SPC-100270, a protein kinase C inhibitor, reduced hypoxic injury due to reperfusion following orthotopic liver transplantation in the rat.
Recently, we reported that SPC-100270, a sphingosine derivative and inhibitor of protein kinase C (50-90 microM) in mixed micelle assays, reduced reperfusion injury resulting from hypoxia in a low-flow, reflow model of liver perfusion. Here we report that SPC-100270 has similar beneficial effects following liver transplantation in vivo. Rat liver transplantation was performed using nonarterial and rearterial techniques. Livers from syngenic rats were harvested surgically, prepared with vascular cuffs and a splint, and stored for 24 or 48 h in University of Wisconsin (UW) cold storage solution. Just prior to completion of vascular reconstruction, the organ was rinsed with 3 or 10 ml of Ringer's solution, vehicle, or a solution containing SPC-100270 (up to 500 microM). Following implantation surgery, low doses of SPC-100270 were ineffective at reducing both parenchymal and nonparenchymal cell death, yet significant (P < 0.05) reductions were observed with 500 microM. Further, nonparechnymal cell viability was improved nearly four fold by the drug. SPC-100270 (500 microM) tended to increase survival following 48 h cold storage in UW solution, but the improvement was not statistically significant. SPC-100270 also did not diminish carbon-centered free radical formation in transplanted livers from alcohol-treated rats. Collectively, these data support the hypothesis that pretreatment of donor livers with an inhibitor of protein kinase C is effective in vivo at reducing reperfusion injury, particularly to nonparenchymal cells, following orthotopic liver transplantation in the rat.
Department of Pharmacology and Curriculum in Toxicology, The University of North Carolina at Chapel Hill, 27599-7365, USA.
R G
RG
Thurman
W
W
Gao
H D
HD
Connor
R P
RP
Mason
J J
JJ
Lemasters
H
H
Bozigian
L M
LM
Adams
D000241:Adenosine; D000493:Allopurinol; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005234:Fatty Liver / Q000503:physiopathology* / Q000601:surgery*; D005260:Female; D005978:Glutathione; D006085:Graft Survival / Q000187:drug effects*; D007328:Insulin; D016031:Liver Transplantation / Q000379:methods / Q000473:pathology / Q000502:physiology*; D019188:Organ Preservation Solutions; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011887:Raffinose; D051381:Rats; D015427:Reperfusion Injury / Q000473:pathology* / Q000517:prevention & control; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014185:Transplantation, Isogeneic
D004791:Enzyme Inhibitors; D007328:Insulin; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D011493:Protein Kinase C; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose; D013110:Sphingosine; C005682:safingol