Differential cardiovascular regulatory activities of the α1B- and α1D-adrenoceptor subtypes

Dan Chalothorn, Dan F. McCune, Stephanie E. Edelmann, Kimimasa Tobita, Bradley B. Keller, Robert D. Lasley, Dianne M. Perez, Akito Tanoue, Gozoh Tsujimoto, Ginell R. Post, Michael T. Piascik

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

The regulation of cardiac and vascular function by the α1B- and α1D-adrenoceptors (ARs) has been assessed in two lines of transgenic mice, one over-expressing a constitutively active α1B-AR mutation (α1B-ARC128F) and the other an α1D-AR knockout line. The advantage of using mice expressing a constitutively active α1B-AR is that the receptor is tonically active, thus avoiding the use of nonselective agonists that can activate all subtypes. In hearts from animals expressing α1B-ARC128F, the activities of the mitogen-activated protein kinases, extracellular signal-regulated kinase, and c-Jun N-terminal kinase were significantly elevated compared with nontransgenic control animals. Mice over-expressing the α1B-ARC128F had echocardiographic evidence of contractile dysfunction and increases in chamber dimensions. In isolated-perfused hearts or left ventricular slices from α1B-ARC128F-expressing animals, the ability of isoproterenol to increase contractile force or increase cAMP levels was significantly decreased. In contrast to the prominent effects on the heart, constitutive activation of the α1B-AR had little effect on the ability of phenylephrine to induce vascular smooth muscle contraction in the isolated aorta. The ability of phenylephrine to stimulate coronary vasoconstriction was diminished in α1D-AR knockout mice. In α1D-AR knockout animals, no negative effects on cardiac contractile function were noted. These results show that the α1-ARs regulate distinctly different physiologic processes. The α1B-AR appears to be involved in the regulation of cardiac growth and contractile function, whereas the α1D-AR is coupled to smooth muscle contraction and the regulation of systemic arterial blood pressure.

Original languageEnglish
Pages (from-to)1045-1053
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume305
Issue number3
DOIs
StatePublished - Jun 1 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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