© 1999 American Heart Association, Inc.
Integrative Physiology |
Overexpression of the Cardiac ß2-Adrenergic Receptor and Expression of a ß-Adrenergic Receptor Kinase-1 (ßARK1) Inhibitor Both Increase Myocardial Contractility but Have Differential Effects on Susceptibility to Ischemic Injury
From the National Institute of Environmental Health Sciences (H.R.C., E.M.), Research Triangle Park; Department of Pathology (C.S.), Duke University Medical Center, Durham; Departments of Medicine and Biochemistry and the Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham; and Department of Surgery (W.J.K.), Duke University Medical Center, Durham, NC.
Correspondence to Heather R. Cross, Mail Drop D2-03, NIEHS, Alexander Dr, Research Triangle Park, NC 27709. E-mail cross{at}niehs.nih.gov
Abstract—Cardiac ß2-adrenergic receptor (ß2AR) overexpression is a potential contractile therapy for heart failure. Cardiac contractility was elevated in mice overexpressing ß2ARs (TG4s) with no adverse effects under normal conditions. To assess the consequences of ß2AR 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 ß2ARs, unlike ß1ARs, couple to Gi as well as Gs, we pretreated mice with the Gi 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 ßARK1 (TGßARK1) or a ßARK1 inhibitor (TGßARKct). Recoveries of function, ATP, and phosphocreatine were higher in TGßARK1 hearts than in wild-type hearts. Despite basal contractility being elevated in TGßARKct hearts to the same level as that of TG4s, ischemic injury was not increased. In summary, ß2AR overexpression increased ischemic injury, whereas ßARK1 overexpression was protective. Ischemic injury in the ß2AR overexpressors was exacerbated by PTX treatment, implying that it was Gs not Gi activity that enhanced injury. Unlike ß2AR overexpression, basal contractility was increased by ßARK1 inhibitor expression without increasing ischemic injury, thus implicating a safer potential therapy for heart failure.
Key Words: adrenergic signaling • energetics • G proteins • ischemia • NMR spectroscopy
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