Differential Free Intracellular Calcium Release by Class II Antiarrhythmics in Cancer Cell Lines

Class II antiarrhythmics or β-blockers are antisympathetic nervous system agents that act by blocking β-adrenoceptors. Despite their common clinical use, little is known about the effects of β-blockers on free intracellular calcium (Ca²⁺ _i), an important cytosolic second messenger and a key regulator of cell function. We investigated the role of four chemical analogs, commonly prescribed β-blockers (atenolol, metoprolol, propranolol, and sotalol), on Ca²⁺ _i release and whole-cell currents in mammalian cancer cells (PC3 prostate cancer and MCF7 breast cancer cell lines). We discovered that only propranolol activated free Ca²⁺ _i release with distinct kinetics, whereas atenolol, metoprolol, and sotalol did not. The propranolol-induced Ca²⁺ _i release was significantly inhibited by the chelation of extracellular calcium with ethylene glycol tetraacetic acid (EGTA) and by dantrolene, an inhibitor of the endoplasmic reticulum (ER) ryanodine receptor channels, and it was completely abolished by 2-aminoethoxydiphenyl borate, an inhibitor of the ER inositol-1,4,5-trisphosphate (IP₃) receptor channels. Exhaustion of ER stores with 4-chloro-m-cresol, a ryanodine receptor activator, or thapsigargin, a sarco/ER Ca²⁺ ATPase inhibitor, precluded the propranolol-induced Ca²⁺ _i release. Finally, preincubation of cells with sotalol or timolol, nonselective blockers of β-adrenoceptors, also reduced the Ca²⁺ _i release activated by propranolol. Our results show that different β-blockers have differential effects on whole-cell currents and free Ca²⁺ _i release and that propranolol activates store-operated Ca²⁺ _i release via a mechanism that involves calcium-induced calcium release and putative downstream transducers such as IP₃ The differential action of class II antiarrhythmics on Ca²⁺ _i release may have implications on the pharmacology of these drugs.