Carvedilol inhibits cADPR- and IP-induced Ca release.

Spontaneous Ca waves, also termed store-overload-induced Ca release (SOICR), in cardiac cells can trigger ventricular arrhythmias especially in failing hearts. SOICR occurs when RyRs are activated by an increase in sarcoplasmic reticulum (SR) luminal Ca. Carvedilol is one of the most effective drugs for preventing arrhythmias in patients with heart failure. Furthermore, carvedilol analogues with minimal β-blocking activity also block SOICR showing that SOICR-inhibiting activity is distinct from that for β-block. We show here that carvedilol is a potent inhibitor of cADPR-induced Ca release in sea urchin egg homogenate. In addition, the carvedilol analog VK-II-86 with minimal β-blocking activity also suppresses cADPR-induced Ca release. Carvedilol appeared to be a non-competitive antagonist of cADPR and could also suppress Ca release by caffeine. These results are consistent with cADPR releasing Ca in sea urchin eggs by sensitizing RyRs to Ca involving a luminal Ca activation mechanism. In addition to action on the RyR, we also observed inhibition of inositol 1,4,5-trisphosphate (IP)-induced Ca release by carvedilol suggesting a common mechanism between these evolutionarily related and conserved Ca release channels.