title: Arrhythmogenic adverse effects of cardiac glycosides are mediated by redox modification of ryanodine receptors.
abstract: 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.
authors.affiliation: Davis Heart and Lung Research Institute, The Ohio State University Medical Centre, 473 W. 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Hsiang-Ting
authors.initials: HT
authors.lastname: Ho
authors.forename: Sarah C W
authors.initials: SC
authors.lastname: Stevens
authors.forename: Radmila
authors.initials: R
authors.lastname: Terentyeva
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Carnes
authors.forename: Dmitry
authors.initials: D
authors.lastname: Terentyev
authors.forename: Sandor
authors.initials: S
authors.lastname: Györke
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002301:Cardiac Glycosides / Q000633:toxicity*; D004074:Digitoxin / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors; D000083162:Mitochondrial Permeability Transition Pore; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D002301:Cardiac Glycosides; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C110658:N-(2-mercaptoproprionyl)-glycine; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; D013438:Sulfhydryl Compounds; D004074:Digitoxin; D019255:NADPH Oxidases; D002118:Calcium; D005998:Glycine