Protein kinase C inhibition abrogates hepatic ischemic preconditioning responses

Introduction. A transient period of warm ischemia prior to a longer ischemi c episode (ischemic preconditioning) protects the hepatic graft from cold i schemia. The mechanism for this protection is unknown, as is the role of pr otein kinase C in ischemic preconditioning responses. Methods. Livers from 40 kg Yorkshire pigs were harvested and subjected to 2 h of cold ischemia (n = 6) (control). Another group of harvested livers wa s pretreated with a 15-min ischemic period followed by 15 min of in situ pe rfusion with (n = 5) or without (n = 5) a protein kinase C inhibitor, chele rythrine. Following cold ischemia, all grafts were reperfused on a perfusio n circuit and the following variables evaluated: (1) hepatic graft function , (2) graft circulatory impairment, (3) hepatocellular damage, and (4) endo thelial cell damage. Protein kinase C levels were also evaluated by Western blot in the cytoplasm of all grafts. Results and discussion. Ischemic preconditioned grafts demonstrate improved graft function, reduced graft circulatory impairment, and reduced endothel ial cell damage as compared to cold ischemia controls. When preconditioned grafts were pretreated with chelerythrine, graft function, graft circulator y impairment, and endothelial cell damage were mo different than cold ische mia controls. Ischemic preconditioned grafts demonstrated decreased levels of protein kinase C prior to cold ischemia. There was no change in protein kinase C levels in cold ischemia controls or chelerythrine-pretreated graft s prior to cold ischemia. These data indicate that modulation of protein ki nase C is essential for ischemic preconditioning responses in the cold pres erved hepatic graft, (C) 2001 Academic Press.