Feedback inhibition of catecholamine release by two different alpha2-adrenoceptor subtypes prevents progression of heart failure.
BACKGROUND
Elevated plasma norepinephrine levels are associated with increased mortality in patients and in animal models with chronic heart failure. To test which alpha2-adrenoceptor subtypes operate as presynaptic inhibitory receptors to control norepinephrine release in heart failure, we investigated the response of gene-targeted mice lacking alpha2-adrenoceptor subtypes (alpha2-KO) to chronic left ventricular pressure overload. In addition, we determined the functional consequences of genetic variants of alpha2-adrenoceptors in human patients with chronic heart failure.


RESULTS
Cardiac pressure overload was induced by transverse aortic constriction. Three months after aortic banding, survival was dramatically reduced in alpha2A-KO (52%) and alpha2C-KO (47%) mice compared with wild-type and alpha2B-deficient (86%) animals. Excess mortality in alpha2A- and alpha2C-KO strains was attributable to heart failure with enhanced left ventricular hypertrophy and fibrosis and elevated circulating catecholamines. The clinical importance of this finding is emphasized by the fact that heart failure patients with a dysfunctional variant of the alpha2C-adrenoceptor had a worse clinical status and decreased cardiac function as determined by invasive catheterization and by echocardiography.


CONCLUSIONS
Our results indicate an essential function of alpha2A- and alpha2C-adrenoceptors in the prevention of heart failure progression in mice and human patients. Identification of heart failure patients with genetic alpha2-adrenoceptor variants as well as new alpha2-receptor subtype-selective drugs may represent novel therapeutic strategies in chronic heart failure and other diseases with enhanced sympathetic activation.
Brede
Marc
M
Institut für Pharmakologie und Toxikologie, Universität Würzburg, Germany.
Wiesmann
Frank
F
Jahns
Roland
R
Hadamek
Kerstin
K
Arnolt
Carsten
C
Neubauer
Stefan
S
Lohse
Martin J
MJ
Hein
Lutz
L
D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications / Q000503:physiopathology; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology; D002395:Catecholamines / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D025461:Feedback, Physiological / Q000502:physiology; D006333:Heart Failure / Q000209:etiology / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009638:Norepinephrine / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D015996:Survival Rate
C547768:ADRA2A protein, human; C547771:ADRA2B protein, human; C547774:ADRA2C protein, human; C547769:Adra2a protein, mouse; C547772:Adra2b protein, mouse; C547775:Adra2c protein, mouse; D002395:Catecholamines; D018341:Receptors, Adrenergic, alpha-2; D009638:Norepinephrine