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Ouabain decreases sarco(endo)plasmic reticulum calcium ATPase activity in rat hearts by a process involving protein oxidation

¹Departments of Medicine and Pharmacology, Medical University of Ohio, Toledo, Ohio; ²Department of Medicine, Friendship Hospital, Beijing; ³The Institute of Nutrition and Food Hygiene, Chinese Academy of Medical Sciences, Beijing, China; and ⁴Proteomics Core Laboratory, Medical University of Ohio, Toledo, Ohio

Submitted 8 June 2006 ; accepted in final form 17 July 2006

The effect of cardiac glycosides to increase cardiac inotropy by altering Ca²⁺ cycling is well known but still poorly understood. The studies described in this report focus on defining the effects of ouabain signaling on sarcoplasmic reticulum Ca²⁺-ATPase function. Rat cardiac myocytes treated with 50 µM ouabain demonstrated substantial increases in systolic and diastolic Ca²⁺ concentrations. The recovery time constant for the Ca²⁺ transient, , was significantly prolonged by ouabain. Exposure to 10 µM H₂O₂, which causes an increase in intracellular reactive oxygen species similar to that of 50 µM ouabain, caused a similar increase in . Concurrent exposure to 10 mM N-acetylcysteine or an aqueous extract from green tea (50 mg/ml) both prevented the increases in as well as the changes in systolic or diastolic Ca²⁺ concentrations. We also observed that 50 µM ouabain induced increases in developed pressure in addition to diastolic dysfunction in the isolated perfused rat heart. Coadministration of ouabain with N-acetylcysteine prevented these increases. Analysis of sarcoplasmic reticulum Ca²⁺-ATPase protein revealed increases in both the oxidation and nitrotyrosine content in the ouabain-treated hearts. Liquid chromatography-mass spectrometric analysis confirmed that the sarcoplasmic reticulum Ca²⁺-ATPase protein from ouabain-treated hearts had modifications consistent with oxidative and nitrosative stress. These data suggest that ouabain induces oxidative changes of the sarcoplasmic reticulum Ca²⁺-ATPase structure and function that may, in turn, produce some of the associated changes in Ca²⁺ cycling and physiological function.

reactive oxygen species; cardiac signaling

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