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(Circulation Research. 2007;101:802.)
© 2007 American Heart Association, Inc.

Cellular Biology

Intra–Sarcoplasmic Reticulum Free [Ca²⁺] and Buffering in Arrhythmogenic Failing Rabbit Heart

Tao Guo, Xun Ai, Thomas R. Shannon, Steven M. Pogwizd, Donald M. Bers

From the Department of Physiology and Cardiovascular Institute (T.G., D.M.B.), Loyola University Chicago, Stritch School of Medicine, Maywood, Ill; Department of Medicine (X.A., S.M.P.), University of Illinois at Chicago; and Department of Molecular Biophysics & Physiology (T.R.S.), Rush University, Chicago, Ill.

Correspondence to Donald M. Bers, PhD, Department of Physiology, Loyola University Chicago, 2160 South First Ave, Maywood, IL 60153. E-mail dbers{at}lumc.edu

Smaller Ca²⁺ transients and systolic dysfunction in heart failure (HF) can be largely explained by reduced total sarcoplasmic reticulum (SR) Ca²⁺ content ([Ca]_SRT). However, it is unknown whether low [Ca]_SRT is manifest as reduced: (1) intra-SR free [Ca²⁺] ([Ca²⁺]_SR), (2) intra-SR Ca²⁺ buffering, or (3) SR volume (as percentage of cell volume). Here we assess these possibilities in a well-characterized rabbit model of nonischemic HF. In HF versus control myocytes, diastolic [Ca²⁺]_SR is similar at 0.1-Hz stimulation, but the increase in both [Ca²⁺]_SR and [Ca]_SRT as frequency increases to 1 Hz is blunted in HF. Direct measurement of intra-SR Ca²⁺ buffering (by simultaneous [Ca²⁺]_SR and [Ca]_SRT measurement) showed no change in HF. Diastolic [Ca]_SRT changes paralleled [Ca²⁺]_SR, suggesting that SR volume is not appreciably altered in HF. Thus, reduced [Ca]_SRT in HF is associated with comparably reduced [Ca²⁺]_SR. Fractional [Ca²⁺]_SR depletion increased progressively with stimulation frequency in control but was blunted in HF (consistent with the blunted force–frequency relationship in HF). By studying a range of [Ca²⁺]_SR, analysis showed that for a given [Ca]_SR, fractional SR Ca²⁺ release was actually higher in HF. For both control and HF myocytes, SR Ca²⁺ release terminated when [Ca²⁺]_SR dropped to 0.3 to 0.5 mmol/L during systole, consistent with a role for declining [Ca²⁺]_SR in the dynamic shutoff of SR Ca²⁺ release. We conclude that low total SR Ca²⁺ content in HF, and reduced SR Ca²⁺ release, is attributable to reduced [Ca²⁺]_SR, not to alterations in SR volume or Ca²⁺ buffering capacity.

Key Words: excitation–contraction coupling • heart failure • sarcoplasmic reticulum • [Ca²⁺]_SR • [Ca]_SRT • intra-SR Ca²⁺ buffering

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