Abstract
Objectives We investigated whether defective intracellular Ca2+ handling can be controlled by timolol in age- as well as in diabetes-related cardiac dysfunction. Background It has been shown that the defects observed in mechanical activity of heart from both aging and diabetic subjects include alteration of intracellular Ca2+ handling via changes in critical processes responsible for its regulation, in part due to increased oxidative stress. Furthermore, increasing evidence shows a marked beneficial effect with beta-blockers, additional to their blocker actions, in the heart dysfunction via scavenging free radicals and/or acting as an antioxidant. Methods To explore the antioxidant role of chronic timolol treatment (25 mg/kg, daily, 12 weeks) on either age- or diabetes-related changes in heart function, we used Langendorff-perfused rat hearts to determine hemodynamic parameters, patch-clamp technique to monitor L-type Ca2+-current (ICaL), and confocal microscopy to study intracellular both global Ca2+ transients evoked by electrical stimulation and local Ca2+ changes (sparks) in quiescent cardiomyocytes loaded with fluorescence Ca2+ dye fluo-3AM. Results Normal cardiac function was well preserved in timololtreated either diabetic or 12-month old rats compared to their age-matched controls. Moreover, our data strongly point out that this reverse remodeling is associated with normalization of the diastolic Ca2+, rynodine receptor Ca2+ release channel (RyR2) macromolecular complex, ICaL function, unbalanced oxidant/antioxidant-defence system as well as cellular redox state both in circulation and in heart. The antioxidant N-acetyl-L-cysteine showed an effect similar to that of timolol. Conclusion Timolol, at a low concentration that is sufficient to produce antioxidant effect, improves the intracellular Ca2+ handling and contractile dysfunction by preventing the protein-thiol oxidation in leaky-RyR2 from both aged and diabetic rat hearts.
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