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Department of Physiology, Stritch School of Medicine, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA

In the heart ischaemic conditions induce metabolic changes known to have profound effects on Ca²⁺ signalling during excitation–contraction coupling. Ischaemia also affects the redox state of the cell. However, the role of cytosolic redox couples, such as the NADH/NAD⁺ redox system, for the regulation of Ca²⁺ homeostasis has remained elusive. We studied the effects of NADH and NAD⁺ on sarcoplasmic reticulum (SR) Ca²⁺ release in permeabilized rat ventricular myocytes as well as on Ca²⁺ uptake by SR microsomes and ryanodine receptor (RyR) single channel activity. Exposure of permeabilized myocytes to NADH (2 mM; [Ca²⁺]_cyt= 100nM) decreased the frequency and the amplitude of spontaneous Ca²⁺ sparks by 62% and 24%, respectively. This inhibitory effect was reversed by NAD⁺ (2 mM) and did not depend on mitochondrial function. The inhibition of Ca²⁺ sparks by NADH was associated with a 52% decrease in SR Ca²⁺ load. Some of the effects observed with NADH may involve the generation of superoxide anion (O₂^-·) as they were attenuated to just a transient decrease of Ca²⁺ spark frequency by superoxide dismutase (SOD). O₂^-· generated in situ from the xanthine/xanthine oxidase reaction caused a slowly developing decrease of Ca²⁺ spark frequency and SR Ca²⁺ load by 44% and 32%, respectively. Furthermore, in studies with cardiac SR microsomes NADH slowed the rate of ATP-dependent Ca²⁺ uptake by 39%. This effect also appeared to depend on O₂^-· formation. Single channel recordings from RyRs incorporated into lipid bilayers revealed that NADH (2 mM) inhibited the activity of RyR channels by 84%. However, NADH inhibition of RyR activity was O₂^-·-independent. In summary, an increase of the cytoplasmic NADH/NAD⁺ ratio depresses SR Ca²⁺ release in ventricular cardiomyocytes. The effect appears to be mediated by direct NADH inhibition of RyR channel activity and by indirect NADH inhibition (O₂^-· mediated) of SR Ca²⁺-ATPase activity with a subsequent decrease in SR Ca²⁺ content.

(Received 25 September 2003; accepted after revision 8 January 2004; first published online 14 January 2004)
Corresponding author L. A. Blatter: Department of Physiology, Stritch School of Medicine, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA. Email: lblatte{at}lumc.edu

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