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Upregulation of -adrenergic receptors in heart failure due to volume overload

Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre and Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada

Submitted 24 January 2005 ; accepted in final form 23 February 2005

To examine the mechanisms of changes in -adrenergic signal transduction in heart failing due to volume overload, we studied the status of -adrenoceptors (-ARs), G protein-coupled receptor kinase (GRK), and -arrestin in heart failure due to aortocaval shunt (AVS). Heart failure in rats was induced by creating AVS for 16 wk, and -AR binding, GRK activity, as well as their protein content, and mRNA levels were determined in both left and right ventricles. The density and protein content for ₁-ARs, unlike those for ₂-ARs, were increased in the failing hearts. Furthermore, protein contents for GRK isoforms and -arrestin-1 were decreased in membranous fractions and increased in cytosolic fractions from the failing hearts. On the other hand, steady-state mRNA levels for ₁-ARs and GRK2, as well as protein content for G-subunits, did not change in the failing heart. Basal cardiac function was depressed; however, both in vivo and ex vivo positive inotropic responses of the failing hearts to isoproterenol were augmented. Treatment of AVS animals with imidapril (1 mg·kg^–1·day^–1) or losartan (20 mg·kg^–1·day^–1) retarded the progression of heart failure; partially prevented changes in ₁-ARs, GRKs, and -arrestin-1 in the failing myocardium; and attenuated the increase in positive inotropic effect of isoproterenol. These results indicate that upregulation of ₁-ARs is associated with subcellular redistribution of GRKs and -arrestin-1 in the failing heart due to volume overload. Furthermore, attenuation of alterations in -adrenergic system by imidapril or losartan may be due to blockade of the renin-angiotensin system in the AVS model of heart failure.

-adrenoceptors; congestive heart failure; G protein-coupled receptor kinase; renin-angiotensin system blockade

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