An antagonist of cADP-ribose inhibits arrhythmogenic oscillations of intracellular Ca2+ in heart cells.
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 beta-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+.
Rakovic
S
S
University Department Of Pharmacology, Oxford University Oxford OX1 3QT, United Kingdom.
Cui
Y
Y
Iino
S
S
Galione
A
A
Ashamu
G A
GA
Potter
B V
BV
Terrar
D A
DA
D000200:Action Potentials / Q000187:drug effects; D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives; D016257:Fura-2; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D007545:Isoproterenol / Q000494:pharmacology; D018613:Microscopy, Confocal; D010042:Ouabain / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D019837:Ryanodine Receptor Calcium Release Channel; D036563:Cyclic ADP-Ribose; C082175:8-aminoadenosine cyclic 3',5'-(hydrogen phosphate) 5'-ribofuranosyl ester; D000246:Adenosine Diphosphate Ribose; D010042:Ouabain; D007545:Isoproterenol; D002118:Calcium; D016257:Fura-2