Heterozygous alpha 2C-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction.
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.
Gilsbach
Ralf
R
Institute of Experimental and Clinical Pharmacology, University of Freiburg, Germany.
Brede
Marc
M
Beetz
Nadine
N
Moura
Eduardo
E
Muthig
Verena
V
Gerstner
Carolin
C
Barreto
Frederico
F
Neubauer
Stefan
S
Vieira-Coelho
Maria Augusta
MA
Hein
Lutz
L
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
C547774:ADRA2C protein, human; C547775:Adra2c protein, mouse; D018341:Receptors, Adrenergic, alpha-2; D004837:Epinephrine