclohexane (δ-HCH) is shown to be 30-fold more potent as a positive inotropic with rat atrial strips compared with lindane (γ-HCH). Threshold and ED50 values for enhanced contractile force at a pacing frequency of 0.5 Hz are <1 μM and 2.2 μM for δ-HCH and 40 μM and 63 μM for γ-HCH, respectively. Contracture developed in atria exposed to >4 μM δ-HCH (ED50 = 11 μM) but not in atria exposed to γ-HCH. Uptake and release of Ca++ measured from actively loaded cardiac sarcoplasmic reticulum (SR) vesicles is measured with antipyrylazo III. Although δ-HCH (30 μM) decreases Ca++-dependent ATPase by 20%, it does not significantly alter Ca++ loading in the presence of ruthenium red. Addition of δ-HCH (5- 50 μM) after loading is complete causes rapid, dose-dependent release of Ca++ from SR. Ca++ release induced by δ-HCH is markedly stereoselective. Compared with γ-HCH (50 μM), δ-HCH (50 μM) induces a nearly 20-fold higher initial rate of Ca++ release (4.3 nmol of Ca++/mg/sec). Studies with [3H]ryanodine demonstrate that δ-HCH sharply inhibits Ca++- or daunorubicin-activated radioligand binding (IC50 = 37 and 25 μM, respectively, logit slope = 2). Inhibition of [3H]ryanodine-binding by δ- HCH is stereoselective inasmuch as IC50 values for α, β and γ isomers are >100 μM. The δ-HCH modified Ca++ channel appears to proceed by a noncompetitive mechanism (reducing B(max) in equilibrium experiments) with respect to the conformationally sensitive binding site for [3H]ryanodine. The mechanism is more complex, however, because δ-HCH significantly enhances the observed association rate constant of the remaining sites, and pretreatment of SR induces persistent, concentration-dependent activation or inactivation of [3H]ryanodine-binding sites. The effects of δ-HCH on the ryanodine-sensitive Ca++ channel of cardiac SR is also observed with the brain receptor, suggesting existence of a common mechanism by which chlorinated hydrocarbons can modify Ca++ homeostasis and cell excitability.

Original languageEnglish (US)
Pages (from-to)661-669
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume262
Issue number2
StatePublished - 1992

ASJC Scopus subject areas

  • Pharmacology

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