L-Type Ca Channel Density and Regulation Are Altered in Failing Human Ventricular Myocytes and Recover After Support With Mechanical Assist Devices

Ca influx through the L-type calcium channel (LTCC) induces Ca release from the sarcoplasmic reticulum (SR) and maintains SR Ca loading. Alterations in LTCC properties, their contribution to the blunted adrenergic responsiveness in failing hearts and their recovery after support with LV assist devices (LVAD) were studied. L-type Ca current (ICa,L) was measured under basal conditions and in the presence of isoproterenol (ISO), dibutyryl-cAMP (db-cAMP), Bay K 8644 (BayK), Okadaic acid (OA, a phosphatase inhibitor), and phosphatase 2A (PP2A) in nonfailing (NF), failing (F), and LVAD-supported human left ventricular myocytes (HVMs). Basal ICa,L density was not different in the 3 groups but ICa,L was activated at more negative voltages in Fand LVADversus NF-HVMs (V0.5: 7.18 1.4 and 7.0 0.9 versus 0.46 1.1 mV). Both ISO and db-cAMP increased ICa,L in NFand LVADsignificantly more than in F-HVMs (NF LVAD F: ISO: 90 15% versus 77 19% versus 24 12%; db-cAMP: 235% 172% 90%). ISO caused a significant leftward shift of the ICa,L activation curve in NFand LVADbut not in F-HVMs. After ISO and db-cAMP, the ICa,L activation was not significantly different between groups. BayK also increased ICa,L more in NF(81 30%) and LVAD(70 15%) than in F(51 8%) HVMs. OA increased ICa,L by 85.6% in NF-HVMs but had no effect in F-HVMs, while PP2A decreased ICa,L in F-HVMs by 35% but had no effect in NF-HVMs. These results suggest that the density of LTCC is reduced in F-HVMs but basal ICa,L density is maintained by increasing in LTCC phosphorylation. (Circ Res. 2002;91:517-524.)