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

Abstract

Oscillations of Ca2؉ 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 ␤-adrenoreceptor agonist isoproterenol or the Na

Potentiation of Ca 2+ Release by cADP-Ribose in the Heart Is Mediated by Enhanced SR Ca 2+ Uptake Into the Sarcoplasmic Reticulum

“…1 Thus, it is possible that the estimates of SR Ca 2ϩ content changes using contraction measurements were influenced by effects of caffeine on myofilaments. Interestingly, in a more recent study, Rakovic et al 9 showed that 8-amino-cADPR reduced the frequency of spontaneous Ca 2ϩ waves, although cADPR itself enhanced the incidents of waves in cardiac myocytes exposed to ouabain. Spontaneous Ca 2ϩ waves are generally associated with increased SR Ca 2ϩ content.…”

“…In guinea pig ventricular cells, the cADPR antagonists 8-amino-cADPR and 8-Br-cADPR have inhibited both depolarization-induced Ca 2ϩ transients and spontaneous Ca 2ϩ waves. 8,9 It has been further demonstrated that cADPR applied to the cytosol increases cell-average Ca 2ϩ transients and contractions 10 -13 and enhances the frequency of local Ca 2ϩ release events (ie, sparks) in both intact and permeabilized cardiac myocytes. 11,14 The effects of cADPR on Ca 2ϩ release are highly temperature dependent and relatively slow kinetically.…”

Selective inhibitors of cardiac ADPR cyclase as novel anti-arrhythmic compounds

“…Moreover, cADPR infusion was associated with spontaneous electrical and contractile activity, pointing towards the possibility that cADPR may exert arrhythmogenic activity in the heart (Rakovic et al 1999). …”

Effects of photoreleased cADP-ribose on calcium transients and calcium sparks in myocytes isolated from guinea-pig and rat ventricle

“…Recent preliminary evidence shows that the synthesis of cADPR is enhanced by protein kinase A [25], raising the possibility that elevation of cADPR levels may be added to the variety of mechanisms leading to the positive inotropic actions of β-adrenoceptor agonists. It also appears that an excess of cADPR may increase the gain of CICR to such an extent that arrhythmogenic mechanisms are provoked [26].…”