In isolated rat ventricular myocytes, the cardiac glycoside digitoxin increased arrhythmogenic spontaneous Ca(2+) waves and RyR2 oxidation, effects prevented by antioxidants and specific inhibitors.
Does digitoxin induce arrhythmogenesis through ROS-mediated redox modification of ryanodine receptors in isolated rat ventricular myocytes?
The arrhythmogenic toxicity of cardiac glycosides is mediated by ROS-dependent oxidation of ryanodine receptors, highlighting a novel mechanism beyond Na+/K+-ATPase inhibition.
The therapeutic use of cardiac glycosides (CGs), agents commonly used in treating heart failure (HF), is limited by arrhythmic toxicity. The adverse effects of CGs have been attributed to excessive accumulation of intracellular Ca(2+) resulting from inhibition of Na(+)/K(+)-ATPase ion transport activity. However, CGs are also known to increase intracellular reactive oxygen species (ROS), which could contribute to arrhythmogenesis through redox modification of cardiac ryanodine receptors (RyR2s). Here we sought to determine whether modification of RyR2s by ROS contributes to CG-dependent arrhythmogenesis and examine the relevant sources of ROS. In isolated rat ventricular myocytes, the CG digitoxin (DGT) increased the incidence of arrhythmogenic spontaneous Ca(2+) waves, decreased the sarcoplasmic reticulum (SR) Ca(2+) load, and increased both ROS and RyR2 thiol oxidation. Additionally, pretreatment with DGT increased spark frequency in permeabilized myocytes. These effects on Ca(2+) waves and sparks were prevented by the antioxidant N-(2-mercaptopropionyl) glycine (MPG). The CG-dependent increases in ROS, RyR2 oxidation and arrhythmogenic propensity were reversed by inhibitors of NADPH oxidase, mitochondrial ATP-dependent K(+) channels (mito-K(ATP)) or permeability transition pore (PTP), but not by inhibition of xanthine oxidase. These results suggest that the arrhythmogenic adverse effects of CGs involve alterations in RyR2 function caused by oxidative changes in the channel structure by ROS. These CG-dependent effects probably involve release of ROS from mitochondria possibly mediated by NADPH oxidase.
Ho et al. (Tue,) conducted a other in Arrhythmogenic adverse effects of cardiac glycosides. Cardiac glycosides (digitoxin) vs. Antioxidants and specific inhibitors was evaluated on Incidence of arrhythmogenic spontaneous Ca(2+) waves, ROS, and RyR2 thiol oxidation. In isolated rat ventricular myocytes, the cardiac glycoside digitoxin increased arrhythmogenic spontaneous Ca(2+) waves and RyR2 oxidation, effects prevented by antioxidants and specific inhibitors.