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Heterozygous α2C-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction

  1. Ralf Gilsbacha,1,
  2. Marc Bredeb,c,1,
  3. Nadine Beetza,
  4. Eduardo Mouraa,d,
  5. Verena Muthiga,
  6. Carolin Gerstnerb,
  7. Frederico Barretoa,
  8. Stefan Neubauere,
  9. Maria Augusta Vieira-Coelhod and
  10. Lutz Heina,*
  1. aInstitute of Experimental and Clinical Pharmacology, University of Freiburg, Germany
  2. bDepartment of Anesthesiology, University of Würzburg, Germany
  3. cDepartment of Pharmacology, University of Würzburg, Germany
  4. dInstituto de Farmacologia e Terapêutica, Faculdade de Medicina, Universidade do Porto, Portugal
  5. eDepartment of Cardiovascular Medicine, University of Oxford, UK
  1. * Corresponding author. Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany. Tel.: +49 761 2035314; fax: +49 761 2035318. lutz.hein{at}pharmakol.uni-freiburg.de
  • Received February 5, 2007.
  • Revision requested April 28, 2007.
  • Accepted May 15, 2007.

Abstract

Objective Feedback regulation of norepinephrine release from sympathetic nerves is essential to control blood pressure, heart rate and contractility. Recent experiments in gene-targeted mice have suggested that α2C-adrenoceptors may operate in a similar feedback mechanism to control the release of epinephrine from the adrenal medulla. As heterozygous polymorphisms in the human α2C-adrenoceptor gene have been associated with cardiovascular disease including hypertension and chronic heart failure, we have sought to characterize the relevance of α2C-gene copy number for feedback control of epinephrine release in gene-targeted mice.

Methods Adrenal catecholamine release, basal hemodynamics and susceptibility to develop heart failure after transverse aortic constriction were tested in mice with two copies (+/+), one copy (+/−) or no functional α2C-adrenoceptor gene (α2C−/−).

Results Heterozygous α2C-receptor deletion (α2C+/−) resulted in a 43% reduction of adrenal α2C mRNA copy number and in a similar decrease in α2-receptor-mediated inhibition of catecholamine release from isolated adrenal glands in vitro. Urinary excretion of epinephrine was increased by 74±15% in α2C+/− and by 142±23% in α2C−/− mice as compared with wild-type control mice. Telemetric determination of cardiovascular function revealed significant tachycardia but no hypertension in α2C-adrenoceptor-deficient mice. α2C+/− mice were more susceptible to develop cardiac hypertrophy, failure and mortality after left-ventricular pressure overload than α2C+/+ mice.

Conclusion Adrenal α2-mediated feedback regulation of epinephrine secretion differs fundamentally from sympathetic feedback control. A single adrenoceptor subtype, α2C, operates without a significant receptor reserve to prevent elevation of circulating epinephrine levels. This genetic model may provide an experimental basis to study the pathophysiology of α2C-adrenoceptor dysfunction in humans.

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    1. Cardiovasc Res (2007) 75 (4): 728-737. doi: 10.1016/j.cardiores.2007.05.017
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