Antidiabetic drug pioglitazone protects the heart via activation of PPAR-gamma receptors, PI3-kinase, Akt, and eNOS pathway in a rabbit model of myocardial infarction.

The insulin-sensitizing drug pioglitazone has been reported to be protective against myocardial infarction. However, its precise mechanism is unclear. Rabbits underwent 30 min of coronary occlusion followed by 48 h of reperfusion. Rabbits were assigned randomly to nine groups (n = 10 in each): the control group (fed a normal diet), pioglitazone group (fed diets containing 1 mg.kg(-1).day(-1) pioglitazone), pioglitazone + 5-hydroxydecanoic acid (HD) group [fed the pioglitazone diet + 5 mg/kg iv 5-HD, a mitochondrial ATP-sensitive K(+) (K(ATP)) channel blocker], pioglitazone + GW9662 group [fed the pioglitazone diet + 2 mg/kg iv GW9662, a peroxisome proliferator activated receptor (PPAR)-gamma antagonist], GW9662 group (fed a normal diet + iv GW9662), pioglitazone + wortmannin group [fed the pioglitazone diet + 0.6 mg/kg iv wortmannin, a phosphatidylinositol (PI)3-kinase inhibitor], wortmannin group (fed a normal diet + iv wortmannin), pioglitazone + nitro-l-arginine methyl ester (l-NAME) group [fed the pioglitazone diet + 10 mg/kg iv l-NAME, a nitric oxide synthase (NOS) inhibitor], and l-NAME group (fed a normal diet + iv l-NAME). All groups were fed the diets for 7 days. The risk area and nonrisk area of the left ventricle (LV) were separated by Evans blue dye, and the infarct area was determined by triphenyltetrazolium chloride staining. The infarct size was calculated as a percentage of the LV risk area. Western blotting was performed to assess levels of Akt and phospho-Akt and phospho-endothelial NOS (eNOS) in the myocardium following reperfusion. The infarct size was significantly smaller in the pioglitazone group (21 +/- 2%) than in the control group (43 +/- 3%). This effect was abolished by GW9662 (42 +/- 3%), wortmannin (40 +/- 3%), or l-NAME (42 +/- 7%) but not by 5-HD (24 +/- 5%). Western blotting showed higher levels of phospho-Akt and phospho-eNOS in the pioglitazone group. Pioglitazone reduces the myocardial infarct size via activation of PPAR-gamma, PI3-kinase, Akt, and eNOS pathways, but not via opening the mitochondrial K(ATP) channel. Pioglitazone may be a novel strategy for the treatment of diabetes mellitus with coronary artery disease.

Celiprolol, a selective beta1-blocker, reduces the infarct size through production of nitric oxide in a rabbit model of myocardial infarction.

BACKGROUND: It is still unclear whether celiprolol, a beta(1)-selective blocker, reduces myocardial infarct size. This study will examine whether celiprolol reduces myocardial infarct size, as well as investigate the mechanisms for its infarct size-reducing effect in rabbits. METHODS AND RESULTS: Japanese white rabbits underwent 30 min of ischemia and 48 h of reperfusion. Celiprolol (1 or 10 mg x kg (-1) x h(-1) for 60 min, iv) was administered 20 min before ischemia with or without pretreatment with N(omega)-nitro-L-arginine methylester (L-NAME, 10 mg/kg, iv, a nitric oxide synthase inhibitor) or 5-hydroxydecanoic acid sodium salt (5-HD, 5 mg/kg, iv, a mitochondrial K(ATP) channel blocker). The area at risk as a percentage of the left ventricle was determined by using Evans blue dye, and the infarct size was determined as a percentage of the area at risk by triphenyl tetrazolium chloride staining. Celiprolol 1 and 10 mg x kg(-1) x h(-1) significantly reduced the infarct size in a dose-dependent manner (36.4+/-1.7%, n=7 and 25.4+/-2.9%, n=7, respectively) compared with the control (46.2+/-3.1%, n=8). The infarct size-reducing effect of celiprolol was completely blocked by L-NAME (40.4 +/-2.8%, n=8) but not by 5-HD (27.3+/-1.0%, n=8). Celiprolol 1 mg x kg(-1) x h (-1) increased the myocardial interstitial levels of NOx, an indicator of nitric oxide, and reduced the intensity of dihydro-ethidium staining of myocardium, an indicator of superoxide, during reperfusion after 30 min of ischemia. CONCLUSION: Celiprolol reduces myocardial infarct size and also increases nitric oxide production and reduces superoxide levels but not mitochondrial K(ATP) channels in rabbits.