1-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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)1005 - 1015
Number of pages11
JournalJournal of Clinical Investigation
Volume116
Issue number4
Publication statusPublished - 2006

Cite this

O'Connell, T. D., Swigart, P. M., Rodrigo, M. C., Ishizaka, S., Joho, S., Turnbull, L., ... Simpson, P. C. (2006). 1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload. Journal of Clinical Investigation, 116(4), 1005 - 1015.
O'Connell, Timothy D ; Swigart, Philip M ; Rodrigo, M C ; Ishizaka, Shinji ; Joho, Shuji ; Turnbull, Lynne ; Tecott, Laurence H ; Baker, Anthony J ; Foster, Elyse ; Grossman, William ; Simpson, Paul C. / 1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload. In: Journal of Clinical Investigation. 2006 ; Vol. 116, No. 4. pp. 1005 - 1015.
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abstract = "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.",
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O'Connell, TD, Swigart, PM, Rodrigo, MC, Ishizaka, S, Joho, S, Turnbull, L, Tecott, LH, Baker, AJ, Foster, E, Grossman, W & Simpson, PC 2006, '1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload', Journal of Clinical Investigation, vol. 116, no. 4, pp. 1005 - 1015.

1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload. / O'Connell, Timothy D; Swigart, Philip M; Rodrigo, M C; Ishizaka, Shinji; Joho, Shuji; Turnbull, Lynne; Tecott, Laurence H; Baker, Anthony J; Foster, Elyse; Grossman, William; Simpson, Paul C.

In: Journal of Clinical Investigation, Vol. 116, No. 4, 2006, p. 1005 - 1015.

Research output: Contribution to journalArticleResearchpeer-review

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AU - O'Connell, Timothy D

AU - Swigart, Philip M

AU - Rodrigo, M C

AU - Ishizaka, Shinji

AU - Joho, Shuji

AU - Turnbull, Lynne

AU - Tecott, Laurence H

AU - Baker, Anthony J

AU - Foster, Elyse

AU - Grossman, William

AU - Simpson, Paul C

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AB - 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.

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O'Connell TD, Swigart PM, Rodrigo MC, Ishizaka S, Joho S, Turnbull L et al. 1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload. Journal of Clinical Investigation. 2006;116(4):1005 - 1015.