title: Heterozygous alpha 2C-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction.
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 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) mRNA 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, University of Freiburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gilsbach
authors.forename: Marc
authors.initials: M
authors.lastname: Brede
authors.forename: Nadine
authors.initials: N
authors.lastname: Beetz
authors.forename: Eduardo
authors.initials: E
authors.lastname: Moura
authors.forename: Verena
authors.initials: V
authors.lastname: Muthig
authors.forename: Carolin
authors.initials: C
authors.lastname: Gerstner
authors.forename: Frederico
authors.initials: F
authors.lastname: Barreto
authors.forename: Stefan
authors.initials: S
authors.lastname: Neubauer
authors.forename: Maria Augusta
authors.initials: MA
authors.lastname: Vieira-Coelho
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
mesh_terms: D000313:Adrenal Medulla / Q000378:metabolism*; D000818:Animals; D001011:Aorta; D001794:Blood Pressure; D018450:Disease Progression; D004837:Epinephrine / Q000032:analysis / Q000378:metabolism* / Q000652:urine; D025461:Feedback, Physiological; D005787:Gene Frequency; D005818:Genetic Engineering; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism*; D006339:Heart Rate; D006579:Heterozygote; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011110:Polymorphism, Genetic; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism*; D013686:Telemetry; D046509:Tissue Culture Techniques; D014661:Vasoconstriction
chemical_list: C547774:ADRA2C protein, human; C547775:Adra2c protein, mouse; D018341:Receptors, Adrenergic, alpha-2; D004837:Epinephrine