Abstract
BACKGROUND: The role of the L-type calcium channel in human heart
failure is unclear, on the basis of previous whole-cell recordings.
METHODS AND RESULTS: We investigated the properties of L-type calcium
channels in left ventricular myocytes isolated from nonfailing donor
hearts (n= 16 cells) or failing hearts of transplant recipients with
dilated (n=9) or ischemic (n=7) cardiomyopathy. The single-channel
recording technique was used (70 mmol/L Ba2+). Peak average currents
were significantly enhanced in heart failure (38.2+/-9.3 fA) versus
nonfailing control hearts (13.2+/-4.5 fA, P=0.02) because of an elevation
of channel availability (55.9+/-6.7\% versus 26.4+/-5.3\%, P=0.001)
and open probability within active sweeps (7.36+/-1.51\% versus 3.18+/-1.33\%,
P=0.04). These differences closely resembled the effects of a cAMP-dependent
stimulation with 8-Br-cAMP (n= 11). Kinetic analysis of the slow
gating shows that channels from failing hearts remain available for
a longer time, suggesting a defect in the dephosphorylation. Indeed,
the phosphatase inhibitor okadaic acid was unable to stimulate channel
activity in myocytes from failing hearts (n=5). Expression of calcium
channel subunits was measured by Northern blot analysis. Expression
of alpha1c- and beta-subunits was unaltered. Whole-cell current measurements
did not reveal an increase of current density in heart failure. CONCLUSIONS:
Individual L-type calcium channels are fundamentally affected in
severe human heart failure. This is probably important for the impairment
of cardiac excitation-contraction coupling.
- 8-bromo
- 9737516
- adenosine
- amp,
- atria,
- barium,
- calcineurin,
- calcium
- calcium,
- cardiomyopathies,
- cardiomyopathy,
- cell
- cells,
- channel
- channels,
- comparative
- congestive,
- cultured,
- cyclic
- cyclosporine,
- dilated,
- factors,
- failure,
- gating,
- gov't,
- heart
- heart,
- humans,
- ion
- ischemia,
- kinetics,
- l
- l-type,
- line,
- membrane
- monophosphate,
- muscle
- myocardia,
- non-u.s.
- p.h.s.,
- potentials,
- probability,
- proteins,
- recombinant
- reference
- research
- study,
- support,
- time
- u.s.
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