To investigate the cardioprotective effects and mechanism of action of
KR-32560 {[5-(2-methoxy-5-fluorophenyl)
furan-2-ylcarbonyl]
guanidine}, a newly synthesized NHE-1 inhibitor, we evaluated the effects of
KR-32560 on cardiac function in a rat model of
ischemia/reperfusion (I/R)-induced
heart injury as well as the role
antioxidant enzymes and pro-survival
proteins play these observed effects. In isolated rat hearts subjected to 25 min of global
ischemia followed by 30 min of reperfusion,
KR-32560 (3 and 10 microM) significantly reversed the I/Rinduced decrease in left ventricular developed pressure and increase in left ventricular enddiastolic pressure. In rat hearts reperfused for 30 min,
KR-32560 (10 microM) significantly decreased the
malondialdehyde content while increasing the activities of both
glutathione peroxidase and
catalase, two important
antioxidant enzymes. Western blotting analysis of left ventricles subjected to I/R showed that
KR-32560 significantly increased phosphorylation of both Akt and
GSK-3beta in a dose-dependent manner, with no effect on the phosphorylation of eNOS. These results suggest that
KR-32560 exerts potent cardioprotective effects against I/Rinduced rat
heart injury and that its mechanism involves
antioxidant enzymes and the Akt-GSK-3beta cell survival pathway.