Aldose reductase inhibition alone or combined with an adenosine A₃agonist reduces ischemic myocardial injury

Abstract

This study investigated whether aldose reductase (AR) inhibition with zopolrestat, either alone or in combination with an adenosine A(3)-receptor agonist (CB-MECA), reduced myocardial ischemic injury in rabbit hearts subjected to 30 min of regional ischemia and 120 min of reperfusion. Zopolrestat reduced infarct size by up to 61%, both in vitro (2 nM to 1 microM; EC(50) = 24 nM) and in vivo (50 mg/kg). Zopolrestat reduced myocardial sorbitol concentration (index of AR activity) by >50% (control, 15.0 +/- 2.2 nmol/g; 200 nM zopolrestat, 6.7 +/- 1.3 nmol/g). A modestly cardioprotective concentration of CB-MECA (0.2 nM) allowed a 50-fold reduction in zopolrestat concentration while providing a similar reduction in infarct size (infarct area/area at risk: control, 62 +/- 2%; 1 microM zopolrestat, 24 +/- 5%; 20 nM zopolrestat plus 0.2 nM CB-MECA, 20 +/- 4%). In conclusion, AR inhibition is cardioprotective both in vitro and in vivo. Furthermore, combining zopolrestat with an A(3) agonist allows a reduction in the zopolrestat concentration while maintaining an equivalent degree of cardioprotection.