Zhen Tan, Zhichao Xiao, Jinhong Wei, Jingqun Zhang, Qiang Zhou, Chris D. Smith, Alma Nani, Guogen Wu, Long-Sheng Song, Thomas G. Back, Michael Fill, S.R. Wayne Chen

Beta-blockers are a standard treatment for heart failure and cardiac arrhythmias. There are about 30 commonly used beta-blockers representing a diverse class of drugs with different receptor affinities and pleiotropic properties. We reported that among 14 beta-blockers tested previously, only carvedilol effectively suppressed cardiac ryanodine receptor (RyR2) mediated spontaneous Ca(2+) waves during store Ca(2+) overload, also known as store-overload induced Ca(2+) release (SOICR). Given the critical role of SOICR in arrhythmogenesis, it is of importance to determine whether there are other beta-blockers that suppress SOICR. Here we assessed the effect of other commonly used beta-blockers on RyR2-mediated SOICR in HEK293 cells using single cell Ca(2+) imaging. Of the 13 beta-blockers tested, only nebivolol, a beta-1 selective beta-blocker with nitric oxide synthase (NOS) stimulating action, effectively suppressed SOICR. The NOS inhibitor (N-nitro-L-arginine methyl ester) had no effect on nebivolol's SOICR inhibition, and the NOS activator (histamine or prostaglandin E2) alone did not inhibit SOICR. Hence, nebivolol's SOICR inhibition was independent of NOS stimulation. Like carvedilol, nebivolol reduced opening of single RyR2 channels and suppressed spontaneous Ca(2+) waves in intact hearts and catecholaminergic polymorphic ventricular tachycardia (CPVT) in mice harboring a RyR2 mutation (R4496C). Interestingly, a non-beta-blocking nebivolol enantiomer, ( l )-nebivolol, also suppressed SOICR and CPVT without lowering heart rate. These data indicate that nebivolol, like carvedilol, possesses a RyR2-targeted action that suppresses SOICR and SOICR-evoked VTs. Thus, nebivolol represents a promising agent for Ca(2+)-triggered arrhythmias.