Aldose reductase inhibition alone or combined with an adenosine A(3) agonist reduces ischemic myocardial injury

This study investigated whether aldose reductase (AR) inhibition with zopol restat, either alone or in combination with an adenosine A(3)-receptor agon ist (CB-MECA), reduced myocardial ischemic injury in rabbit hearts subjecte d to 30 min of regional ischemia and 120 min of reperfusion. Zopolrestat re duced infarct size by up to 61%, both in vitro (2 nM to 1 mu M; EC50 = 24 n M) and in vivo (50 mg/kg). Zopolrestat reduced myocardial sorbitol concentr ation (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 concentrati on while providing a similar reduction in infarct size (infarct area/area a t risk: control, 62 +/- 2%; 1 mM zopolrestat, 24 +/- 5%; 20 nM zopolrestat plus 0.2 nM CB-MECA, 20 +/- 4%). In conclusion, AR inhibition is cardioprot ective both in vitro and in vivo. Furthermore, combining zopolrestat with a n A(3) agonist allows a reduction in the zopolrestat concentration while ma intaining an equivalent degree of cardioprotection.