I A Hobai1, B O'Rourke. 1. Institute of Molecular Cardiobiology, Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Md, USA.
Abstract
BACKGROUND: Altered excitation-contraction (E-C) coupling in canine pacing-induced heart failure involves decreased sarcoplasmic reticulum (SR) Ca uptake and enhanced Na/Ca exchange, which could be expected to decrease SR Ca content (Ca(SR)) and may explain the reduced intracellular Ca (Ca(i)) transient. Studies in other failure models have suggested that the intrinsic coupling between L-type Ca current (I:(Ca,L)) and SR Ca release is reduced without a change in SR Ca load. The present study investigates whether Ca(SR) and/or coupling is altered in midmyocardial myocytes from failing canine hearts (F). METHODS AND RESULTS: Myocytes were indo-1-loaded via patch pipette (37 degrees C), and Ca(i) transients were elicited with voltage-clamp steps applied at various frequencies. I(Ca,L) density was not significantly decreased in F, but steady-state Ca(i) transients were reduced to 20% to 40% of normal myocytes (N). Ca(SR), measured by integrating Na/Ca exchange currents during caffeine-induced release, was profoundly decreased in F, to 15% to 25% of N. When Ca(SR) was normalized in F by preloading in 5 mmol/L external Ca before a test pulse at 2 mmol/L Ca, a normal-amplitude Ca(i) transient was elicited. E-C coupling gain was dependent on Ca(SR) but was affected similarly in both groups, indicating that intrinsic coupling is unaltered in F. CONCLUSIONS: A decrease in Ca(SR) is sufficient to explain the diminished Ca(i) transients in F, without a change in the effectiveness of coupling. Therefore, therapeutic approaches that increase Ca(SR) may be able to fully correct the Ca handling deficit in heart failure.
BACKGROUND: Altered excitation-contraction (E-C) coupling in canine pacing-induced heart failure involves decreased sarcoplasmic reticulum (SR) Ca uptake and enhanced Na/Ca exchange, which could be expected to decrease SR Ca content (Ca(SR)) and may explain the reduced intracellular Ca (Ca(i)) transient. Studies in other failure models have suggested that the intrinsic coupling between L-type Ca current (I:(Ca,L)) and SR Ca release is reduced without a change in SR Ca load. The present study investigates whether Ca(SR) and/or coupling is altered in midmyocardial myocytes from failing canine hearts (F). METHODS AND RESULTS: Myocytes were indo-1-loaded via patch pipette (37 degrees C), and Ca(i) transients were elicited with voltage-clamp steps applied at various frequencies. I(Ca,L) density was not significantly decreased in F, but steady-state Ca(i) transients were reduced to 20% to 40% of normal myocytes (N). Ca(SR), measured by integrating Na/Ca exchange currents during caffeine-induced release, was profoundly decreased in F, to 15% to 25% of N. When Ca(SR) was normalized in F by preloading in 5 mmol/L external Ca before a test pulse at 2 mmol/L Ca, a normal-amplitude Ca(i) transient was elicited. E-C coupling gain was dependent on Ca(SR) but was affected similarly in both groups, indicating that intrinsic coupling is unaltered in F. CONCLUSIONS: A decrease in Ca(SR) is sufficient to explain the diminished Ca(i) transients in F, without a change in the effectiveness of coupling. Therefore, therapeutic approaches that increase Ca(SR) may be able to fully correct the Ca handling deficit in heart failure.
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