BACKGROUND/AIMS:Portal hypertensive (PHT) gastric mucosa has increased susceptibility to ischemic damage; however, the molecular basis for this remains unknown. Ischemic preconditioning (IPC) protects gastric mucosa and other tissues against ischemia/reperfusion (I/R) injury but the signaling pathway(s) crucial for this remain(s) unclear. Since hemorrhagic shock is a frequent complication of portal hypertension requiring reperfusion, this study was aimed to determine whether:1) IPC protection against I/R injury is altered in PHT gastric mucosa;2) IPC requires PI 3-kinase/Akt and/or Erk activation.METHODS:PHT was produced in rats by staged portal vein occlusion and splenic vein ligation. Sham operated rats served as normotensive (NT) controls. At 14 days after PHT induction, rats were pretreated i.p. with vehicle, wortmannin (PI 3-kinase inhibitor) or PD98059 (Erk kinase inhibitor). IPC was achieved by pulse-clamping the celiac artery (5 min. twice) prior to I/R for 30 min and 1 hr, respectively. STUDIES:1) Extent of macroscopic injury; 2) PI 3-Kinase activity;3) Akt and Erk phosphorylation levels;4) HIF-1a, VEGF and COX-2 expression levels. RESULTS:I/R alone caused gastric damage in both NT and PHT rats with damage being more severe in PHT vs. NT gastric mucosa (70 ± 24% vs. 25 ± 12% total gastric mucosal area; P<0.01). IPC significantly reduced I/R injury to NT gastric mucosa by 80% (P<0.005) but failed to reduce I/R injury to PHT gastric mucosa (P=0.8). In NT gastric mucosa, IPC was accompanied by significant increases in PI 3-kinase activity (P<0.05) and Akt phosphorylation (P<0.05) whereas Erk phosphorylation was not affected. In PHT gastric mucosa, IPC failed to increase PI 3-Kinase activity and Akt phosphorylation. In NT gastric mucosa, the protective effect of IPC was abolished by pretreatment with the PI 3-kinase inhibitor. In NT gastric mucosa, IPC resulted in significant increases in HIF-1a, VEGF and COX-2 whereas in PHT gastric mucosa it did not.CONCLUSIONS:1) In normal gastric mucosa, IPC protects against I/R injury via activation of PI 3-kinase/Akt;2) In PHT gastric mucosa, protection afforded by IPC against I/R injury is completely abolished as a result of impaired PI 3-kinase/Akt activation; 3) Impaired PI 3-kinase/Akt signaling may explain, in part, the increased susceptibility of PHT gastric mucosa to ischemic injury.