An Antagonist of cADP-ribose Inhibits Arrhythmogenic Oscillations of Intracellular Ca2+In Heart Cells
Journal of Biological Chemistry
Oscillations of Ca 2؉ in heart cells are a major underlying cause of important cardiac arrhythmias, and it is known that Ca 2؉ -induced release of Ca 2؉ 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 Ca 2؉ release channel of the sarcoplasmic reticulum (the ryanodine receptor), raising the possibility that cADP-ribose may influence arrhythmogenic mechanisms
... n the heart. 8-Amino-cADP-ribose, an antagonist of cADP-ribose, suppressed oscillatory activity associated with overloading of intracellular Ca 2؉ 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 Ca 2؉ 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 cADPribose concentration is present within the cell, we propose that 8-amino-cADP-ribose and 8-bromo-cADP-ribose suppress cytosolic Ca 2؉ oscillations by antagonism of endogenous cADP-ribose, which sensitizes the Ca 2؉ release channels of the sarcoplasmic reticulum to Ca 2؉ .