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⁺-Ca ²⁺ 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.