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

• Published in: The Journal of biological chemistry Vol. 274; no. 25; pp. 17820 - 17827
• Main Authors: Rakovic, S, Cui, Y, Iino, S, Galione, A, Ashamu, G A, Potter, B V, Terrar, D A
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 18.06.1999
• Subjects: Action Potentials - drug effects; Adenosine Diphosphate Ribose - analogs & derivatives; Adenosine Diphosphate Ribose - antagonists & inhibitors; Adenosine Diphosphate Ribose - pharmacology; Animals; Anti-Arrhythmia Agents - pharmacology; Arrhythmias, Cardiac - metabolism; Calcium - metabolism; Cells, Cultured; Cyclic ADP-Ribose; Fura-2; Guinea Pigs; Heart - drug effects; Image Processing, Computer-Assisted; Isoproterenol - pharmacology; Microscopy, Confocal; Ouabain - pharmacology; Patch-Clamp Techniques; Ryanodine Receptor Calcium Release Channel - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.25.17820

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 in 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 β-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 cADP-ribose 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+ .