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Defective cardiac mechanical activity in diabetes results from alterations in intracellular Ca 2+  handling, in part, due to increased oxidative stress. Beta-blockers demonstrate marked beneficial effects in heart dysfunction with scavenging free radicals and/or acting as an antioxidant. The aim of this study was to address how β-blocker timolol-treatment of diabetic rats exerts cardioprotection. Timolol-treatment (12-week), one-week following diabetes induction, prevented diabetes-induced depressed left ventricular basal contractile activity, prolonged cellular electrical activity, and attenuated the increase in isolated-cardiomyocyte size without hyperglycemic effect. Both  in vivo  and  in vitro  timolol-treatment of diabetic cardiomyocytes prevented the altered kinetic parameters of Ca 2+  transients and reduced Ca 2+  loading of sarcoplasmic reticulum (SR), basal intracellular free Ca 2+  and Zn 2+  ([Ca 2+ ] i  and [Zn 2+ ] i ), and spatio-temporal properties of the Ca 2+  sparks, significantly. Timolol also antagonized hyperphosphorylation of cardiac ryanodine receptor (RyR2), and significantly restored depleted protein levels of both RyR2 and calstabin2. Western blot analysis demonstrated that timolol-treatment also significantly normalized depressed levels of some [Ca 2+ ] i -handling regulators, such as Na + /Ca 2+  exchanger (NCX) and phospho-phospholamban (pPLN) to PLN ratio. Incubation of diabetic cardiomyocytes with 4-mM glutathione exerted similar beneficial effects on RyR2-macromolecular complex and basal levels of both [Ca 2+ ] i  and [Zn 2+ ] i , increased intracellular Zn 2+  hyperphosphorylated RyR2 in a concentration-dependent manner. Timolol also led to a balanced oxidant/antioxidant level in both heart and circulation and prevented altered cellular redox state of the heart. We thus report, for the first time, that the preventing effect of timolol, directly targeting heart, seems to be associated with a normalization of macromolecular complex of RyR2 and some Ca 2+  handling regulators, and prevention of Ca 2+  leak, and thereby normalization of both [Ca 2+ ] i  and [Zn 2+ ] i  homeostasis in diabetic rat heart, at least in part by controlling the cellular redox status of hyperglycemic cardiomyocytes.

ß-Blocker Timolol Prevents Arrhythmogenic Ca2+ Release and Normalizes Ca2+ and Zn2+ Dyshomeostasis in Hyperglycemic Rat Heart