Document Detail

Alpha1-adrenergic receptors prevent a maladaptive cardiac response to pressure overload.
MedLine Citation:
PMID:  16585965     Owner:  NLM     Status:  MEDLINE    
An alpha1-adrenergic receptor (alpha1-AR) antagonist increased heart failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), but it is unknown whether this adverse result was due to alpha1-AR inhibition or a nonspecific drug effect. We studied cardiac pressure overload in mice with double KO of the 2 main alpha1-AR subtypes in the heart, alpha 1A (Adra1a) and alpha 1B (Adra1b). At 2 weeks after transverse aortic constriction (TAC), KO mouse survival was only 60% of WT, and surviving KO mice had lower ejection fractions and larger end-diastolic volumes than WT mice. Mechanistically, final heart weight and myocyte cross-sectional area were the same after TAC in KO and WT mice. However, KO hearts after TAC had increased interstitial fibrosis, increased apoptosis, and failed induction of the fetal hypertrophic genes. Before TAC, isolated KO myocytes were more susceptible to apoptosis after oxidative and beta-AR stimulation, and beta-ARs were desensitized. Thus, alpha1-AR deletion worsens dilated cardiomyopathy after pressure overload, by multiple mechanisms, indicating that alpha1-signaling is required for cardiac adaptation. These results suggest that the adverse cardiac effects of alpha1-antagonists in clinical trials are due to loss of alpha1-signaling in myocytes, emphasizing concern about clinical use of alpha1-antagonists, and point to a revised perspective on sympathetic activation in heart failure.
Timothy D O'Connell; Philip M Swigart; M C Rodrigo; Shinji Ishizaka; Shuji Joho; Lynne Turnbull; Laurence H Tecott; Anthony J Baker; Elyse Foster; William Grossman; Paul C Simpson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  116     ISSN:  0021-9738     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2006 Apr 
Date Detail:
Created Date:  2006-04-04     Completed Date:  2006-05-16     Revised Date:  2010-09-15    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1005-15     Citation Subset:  AIM; IM    
Cardiology Division, San Francisco Veterans Affairs Medical Center, San Francisco, California 94121, USA.
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MeSH Terms
Blood Pressure / physiology*
Cardiomyopathy, Dilated / metabolism
Cells, Cultured
Fibrosis / pathology
Gene Expression Regulation
Hypertension / metabolism,  physiopathology
Mice, Inbred C57BL
Mice, Inbred Strains
Mice, Knockout
Myocardium / metabolism*,  pathology
Myocytes, Cardiac
Receptors, Adrenergic, alpha-1 / metabolism*
Signal Transduction
Grant Support
Reg. No./Substance:
0/Receptors, Adrenergic, alpha-1; 0/adrenergic receptor alpha(1a); 0/adrenergic receptor alpha(1b)
Comment In:
J Clin Invest. 2006 Apr;116(4):875-7   [PMID:  16585959 ]

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