G-protein-coupled receptor kinase activity in human heart failure: Effects of {beta}-adrenoceptor blockade

doi:10.1016/j.cardiores.2005.01.025

Cardiovascular Research 2005 66(3):512-519; doi:10.1016/j.cardiores.2005.01.025

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G-protein-coupled receptor kinase activity in human heart failure: Effects of β-adrenoceptor blockade

Kirsten Leineweber^a^,*, Patrick Rohe^b, Anja Beilfuß^a, Christina Wolf^a, Heike Sporkmann^a, Heike Bruck^a, Heinz-Günther Jakob^b, Gerd Heusch^a, Thomas Philipp^a and Otto-Erich Brodde^a

^aDepartments of Pathophysiology and Nephrology, University of Essen School of Medicine, Hufelandstr. 55, D-45147 Essen, Germany
^bClinic for Cardio-Thoracic Surgery, University of Essen School of Medicine, Hufelandstr. 55, D-45147 Essen, Germany

^* Corresponding author. Tel.: +49 201 723 4457; fax: +49 201 723 5963. Email address: kirsten.leineweber{at}uni-essen.de

Objectives: In human end-stage heart failure as well as in experimentalanimal models of heart failure, G-protein-coupled receptor kinaseactivity (GRK) is increased while β-adrenoceptor responsivenessis diminished. In animal studies, β-adrenoceptor blockersreverse the GRK-mediated desensitization and down-regulationof myocardial β-adrenoceptors. The aim of this study wasto investigate whether alterations in GRK activity are an earlyor late accompaniment of human heart failure and whether alsoin humans β-adrenoceptor blocker treatment is able to influencemyocardial GRK activity.

Methods: We assessed in right atria, obtained from patientsat different stages of heart failure, treated with or not treatedwith β-adrenoceptor blockers, and in the four chambersof explanted hearts, obtained from patients with end-stage heartfailure, β-adrenoceptor density (by (-)-[¹²⁵I]-iodocyanopindololbinding) and GRK activity (by an in vitro rhodopsin phosphorylationassay).

Results: With increasing severity of heart failure, plasma noradrenalinelevels increased while myocardial β-adrenoceptor densitydecreased with a maximum in GRK activity in end-stage heartfailure. However, in relation to the progression of heart failure,we found that GRK activity transiently increased at an earlystage of heart failure (NYHA I and II) but decreased back tocontrol values in patients at NYHA III and IV. β-Adrenoceptorblockers were able to reduce the early increase in GRK activityat NYHA I and II to control levels, whereas in those patientswho did not have increased GRK activity (NYHA III and IV), theyhad only a marginal effect.

Conclusion: According to our results, an increase in GRK activityis an early and transient event in the course of heart failurethat can be prevented by β-adrenoceptor blocker treatment.

KEYWORDS β-Adrenoceptor; Heart failure; β-Arrestins

Time for primary review 20 days

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