Chronic intermittent high altitude (IHA) hypoxia leads to long-lasting adaptation protecting myocardium against all major manifestations of acute ischaemia/reperfusion (I/R) injury. Molecular mechanism of this phenomenon is less understood, and direct evidence is confined to some signalling elements utilized by ischaemic preconditioning (IP) including reactive oxygen species (ROS), protein kinase C and mitochondrial K(ATP) channels [mK(ATP)], whereas the role of pro-survival kinases remains elusive (1). Recent observations suggest that activation of PI3/Akt kinase promotes cardiomyocyte survival through a complex pathway that involves opening of mK(ATP) and generation of ROS. However, less is known about its effect on clinically relevant end-points, such as myocardial infarction. In adult male Wistar rats, we examined the role of PI3/Akt in the infarct-limiting effect of long-term IHA hypoxia simulated in a hypobaric chamber (7000 m, 8 h/day, 25 exposures) compared with short-term protection by IP. Both open-chest artificially ventilated animals (n=8-10 per group) and rats employed for the ex vivo studies (n=10-12 per group), were anaesthetised with sodium pentobarbitone (60 mg/kg b.w.). Data were expressed as means ± S.E.M. One-way ANOVA and Student-Newman-Keuls test were used for analysis of differences between the groups with P<0.05 considered as significant. Adaptation to hypoxia reduced the size of infarction (IS) induced by 20-min LAD coronary artery occlusion and 3-h reperfusion (TTC staining) from 64.9 ± 5.1% of the area at risk (AR) in the normoxic controls to 51.8 ± 4.4% in the IHA group (P<0.05). In the Langendorff-perfused hearts, IP induced by 2 episodes of ischaemia (5 min each) prior to a similar protocol of test I/R decreased IS/AR to 15.2 ± 1.0% as compared with 42.0 ± 5.1% in the controls (P<0.05). Enhanced Akt phosphorylation was observed in the adapted hearts. To explore the role of PI3/Akt in anti-infarct protection, PI3/Akt inhibitor LY294002 was given (0.3 mg/kg, i.v.) 5 min before I/R in the in vivo model. In the isolated hearts, LY (5μM) was administered in the perfusion medium 15 min before I/R or bracketing IP. The size of infarction was not affected by LY in the non-adapted controls in both models. In isolated hearts, LY completely abolished cardioprotective effect of IP and even enhanced the extent of myocardial injury (IS/AR 55.0 ± 4.2%) compared with controls. In the IHA rats, treatment with LY increased the size of infarction to that in the normoxic rats but a tendency to abrogate cardioprotection did not reach a level of significance (IS/AR 59.7± 4.1%). In conclusion, the results suggest that activation of pro-survival PI3/Akt cascade plays a role in the infarct size-limiting mechanism and might represent a potential common protective pathway in the models of both, acute and chronic cardiac adaptation to oxygen deprivation.