Heterozygous alpha(2C)-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction

• Type: Article in International Scientific Journal
• Date: 2007

Authors

gilsbach, r (Author) Other; brede, m (Author) Other; beetz, n (Author) Other; moura, e (Author) Other; muthig, v (Author) Other; gerstner, c (Author) Other; barreto, f (Author) Other; neubauer, s (Author) Other; vieira-coelho, ma (Author) FMUP; hein, l (Author) Other

Journal

Title: Cardiovascular Research

Vol. 75

Pages: 728-737

ISSN: 0008-6363

Publisher: Oxford University Press

Indexing

ISI Web of Knowledge - 36 Citations

Scopus - 40 Citations

Other information

Authenticus ID: P-004-7MX

DOI: 10.1016/j.cardiores.2007.05.017

Abstract (EN): 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 alpha(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 alpha(2C)-adrenoceptor gene have been associated with cardiovascular disease including hypertension and chronic heart failure, we have sought to characterize the relevance of alpha(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 alpha(2C)-adrenoceptor gene (alpha(2C)-/-). Results: Heterozygous alpha(2C)-receptor deletion (alpha(2C)+/-) resulted in a 43% reduction of adrenal alpha(2C) rnRNA copy number and in a similar decrease in alpha(2)-receptor-mediated inhibition of catecholamine release from isolated adrenal glands in vitro. Urinary excretion of epinephrine was increased by 74 +/- 15% in alpha(2C)+/- and by 142 +/- 23% in alpha(2C)-/- mice as compared with wild-type control mice. Telemetric determination of cardiovascular function revealed significant tachycardia but no hypertension in alpha(2C)-adrenoceptor-deficient mice. alpha(2C)+/- mice were more susceptible to develop cardiac hypertrophy, failure and mortality after left-ventricular pressure overload than alpha(2C)+/+ mice. C onclusion: Adrenal alpha(2)-mediated feedback regulation of epinephrine secretion differs fundamentally from sympathetic feedback control. A single adrenoceptor subtype, alpha(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 alpha(2C)-adrenoceptor dysfunction in humans.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 10