Effect of a Novel Inducible Nitric Oxide Synthase Inhibitor, FR260330, in Prevention of Renal Ischemia/Reperfusion Injury in Vervet Monkeys

Abstract

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.

Implantation of a porcine acellular dermal graft in a primate model of rotator cuff repair

“…This model was shown to be capable of providing information regarding host cell response to implanted biologic matrices, which most likely translates to implantation in humans because of the close genomic homology and history of the use of the vervet in immunologic and transplantation studies. 28,29 Additional studies using a larger number of animals would address many of the limitations inherent to a small pilot study such as this study, including the ability to have greater histologic sampling, the use of mechanical tensile testing of the repaired defect to assess healing strength over time, and the addition of an unrepaired tendon defect in the contralateral control shoulder, as well as the ability to run a true comparative study of biologic grafts.…”

“…1 However, an even more valuable data set might be obtained by implantation of acellular dermal matrices in a primate model that is immunologically similar to humans. The African green monkey, or vervet (Cercopithecus aethiops), shares more than 98% genomic homology with humans and has been used to mimic clinical immune response to infectious agents, vaccines, drugs, and transplanted organs, 18,23,28,29 because of its comparable anatomy, metabolism, physiology, and immunology. Similarities to the human immune system include the absence of both cell-associated and non-cell-associated xenogeneic epitopes (including a-gal epitopes), the presence of antibodies to these epitopes in the serum, and the ability to mount a normal foreign-body response.…”

Novel resveratrol analogues attenuate renal ischemic injury in rats

“…Particularly, iNOS has been implicated in the pathogenesis of renal I/R-induced oxidative injury (32, 35, 36, 38). iNOS catalyses the production of nitric oxide which reacts with free oxygen radicals and form peroxynitrite.…”

FK330, a Novel Inducible Nitric Oxide Synthase Inhibitor, Prevents Ischemia and Reperfusion Injury in Rat Liver Transplantation

“…Their results suggest that I/R-induced iNOS exerts cytotoxic, whereas iNOS pre-conditioning results in cytoprotective functions in liver IRI. Although excessive NO synthesized by iNOS has been indicated as an important mediator in the development of IRI, inhibition of iNOS or iNOS deficiency reduced IRI in liver (13), heart (25), kidney (14,21) and intestine (18,26). Hepatic iNOS expression has been observed during early phase of IRI.…”

“…Recently, the effective dose of FK330 to inhibit NO production, and its efficacy to prevent chronic aortic graft rejection in rats (20) and renal IRI in monkeys (21) have been shown. The aim of this study was to evaluate putative cytoprotective effects of FK330 in rat liver models of cold ischemia followed by ex vivo reperfusion or in vivo syngeneic orthotopic liver transplantation (OLT).…”