Arrhythmogenic adverse effects of cardiac glycosides are mediated by redox modification of ryanodine receptors

• Published in: The Journal of physiology 2011-10, Vol.589 (19), p.4697-4708
• Main Authors: Ho, Hsiang‐Ting, Stevens, Sarah C. W., Terentyeva, Radmila, Carnes, Cynthia A., Terentyev, Dmitry, Györke, Sandor
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - pharmacology; Arrhythmias, Cardiac - chemically induced; Arrhythmias, Cardiac - metabolism; Calcium (intracellular); Calcium (reticular); Calcium - metabolism; Calcium signalling; Cardiac glycosides; Cardiac Glycosides - toxicity; Cardiac muscle; cardiomyocytes; Cardiovascular; Channel pores; congestive heart failure; Digitoxin - pharmacology; Glycine - analogs & derivatives; Glycine - pharmacology; Heart diseases; Heart failure; Male; Membrane permeability; Membrane Potentials - drug effects; Membrane Potentials - physiology; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins - antagonists & inhibitors; Mitochondrial permeability transition pore; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; NAD(P)H oxidase; NADPH Oxidases - antagonists & inhibitors; Oxidation; Oxidation-Reduction; Rats; Reactive oxygen species; Reactive Oxygen Species - metabolism; Rodents; Ryanodine Receptor Calcium Release Channel - metabolism; Ryanodine receptors; Sarcoplasmic reticulum; Sarcoplasmic Reticulum - drug effects; Sarcoplasmic Reticulum - metabolism; Side effects; Sulfhydryl Compounds - pharmacology; Toxicity; Ventricle
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2011.210005

Non‐Technical Summary  Cardiac glycosides (CGs) have been routinely used in the treatment of congestive heart failure (HF). Unfortunately, the therapeutic use of CGs in treating HF is limited by their adverse side effects, including cardiac arrhythmias. The arrhythmic side effects of CGs have been traditionally ascribed to excessive cellular Ca2+ retention (Ca2+ overload) leading to spontaneous discharges of intracellular Ca2+ stores, or Ca2+ waves, in turn causing oscillations of the cardiac membrane potential. In the present study, we demonstrate that the proarrhythmic effects of CGs on Ca2+ cycling in cardiac myocytes involve alterations in the function of ryanodine receptor calcium channels caused by oxidative changes in the channel structure by reactive oxygen species. Our findings reveal a new mechanism for CG‐induced Ca2+ waves and suggest a potential target for antiarrhythmic therapy in HF patients treated with CGs.   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 Ca2+ 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 Ca2+ waves, decreased the sarcoplasmic reticulum (SR) Ca2+ load, and increased both ROS and RyR2 thiol oxidation. Additionally, pretreatment with DGT increased spark frequency in permeabilized myocytes. These effects on Ca2+ 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‐KATP) 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 RO