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TOXICOLOGY

Effects of the Inducible Nitric-Oxide Synthase Inhibitor L-N⁶-(1-Iminoethyl)-lysine on Microcirculation and Reactive Nitrogen Species Generation in the Kidney following Lipopolysaccharide Administration in Mice

Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

The mortality rate for septic patients with acute renal failure is approximately doubled compared with patients with sepsis alone. Unfortunately, the treatment for sepsis-induced renal failure has advanced little during the last several decades. Because sepsis is often caused by lipopolysaccharide (LPS), a mouse model of LPS challenge was used to study the development of kidney injury. We hypothesized that inducible nitric-oxide synthase (iNOS)-catalyzed nitric oxide production and that generation of reactive nitrogen species (RNS) might play a role in the microcirculatory defect and resulting tubular injury associated with LPS administration. Fluorescent intravital videomicroscopy was used to assess renal peritubular capillary perfusion and document RNS generation by renal tubules in real time. As early as 6 h after LPS administration (10 mg/kg i.p.), RNS generation (rhodamine fluorescence), redox stress [NAD(P)H autofluorescence], and the percentage of capillaries without flow were each significantly increased compared with saline-treated mice (p < 0.05). The generation of RNS was supported by the detection of nitrotyrosine-protein adducts in the kidney using immunohistochemistry. The iNOS inhibitor L-N⁶-(1-iminoethyl)-lysine (L-NIL; 3 mg/kg i.p.) completely blocked the increase in rhodamine fluorescence and NAD(P)H autofluorescence and prevented the capillary defects at 6 h after LPS administration. These results suggest that iNOS-derived RNS is an important contributor to the peritubular capillary perfusion defects and RNS generation that occur during sepsis and emphasize that pharmacological inhibition of iNOS may provide beneficial effects during sepsis by improving renal capillary perfusion and reducing RNS generation in the kidney.

Address correspondence to: Dr. Philip R. Mayeux, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, No. 611, Little Rock, AR 72205. E-mail: prmayeux{at}uams.edu