Effect of a novel inducible nitric oxide synthase inhibitor, FR260330, in prevention of renal ischemia/reperfusion injury in vervet monkeys.
Cytotoxic nitric oxide (NO) is produced during ischemia/reperfusion (I/R) injury by the expression of inducible NO synthase (iNOS). Therefore, continuous iNOS inhibition might prevent early graft dysfunction. FR260330, a potent and selective inhibitor of iNOS activity, impedes the dimmerization of iNOS monomer. In this study, the effect of FR260330 in the prevention of renal I/R injury was evaluated in the model of one kidney ischemia in Vervet monkeys. A total of 18 male Vervet monkeys were randomly assigned to two equal groups (n=9). Transient (60 min) left renal ischemia was produced by simultaneous contralateral nephrectomy in treated (FR260330 20 mg/kg/day) and placebo control groups. Renal function and other biochemical parameters as well as FR260330 concentrations were studies until day 15 after I/R injury. All monkeys survived after 60 min I/R injury until sacrifice on day 15. Serum creatinine in the untreated controls increased significantly in comparison to the FR260330-treated group on days 2, 3, 4, and 7 (P<0.05). Plasma FR260330 concentration after oral administration showed that C(max) was 3.251+/-2.526 microg/ml, and T(max) was 4 hr. This study thus finds that FR260330, as a selective iNOS inhibitor, effectively prevents renal I/R injury in Vervet monkeys.
Laboratory of Experimental Surgery, Research Center, Centre Hospitalier de l'Université de Montréal, Notre-Dame Hospital, University of Montreal, Montreal, Canada.
Shijie
S
Qi
Dasheng
D
Xu
Anlun
A
Ma
Xiaochun
X
Zhang
Noboru
N
Chida
Yuji
Y
Sudo
Kouichi
K
Tamura
Pierre
P
Daloze
Huifang
H
Chen
D000818:Animals; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply*; D008297:Male; D023421:Models, Animal; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000517:prevention & control*
D004791:Enzyme Inhibitors; C501443:FR260330; D010880:Piperidines; D052247:Nitric Oxide Synthase Type II