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Elevated Sarcoplasmic Reticulum Ca²⁺ Leak in Intact Ventricular Myocytes From Rabbits in Heart Failure

From the Department of Physiology and Biophysics (T.R.S.), Rush University, Chicago, Ill; the Department of Medicine (S.M.P.), University of Illinois–Chicago, Chicago, Ill; and the Department of Physiology (T.R.S., D.M.B.), Loyola University Chicago, Maywood, Ill.

Correspondence to Thomas R. Shannon, Department of Molecular Biophysics and Physiology, Rush University, 1750 W Harrison Ave, Chicago, IL 60612. E-mail tshannon{at}rush.edu

Abstract

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.

Key Words: sarcoplasmic reticulum • ryanodine receptors • Ca²⁺ pump • excitation-contraction coupling • heart failure

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