Copyright © 2007, European Society of Cardiology
Heterozygous 
2C-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction
aInstitute of Experimental and Clinical Pharmacology, University of Freiburg, Germany
bDepartment of Anesthesiology, University of Würzburg, Germany
cDepartment of Pharmacology, University of Würzburg, Germany
dInstituto de Farmacologia e Terapêutica, Faculdade de Medicina, Universidade do Porto, Portugal
eDepartment of Cardiovascular Medicine, University of Oxford, UK
* 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
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 
2C-adrenoceptors may operate in a similar feedback mechanism to control the release of epinephrine from the adrenal medulla. As heterozygous polymorphisms in the human 2C-adrenoceptor gene have been associated with cardiovascular disease including hypertension and chronic heart failure, we have sought to characterize the relevance of 2C-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 2C-adrenoceptor gene (2C–/–).
Results Heterozygous 2C-receptor deletion (2C+/–) resulted in a 43% reduction of adrenal 2C mRNA copy number and in a similar decrease in 2-receptor-mediated inhibition of catecholamine release from isolated adrenal glands in vitro. Urinary excretion of epinephrine was increased by 74±15% in 2C+/– and by 142±23% in 2C–/– mice as compared with wild-type control mice. Telemetric determination of cardiovascular function revealed significant tachycardia but no hypertension in 2C-adrenoceptor-deficient mice. 2C+/– mice were more susceptible to develop cardiac hypertrophy, failure and mortality after left-ventricular pressure overload than 2C+/+ mice.
Conclusion Adrenal 2-mediated feedback regulation of epinephrine secretion differs fundamentally from sympathetic feedback control. A single adrenoceptor subtype, 2C, 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 2C-adrenoceptor dysfunction in humans.
KEYWORDS Neurotransmitters; Transgenic animal models; Hypertrophy; Autonomic nervous system; Adrenergic system