G-protein-coupled receptor kinase activity in human heart failure: effects of beta-adrenoceptor blockade.
OBJECTIVE
In human end-stage heart failure as well as in experimental animal models of heart failure, G-protein-coupled receptor kinase activity (GRK) is increased while beta-adrenoceptor responsiveness is diminished. In animal studies, beta-adrenoceptor blockers reverse the GRK-mediated desensitization and down-regulation of myocardial beta-adrenoceptors. The aim of this study was to investigate whether alterations in GRK activity are an early or late accompaniment of human heart failure and whether also in humans beta-adrenoceptor blocker treatment is able to influence myocardial GRK activity.


METHODS
We assessed in right atria, obtained from patients at different stages of heart failure, treated with or not treated with beta-adrenoceptor blockers, and in the four chambers of explanted hearts, obtained from patients with end-stage heart failure, beta-adrenoceptor density (by (-)-[(125)I]-iodocyanopindolol binding) and GRK activity (by an in vitro rhodopsin phosphorylation assay).


RESULTS
With increasing severity of heart failure, plasma noradrenaline levels increased while myocardial beta-adrenoceptor density decreased with a maximum in GRK activity in end-stage heart failure. However, in relation to the progression of heart failure, we found that GRK activity transiently increased at an early stage of heart failure (NYHA I and II) but decreased back to control values in patients at NYHA III and IV. beta-Adrenoceptor blockers were able to reduce the early increase in GRK activity at NYHA I and II to control levels, whereas in those patients who did not have increased GRK activity (NYHA III and IV), they had only a marginal effect.


CONCLUSIONS
According to our results, an increase in GRK activity is an early and transient event in the course of heart failure that can be prevented by beta-adrenoceptor blocker treatment.
Leineweber
Kirsten
K
Department of Pathophysiology, University of Essen School of Medicine, Germany. kirsten.leineweber@uni-essen.de
Rohe
Patrick
P
Beilfuss
Anja
A
Wolf
Christina
C
Sporkmann
Heike
H
Bruck
Heike
H
Jakob
Heinz-Günther
HG
Heusch
Gerd
G
Philipp
Thomas
T
Brodde
Otto-Erich
OE
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000368:Aged; D020517:Atrial Appendage / Q000737:chemistry / Q000201:enzymology*; D016022:Case-Control Studies; D003327:Coronary Disease / Q000097:blood / Q000201:enzymology; D018450:Disease Progression; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D009206:Myocardium / Q000737:chemistry; D009638:Norepinephrine / Q000097:blood; D011943:Receptors, Adrenergic, beta / Q000032:analysis; D051552:beta-Adrenergic Receptor Kinases / Q000032:analysis* / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; C496567:GRK2 protein, human; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2; D009638:Norepinephrine