Alpha1-adrenergic receptors prevent a maladaptive cardiac response to pressure overload.
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.
Cardiology Division, San Francisco Veterans Affairs Medical Center, San Francisco, California 94121, USA.
Timothy D
TD
O'Connell
Philip M
PM
Swigart
M C
MC
Rodrigo
Shinji
S
Ishizaka
Shuji
S
Joho
Lynne
L
Turnbull
Laurence H
LH
Tecott
Anthony J
AJ
Baker
Elyse
E
Foster
William
W
Grossman
Paul C
PC
Simpson
D000818:Animals; D017209:Apoptosis; D001794:Blood Pressure / Q000502:physiology*; D002311:Cardiomyopathy, Dilated / Q000378:metabolism; D002478:Cells, Cultured; D005355:Fibrosis / Q000473:pathology; D005786:Gene Expression Regulation; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D015398:Signal Transduction
C547714:Adra1a protein, mouse; C547717:Adra1b protein, mouse; D018340:Receptors, Adrenergic, alpha-1