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.
- 11257088
- animal,
- animals,
- artificial,
- calcium,
- cardiac
- comparative
- contraction,
- disease
- diseases,
- dogs,
- electrophysiology,
- gov't,
- heart
- humans,
- models,
- myocardial
- p.h.s.,
- pacing,
- research
- reticulum,
- sarcoplasmic
- study,
- support,
- u.s.
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