Hypotension, Autonomic Failure, and Cardiac Hypertrophy in Transgenic Mice Overexpressing the α1B-Adrenergic Receptor

Michael J. Zuscik, Dan Chalothorn, David Hellard, Clare Deighan, Ann McGee, Craig J. Daly, David J J Waugh, Sean A. Ross, Robert J. Gaivin, Annitta J. Morehead, James D. Thomas, Edward F. Plow, John C. McGrath, Michael T. Piascik, Dianne M. Perez*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

Abstract

α1-Adrenergic receptors (α1A α 1B, and α1D) are regulators of systemic arterial blood pressure and blood flow. Whereas vasoconstrictory action of the α1A and α1D subtypes is thought to be mainly responsible for this activity, the role of the α1B-adrenergic receptor (α1BAR) in this process is controversial. We have generated transgenic mice that overexpress either wild type or constitutively active α1BARs. Transgenic expression was under the control of the isogenic promoter, thus assuring appropriate developmental and tissue-specific expression. Cardiovascular phenotypes displayed by transgenic mice included myocardial hypertrophy and hypotension. Indicative of cardiac hypertrophy, transgenic mice displayed an increased heart to body weight ratio, which was confirmed by the echocardiographic finding of an increased thickness of the interventricular septum and posterior wall. Functional deficits included an increased isovolumetric relaxation time, a decreased heart rate, and cardiac output. Transgenic mice were hypotensive and exhibited a decreased pressor response. Vasoconstrictory regulation by α1BAR was absent as shown by the lack of phenylephrine-induced contractile differences between ex vivo mesenteric artery preparations. Plasma epinephrine, norepinephrine, and cortisol levels were also reduced in transgenic mice, suggesting a loss of sympathetic nerve activity. Reduced catecholamine levels together with basal hypotension, bradyeardia, reproductive problems, and weight loss suggest autonomic failure, a phenotype that is consistent with the multiple system atrophy-like neurodegeneration that has been reported previously in these mice. These results also suggest that this receptor subtype is not involved in the classic vasoconstrictory action of α1ARs that is important in systemic regulation of blood pressure.

Original languageEnglish (US)
Pages (from-to)13738-13743
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number17
DOIs
StatePublished - Apr 27 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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