Stevia rebaudiana bertoni, an herbaceous plant widely distributed and used in Paraguay and Brazil for its sweetener character, has several medicinal properties including antitumor, antihypertensive and anti-inflammatory actions. The aim of the present study was to investigate the cardioprotection exerted by oral stevioside (E, 168 mg/kg for 15 days), a major component of stevia, and its relationship with the activation of protein kinase B (PKB/Akt) in Langendorff perfused rat hearts subjected to ischemia (I)-reperfusion (RP). Hearts from female Wistar rats (200-250g) fed ad libitum were used. Wortmannin (W, 100nM), PI3K/Akt inhibitor was added 15 min before I. The contractility was evaluated by determining the left ventricular developed pressure (LVDP), rate-pressure product (RPP) was determined by multiplying heart rate (HR) by LVDP, peak rate of contraction and peak rate of relaxation (±dP/dt), and the left ventricular end-diastolic pressure was measured (LVEDP). The creatine kinase (CK) release was determined in the coronary effluent during the first 10 min of RP and the myocardial infarct size (MIS) was determined by staining with triphenyltetrazolium chloride (TTC) dissolved in phosphate buffer. Mitochondrial ultrastructure was analyzed by electron microscopy. ANOVA, n=8/group. E improved postischemic recovery and W annuled the cardioprotective actions mediated by E (at 30 min RP RPP (%): C

55.5±8.8, C+W 52.0±5.1, E 87.2±14.8*, E+W 57.0±14.8; *p<0.05 vs C, W, E+W). These results were accompanied with similar changes in ±dP/dt. LVEDP developed lower values in the E group (LVEDP (%) at 10 min of RP: C 15.5±2.0, C+W 29.0±2.2, E 2.2±0.9*, E+W 24.0±3.6; *p<0.05). E decreased CK release and infarct size (CK (UI/g wet weight) C 40.6±3.5, C+W 47.0±4.7, E 24.8±3.2*, E+W 33.0±3.8; MIS (%) C 62.1±1.5, C+W 68.2±2.1, E 41.6±3.5*; E+W 58,2±2.1; *p<0.05 vs C, W, E+W). Moreover, electron micrographs showed better mitochondrial conservation in the group

treated with E and Akt inhibition with W was accompanied by a deterioration of mitochondrial morphology. These results suggest that oral administration of E presents cardioprotective effects that could be partly mediated by Akt activation.