Carvedilol inhibits cADPR- and IP3-induced Ca2+ release

Abstract

Spontaneous Ca²⁺ waves, also termed store-overload-induced Ca²⁺ 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 Ca²⁺. 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 Ca²⁺ release in sea urchin egg homogenate. In addition, the carvedilol analog VK-II-86 with minimal β-blocking activity also suppresses cADPR-induced Ca²⁺ release. Carvedilol appeared to be a non-competitive antagonist of cADPR and could also suppress Ca²⁺ release by caffeine. These results are consistent with cADPR releasing Ca²⁺ in sea urchin eggs by sensitizing RyRs to Ca²⁺ involving a luminal Ca²⁺ activation mechanism. In addition to action on the RyR, we also observed inhibition of inositol 1,4,5-trisphosphate (IP₃)-induced Ca²⁺ release by carvedilol suggesting a common mechanism between these evolutionarily related and conserved Ca²⁺ release channels.