α1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

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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104 Scopus citations

Abstract

An α1-adrenergic receptor (α1-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 α1-AR inhibition or a nonspecific drug effect. We studied cardiac pressure overload in mice with double KO of the 2 main α1-AR subtypes in the heart, α1A (Adra1a) and α1B (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 β-AR stimulation, and β-ARs were desensitized. Thus, α1-AR deletion worsens dilated cardiomyopathy after pressure overload, by multiple mechanisms, indicating that α1-signaling is required for cardiac adaptation. These results suggest that the adverse cardiac effects of α1-antagonists in clinical trials are due to loss of α1-signaling in myocytes, emphasizing concern about clinical use of α1-antagonists, and point to a revised perspective on sympathetic activation in heart failure.

Original languageEnglish (US)
Pages (from-to)1005-1015
Number of pages11
JournalJournal of Clinical Investigation
Volume116
Issue number4
DOIs
StatePublished - Apr 1 2006

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    O'Connell, T. D., Swigart, P. M., Rodrigo, M. C., Ishizaka, S., Joho, S., Turnbull, L., Tecott, L. H., Baker, A. J., Foster, E., Grossman, W., & Simpson, P. C. (2006). α1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload. Journal of Clinical Investigation, 116(4), 1005-1015. https://doi.org/10.1172/JCI22811