The α1A/C- and α1B-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse

Timothy D. O'Connell, Shinji Ishizaka, Akihiro Nakamura, Philip M. Swigart, M. C. Rodrigo, Gregory L. Simpson, Susanna Cotecchia, D. Gregg Rokosh, William Grossman, Elyse Foster, Paul C. Simpson

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150 Scopus citations


Catecholamines and α1-adrenergic receptors (α 1-ARs) cause cardiac hypertrophy in cultured myocytes and transgenic mice, but heart size is normal in single KOs of the main α1-AR subtypes, α1A/C and α1B. Here we tested whether α1-ARs are required for developmental cardiac hypertrophy by generating α1A/C and α1B double KO (ABKO) mice, which had no cardiac α1-AR binding. In male ABKO mice, heart growth after weaning was 40% less than in WT, and the smaller heart was due to smaller myocytes. Body and other organ weights were unchanged, indicating a specific effect on the heart. Blood pressure in ABKO mice was the same as in WT, showing that the smaller heart was not due to decreased load. Contractile function was normal by echocardiography in awake mice, but the smaller heart and a slower heart rate reduced cardiac output. α1-AR stimulation did not activate extracellular signal-regulated kinase (Erk) and downstream kinases in ABKO myocytes, and basal Erk activity was lower in the intact ABKO heart. In female ABKO mice, heart size was normal, even after ovariectomy. Male ABKO mice had reduced exercise capacity and increased mortality with pressure overload. Thus, α1-ARs in male mice are required for the physiological hypertrophy of normal postnatal cardiac development-and for an adaptive response to cardiac stress.

Original languageEnglish (US)
Pages (from-to)1783-1791
Number of pages9
JournalJournal of Clinical Investigation
Issue number11
StatePublished - Jun 2003

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