Suppression Of Spontaneous Ca(2+) Release By Cardioprotective Drugs

Spontaneous sarcoplasmic reticulum (SR) Ca2+ release in the form of Ca2+ waves occurs in cardiac cells under conditions of SR Ca2+ overload. This store-overload induced Ca2+ release (SOICR) is a well-known cause of delayed afterdepolarization and triggered arrhythmias. Hence, inhibiting SOICR may represent a promising therapeutic strategy for Ca2+-triggered arrhythmias. Indeed, we have recently shown that carvedilol, one of the most effective beta-blockers for preventing ventricular tachyarrhythmias and sudden death in heart failure, possesses a novel anti-SOICR activity. To identify more SOICR inhibitors, we searched the DrugBank database (http://www.drugbank.ca) for chemicals with structures similar to carvedilol. We selected a number of hit compounds and assessed their impact on SOICR in HEK293 cells expressing a SOICR-promoting cardiac ryanodine receptor (RyR2) mutation (R4496C). We found that curcumin and resveratrol (natural phenols) and bevantolol (a beta blocker and a Ca2+ channel blocker) suppress SOICR in HEK293 cells with IC50s of 6.7±0.3, 48.4±3.6, 64.7±11.3μM, respectively. On the other hand, gliclazide, diphenhydramine, crocin, dexrazoxane, and trazodone displayed little or no SOICR inhibition. We also tested several other known cardioprotective drugs. We found that docosahexaenoic acid (DHA), eicosapentaenoic (EPA), arachidonic acid (AA), anandamide, and a novel derivative of anandamide (CS-X-95) inhibit SOICR in HEK293 cells with IC50s of 11.2±4.2, 5.1±0.5, 5.5±0.9, 14.7±5.1, and 11.5±0.7 μM, respectively, whereas ranolazine and S107 have no significant impact on SOICR. These observations indicate that many cardioprotective drugs exhibit anti-SOICR activity, and that SOICR inhibition may contribute, in part, to their cardioprotective effect. (Supported by NIH)