NITRIC-OXIDE SYNTHASE ACTIVITY IN RENAL ISCHEMIA-REPERFUSION INJURY IN THE RAT - IMPLICATIONS FOR RENAL-TRANSPLANTATION

Cadaveric kidney transplants with delayed graft function have poorer g raft survival by an unknown mechanism, Nitric oxide, produced by nitri c oxide synthase (NOS), has a proven role in both recovery of ischemia and promotion of rejection, We therefore wished to study the patterns of NOS activity in a model of renal ischemia, The left renal pedicle of Fisher rats was occluded for 1 hr. Both kidneys were removed at var ious times and frozen, Renal NOS activity was measured by conversion o f [H-3]arginine to [H-3]citrulline and the content of endothelial NOS isoenzyme (eNOS) was compared by Western blot, NOS activity increased significantly in the left ischemic kidney over the first 24 hr, from a control of 33.8 pmol/min/mg to 79.8 at 2 hr and 56.8 at 24 hr. NOS ac tivity then dropped below baseline, returning to near normal levels at day 21. eNOS content was stimulated over the entire time course, cons istent with the presence of an eNOS inhibitor. Oral treatment with the NOS substrate L-arginine at 5 g/L significantly hastened the return o f serum creatinine to baseline, if simultaneous contralateral nephrect omy was performed, The lazaroid U74389G given perioperatively also imp roved renal function and hastened recovery of NOS activity, Because ni tric oxide plays an important role in maintaining blood mow during rec overy from renal ischemia, the observed decrease in NOS activity may b e prevented by perioperative treatment with oral L-arginine and cortic osteroids. In addition, U74389G may provide a clinically useful method of minimizing and/or shortening DGF, thereby improving graft function and survival.