Elevated Sarcoplasmic Reticulum Ca 2+ Leak in Intact Ventricular Myocytes From Rabbits in Heart Failure

Abstract

Altered sarcoplasmic reticulum (SR) Ca 2+ -ATPase and Na + -Ca 2+ exchange (NCX) function have been implicated in depressing SR Ca 2+ content and contractile function in heart failure (HF). Enhanced diastolic ryanodine receptor (RyR) leak could also lower SR Ca 2+ load in HF, but direct cellular measurements are lacking. In this study, we measure SR Ca 2+ leak directly in intact isolated rabbit ventricular myocytes from a well-developed nonischemic HF model. Abrupt block of SR Ca 2+ leak by tetracaine shifts Ca 2+ from the cytosol to SR. The tetracaine-induced decline in [Ca 2+ ] i and increase total SR Ca 2+ load ([Ca 2+ ] SRT ) directly indicate the SR Ca 2+ leak (before tetracaine). Diastolic SR Ca 2+ leak increases with [Ca 2+ ] SRT , and for any [Ca 2+ ] SRT is greater in HF versus control. Mathematical modeling was used to compare the relative impact of alterations in SR Ca 2+ leak, SR Ca 2+ -ATPase, and Na + -Ca 2+ exchange on SR Ca 2+ load in HF. We conclude that increased diastolic SR Ca 2+ leak in HF may contribute to reductions in SR Ca 2+ content, but changes in NCX in this HF model have more impact on [Ca 2+ ] SRT .