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Overexpression of the Cardiac β 2 -Adrenergic Receptor and Expression of a β-Adrenergic Receptor Kinase-1 (βARK1) Inhibitor Both Increase Myocardial Contractility but Have Differential Effects on Susceptibility to Ischemic Injury

1999; Lippincott Williams & Wilkins; Volume: 85; Issue: 11 Linguagem: Inglês

10.1161/01.res.85.11.1077

1524-4571

H. R. Cross, Charles Steenbergen, Robert J. Lefkowitz, Walter J. Koch, Elizabeth Murphy,

Cardiac Arrest and Resuscitation

Abstract —Cardiac β 2 -adrenergic receptor (β 2 AR) overexpression is a potential contractile therapy for heart failure. Cardiac contractility was elevated in mice overexpressing β 2 ARs (TG4s) with no adverse effects under normal conditions. To assess the consequences of β 2 AR overexpression during ischemia, perfused hearts from TG4 and wild-type mice were subjected to 20-minute ischemia and 40-minute reperfusion. During ischemia, ATP and pH fell lower in TG4 hearts than wild type. Ischemic injury was greater in TG4 hearts, as indicated by lower postischemic recoveries of contractile function, ATP, and phosphocreatine. Because β 2 ARs, unlike β 1 ARs, couple to G i as well as G s , we pretreated mice with the G i inhibitor pertussis toxin (PTX). PTX treatment increased basal contractility in TG4 hearts and abolished the contractile resistance to isoproterenol. During ischemia, ATP fell lower in TG4+PTX than in TG4 hearts. Recoveries of contractile function and ATP were lower in TG4+PTX than in TG4 hearts. We also studied mice that overexpressed either βARK1 (TGβARK1) or a βARK1 inhibitor (TGβARKct). Recoveries of function, ATP, and phosphocreatine were higher in TGβARK1 hearts than in wild-type hearts. Despite basal contractility being elevated in TGβARKct hearts to the same level as that of TG4s, ischemic injury was not increased. In summary, β 2 AR overexpression increased ischemic injury, whereas βARK1 overexpression was protective. Ischemic injury in the β 2 AR overexpressors was exacerbated by PTX treatment, implying that it was G s not G i activity that enhanced injury. Unlike β 2 AR overexpression, basal contractility was increased by βARK1 inhibitor expression without increasing ischemic injury, thus implicating a safer potential therapy for heart failure.