Submitted on November 13, 2007
Accepted on March 17, 2008
Reduced Effects of Bay K 8644 on L-type Ca2+ Current in Failing Human Cardiac Myocytes Are Related to Abnormal Adrenergic Regulation
Xiongwen Chen1, Xiaoying Zhang1, David M Harris2, Valentino Piacentino3, Remus M. Berretta1, Kenneth B Margulies4, and Steven R Houser5*
1 Cardiovascular Research Center/Physiology, Temple University, Philadelphia, Pennsylvania, United States
2 Cardiovascular Research Center/Physiology, Temple University, 19140, Pennsylvania, United States
3 Department of Medicine, Duke University, Durham, North Carolina, United States
4 Cardiovascular Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States
5 PCardiovascular Research Center/Physiology, Temple University, Philadelphia, Pennsylvania, United States
* To whom correspondence should be addressed. E-mail: steven.houser{at}temple.edu.
Abnormal L-type calcium channel (LTCC, also named Cav1.2) density and regulation are important contributors to depressed contractility in failing hearts. The LTCC agonist, BayK 8644 (BayK), has reduced inotropic effects on failing myocardium. We hypothesize that BayK effects on the LTCC current (ICa-L) in failing myocytes are 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 hypothesize that BayK effects on ICa-L will 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) BayK had smaller effects on ICa-L in F- compared to NF-HVMs; (2) BayK had diminished effects on ICa-L in NF HVMs pretreated by isoproterenol (ISO) or dibutyryl-cyclic AMP (db-cAMP); (3) BayK effects on ICa-L in F HVMs pretreated with acetylcholine (Ach) were normalized; (4) ISO had no effect on NF HVMs pretreated with BayK; (5) BayK effects on ICa-L in LVAD HVMs were similar to NF HVMs; (6) BayK effects were reduced in LVAD HVMs pretreated with ISO or db-cAMP; (7) ISO had no effect on ICa-L in LVAD HVMs pretreated with BayK. Collectively, these results suggest that the decreased BayK effects on LTCC in F HVMs are caused by increased basal channel activity, which should contribute to abnormal contractility reserve.
