Abstract

Abnormal L-type Ca(2+) channel (LTCC, also named Cav1.2) density and regulation are important contributors to depressed contractility in failing hearts. The LTCC agonist BAY K 8644 (BAY K) has reduced inotropic effects on failing myocardium. We hypothesized that BAY K effects on the LTCC current (I(CaL)) in failing myocytes would be reduced because of increased basal activity. Since support of the failing heart with a left ventricular assist device (LVAD) improves contractility and adrenergic responses, we further hypothesized that BAY K effects on I(CaL) would be restored in LVAD-supported failing hearts. We tested our hypotheses in human ventricular myocytes (HVMs) isolated from nonfailing (NF), failing (F), and LVAD-supported failing hearts. We found that 1) BAY K had smaller effects on I(CaL) in F HVMs compared with NF HVMs; 2) BAY K had diminished effects on I(CaL) in NF HVM pretreated with isoproterenol (Iso) or dibutyryl cyclic AMP (DBcAMP); 3) BAY K effects on I(CaL) in F HVMs pretreated with acetylcholine (ACh) were normalized; 4) Iso had no effect on NF HVMs pretreated with BAY K; 5) BAY K effects on I(CaL) in LVAD HVMs were similar to those in NF HVMs; 6) BAY K effects were reduced in LVAD HVMs pretreated with Iso or DBcAMP; 7) Iso had no effect on I(CaL) in LVAD HVMs pretreated with BAY K. Collectively, these results suggest that the decreased BAY K effects on LTCC in F HVMs are caused by increased basal channel activity, which should contribute to abnormal contractility reserve.