Several clinical studies have shown beneficial cardiovascular effects of fibrates in patients with diabetes and insulin resistance. Ligands of peroxisome proliferator-activated receptor alpha (PPAR-) reduce ischemia-reperfusion injury in non-diabetic animals. We hypothesized that activation of PPAR- would exert cardioprotection in type 2 diabetic Goto-Kakizaki (GK) rats, involving mechanisms related to nitric oxide (NO) production via the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. GK rats and age-matched Wistar rats (n7) were given either 1) the PPAR- agonist WY 14643, 2) Dimethylsulphoxide (DMSO), 3) WY and the NO synthase inhibitor N-nitro-L-arginine (L-NNA), 4) L-NNA, 5) WY and the PI3-K inhibitor wortmannin or 6) wortmannin alone i.v. before a 35 min period of coronary artery occlusion followed by 2 h of reperfusion. Infarct size (IS), expression of eNOS, iNOS and Akt as well as nitrite/nitrate (NOx) were determined. The IS was 75±3% and 72±4% of the area at risk in the Wistar and GK DMSO groups, respectively. WY reduced IS to 56±3% in Wistar (P<0.05) and to 46±5% in GK rats (P<0.001). Addition of either L-NNA or wortmannin reversed the cardioprotective effect of WY in both Wistar (IS 70±5% and 65±5%, respectively) and GK rats (IS 66±4% and 64±4%, P<0.05, respectively). The expression of eNOS and eNOS Ser1177 in the ischemic myocardium from both strains was increased after WY. The expression of Akt, Akt Ser473 and Akt Thr308 was also increased in the ischemic myocardium from GK rats following WY. Myocardial NOx levels were reduced in GK rats (P<0.05). The results suggest that PPAR- activation protects the type 2 diabetic rat myocardium against ischemia-reperfusion injury via activation of PI3-K/Akt and NO pathway.