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

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Abstract
Objectives: 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 β-adrenoceptor responsiveness is diminished. In animal studies, β-adrenoceptor blockers reverse the GRK-mediated desensitization and down-regulation of myocardial β-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 β-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 β-adrenoceptor blockers, and in the four chambers of explanted hearts, obtained from patients with end-stage heart failure, β-adrenoceptor density (by (-)-[125I]-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 β-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. β-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. Conclusion: 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 β-adrenoceptor blocker treatment.

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