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J Biol Chem, Vol. 274, Issue 25, 17820-17827, June 18, 1999

An Antagonist of cADP-ribose Inhibits Arrhythmogenic Oscillations of Intracellular Ca²⁺ In Heart Cells

Stevan Rakovic, Yi Cui, Shigeo Iino, Antony Galione, Gloria A. Ashamu, Barry V. L. Potter, and Derek A. Terrar

From the University Department Of Pharmacology, Oxford University Oxford OX1 3QT, United Kingdom and  School of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom

Oscillations of Ca²⁺ in heart cells are a major underlying cause of important cardiac arrhythmias, and it is known that Ca²⁺-induced release of Ca²⁺ from intracellular stores (the sarcoplasmic reticulum) is fundamental to the generation of such oscillations. There is now evidence that cADP-ribose may be an endogenous regulator of the Ca²⁺ release channel of the sarcoplasmic reticulum (the ryanodine receptor), raising the possibility that cADP-ribose may influence arrhythmogenic mechanisms in the heart. 8-Amino-cADP-ribose, an antagonist of cADP-ribose, suppressed oscillatory activity associated with overloading of intracellular Ca²⁺ stores in cardiac myocytes exposed to high doses of the -adrenoreceptor agonist isoproterenol or the Na⁺/K⁺-ATPase inhibitor ouabain. The oscillations suppressed by 8-amino-cADP-ribose included intracellular Ca²⁺ waves, spontaneous action potentials, after-depolarizations, and transient inward currents. Another antagonist of cADP-ribose, 8-bromo-cADP-ribose, was also effective in suppressing isoproterenol-induced oscillatory activity. Furthermore, in the presence of ouabain under conditions in which there was no arrhythmogenesis, exogenous cADP-ribose was found to be capable of triggering spontaneous contractile and electrical activity. Because enzymatic machinery for regulating the cytosolic cADP-ribose concentration is present within the cell, we propose that 8-amino-cADP-ribose and 8-bromo-cADP-ribose suppress cytosolic Ca²⁺ oscillations by antagonism of endogenous cADP-ribose, which sensitizes the Ca²⁺ release channels of the sarcoplasmic reticulum to Ca²⁺.

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