Intracellular Calcium Protects against Oxidant Injury in Cardiac Muscle: Possible involvement of Intracellular Zinc

Abstract

Reperfusion injury in ischemic myocardium may be caused by neutrophil oxidants such as hypochlorous acid (HOCl). In view of the close association between intracellular Ca²⁺ ([Ca²⁺]_i) and cellular injury, we examined the ability of [Ca²⁺]_i to affect HOCl injury in cardiac muscle. [Ca²⁺]_i was modulated by bathing isolated, isometrically contracting, rat papillary muscles in normal (2.5 mM), low (0.5 mM), or high (5.0 mM) extracellular Ca²⁺ ([Ca²⁺]_o), or with 1 µM nifedipine, an L-type Ca²⁺ channel antagonist, and 1 µM Bay K8644, an L-type Ca²⁺ channel agonist. In normal [Ca²⁺]_o, HOCl (300 µM) caused a rapid decline in contractile function, the onset of contracture, and a decrease in protein sulfhydryl levels (P-SH). Ryanodine, an inhibitor of the sarcoplasmic reticulum Ca²⁺ release channel, protected against injury. Dithiothreitol (DTT) partially restored the lost function and P-SH. Lowering the [Ca²⁺]_i with low [Ca²⁺]_o or nifedipine resulted in a surprising potentiation of HOCl injury, and the inhibition of DTT-induced recovery. Raising [Ca²⁺]_i with high [Ca²⁺]_o or Bay K8644 resulted in protection against injury. Our previous studies have demonstrated an HOCl-induced increase in [Zn²⁺]_i. Since Ca²⁺ can protect against the intracellular effects of Zn²⁺, we therefore propose that HOCl injury may be caused by the binding of mobilized Zn²⁺ to P-SH, and that increased [Ca²⁺]_i protects against this injury Our data therefore provide an explanation for the lack of clinical efficacy of Ca²⁺ channel blockers with early phase acute myocardial infarction, and may therefore have significant clinical implications.