Elevated sarcoplasmic reticulum Ca2+ leak in intact ventricular myocytes from rabbits in heart failure.
Altered sarcoplasmic reticulum (SR) Ca2+-ATPase and Na+-Ca2+ exchange (NCX) function have been implicated in depressing SR Ca2+ content and contractile function in heart failure (HF). Enhanced diastolic ryanodine receptor (RyR) leak could also lower SR Ca2+ load in HF, but direct cellular measurements are lacking. In this study, we measure SR Ca2+ leak directly in intact isolated rabbit ventricular myocytes from a well-developed nonischemic HF model. Abrupt block of SR Ca2+ leak by tetracaine shifts Ca2+ from the cytosol to SR. The tetracaine-induced decline in [Ca2+]i and increase total SR Ca2+ load ([Ca2+]SRT) directly indicate the SR Ca2+ leak (before tetracaine). Diastolic SR Ca2+ leak increases with [Ca2+]SRT, and for any [Ca2+]SRT is greater in HF versus control. Mathematical modeling was used to compare the relative impact of alterations in SR Ca2+ leak, SR Ca2+-ATPase, and Na+-Ca2+ exchange on SR Ca2+ load in HF. We conclude that increased diastolic SR Ca2+ leak in HF may contribute to reductions in SR Ca2+ content, but changes in NCX in this HF model have more impact on [Ca2+]SRT.
Shannon
Thomas R
TR
Department of Molecular Biophysics and Physiology, Rush University, 1750 W Harrison Ave, Chicago, Ill 60612, USA. tshannon@rush.edu
Pogwizd
Steven M
SM
Bers
Donald M
DM
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D013748:Tetracaine / Q000494:pharmacology
D013748:Tetracaine; D002118:Calcium