Increased availability and open probability of single L-type calcium channels from failing compared with nonfailing human ventricle.
BACKGROUND
The role of the L-type calcium channel in human heart failure is unclear, on the basis of previous whole-cell recordings.


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.
Schröder
F
F
Department of Pharmacology, University of Cologne, Germany.
Handrock
R
R
Beuckelmann
D J
DJ
Hirt
S
S
Hullin
R
R
Priebe
L
L
Schwinger
R H
RH
Weil
J
J
Herzig
S
S
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D020746:Calcium Channels, L-Type; D009202:Cardiomyopathies / Q000503:physiopathology*; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D006321:Heart / Q000502:physiology* / Q000503:physiopathology; D006352:Heart Ventricles; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D008564:Membrane Potentials; D017202:Myocardial Ischemia / Q000503:physiopathology*; D011336:Probability; D012016:Reference Values; D013997:Time Factors
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP