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. 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 alpha(1C)- 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.