November 26, 1999Open Access
View Full PaperOverexpression of the Cardiac β2-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
Structured PICO
Does overexpression of beta(2)AR or betaARK1 inhibitor affect myocardial contractility and susceptibility to ischemic injury in mice?
P
Population
Mice overexpressing beta(2)ARs (TG4s), mice overexpressing betaARK1 (TGbetaARK1), mice overexpressing a betaARK1 inhibitor (TGbetaARKct), and wild-type mice
I
Intervention
Overexpression of beta(2)AR, betaARK1, or betaARK1 inhibitor, with or without pertussis toxin (PTX) pretreatment
C
Comparator
Wild-type mice
O
Outcome
Ischemic injury (postischemic recoveries of contractile function, ATP, and phosphocreatine) after 20-minute ischemia and 40-minute reperfusionsurrogate
Inhibition of betaARK1 increases basal contractility without exacerbating ischemic injury, suggesting a potentially safer therapeutic strategy for heart failure compared to beta(2)AR overexpression.
Abstract
Cardiac beta(2)-adrenergic receptor (beta(2)AR) overexpression is a potential contractile therapy for heart failure. Cardiac contractility was elevated in mice overexpressing beta(2)ARs (TG4s) with no adverse effects under normal conditions. To assess the consequences of beta(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 beta(2)ARs, unlike beta(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 betaARK1 (TGbetaARK1) or a betaARK1 inhibitor (TGbetaARKct). Recoveries of function, ATP, and phosphocreatine were higher in TGbetaARK1 hearts than in wild-type hearts. Despite basal contractility being elevated in TGbetaARKct hearts to the same level as that of TG4s, ischemic injury was not increased. In summary, beta(2)AR overexpression increased ischemic injury, whereas betaARK1 overexpression was protective. Ischemic injury in the beta(2)AR overexpressors was exacerbated by PTX treatment, implying that it was G(s) not G(i) activity that enhanced injury. Unlike beta(2)AR overexpression, basal contractility was increased by betaARK1 inhibitor expression without increasing ischemic injury, thus implicating a safer potential therapy for heart failure.