Document Detail


Reduced effects of BAY K 8644 on L-type Ca2+ current in failing human cardiac myocytes are related to abnormal adrenergic regulation.
MedLine Citation:
PMID:  18359894     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Xiongwen Chen; Xiaoying Zhang; David M Harris; Valentino Piacentino; Remus M Berretta; Kenneth B Margulies; Steven R Houser
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Publication Detail:
Type:  Journal Article     Date:  2008-03-21
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  294     ISSN:  0363-6135     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2008 May 
Date Detail:
Created Date:  2008-05-07     Completed Date:  2008-06-12     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H2257-67     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / pharmacology*
Acetylcholine / pharmacology
Adrenergic beta-Agonists / pharmacology*
Bucladesine / pharmacology
Calcium Channel Agonists / pharmacology*
Calcium Channels, L-Type / drug effects*,  metabolism
Cardiotonic Agents / pharmacology*
Catecholamines / metabolism
Drug Resistance
Heart Failure / metabolism*,  physiopathology,  therapy
Heart Ventricles / drug effects,  metabolism
Heart-Assist Devices
Humans
Isoproterenol / pharmacology*
Membrane Potentials / drug effects
Myocardial Contraction / drug effects
Myocytes, Cardiac / drug effects*,  metabolism
Phosphorylation
Grant Support
ID/Acronym/Agency:
R01 HL088243/HL/NHLBI NIH HHS; R01 HL088243-01/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Adrenergic beta-Agonists; 0/CACNA1C protein, human; 0/Calcium Channel Agonists; 0/Calcium Channels, L-Type; 0/Cardiotonic Agents; 0/Catecholamines; 0/L-type calcium channel alpha(1C); 63X7MBT2LQ/Bucladesine; 71145-03-4/3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; L628TT009W/Isoproterenol; N9YNS0M02X/Acetylcholine
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