Inhibition of nitric oxide synthase reduces renal ischemia/reperfusion injury.

Abstract

BACKGROUND:

The role of nitric oxide (NO) production because of inducible nitric oxide synthase (iNOS) in the pathogenesis of renal ischemia/reperfusion (I/R) injury is unclear. In this study the roles of both iNOS and NO were characterized in a rat model of renal I/R injury. In addition, the effect of iNOS inhibition on renal function was evaluated.

METHODS:

Sprague-Dawley rats underwent 45 min of left renal ischemia and contralateral nephrectomy followed by various periods of reperfusion and renal function analysis [plasma creatinine, fractional excretion of sodium (FENa), creatinine clearance (CrCl), and measurement of plasma and urine NO levels]. In addition, the effect of treatment with 1400W, a highly selective iNOS inhibitor, was evaluated.

RESULTS:

Renal dysfunction peaked at 48 h after reperfusion and immunohistochemistry studies revealed iNOS expression in the vasculature (3 h) and renal tubules (48 h) after reperfusion. Renal function improved significantly in treated animals compared to controls [creatinine of 1.1 v. 1.9 mg/dl (P < 0.05) and CrCl of 0.54 v. 0.31 ml/min (P < 0.05), respectively]. In addition, FENa was decreased by 50%, plasma NO levels were significantly lower (32.7 v. 45.7 micromol/L, P < 0.01), and deposition of nitrotyosine in the tubules of treated rats was less than in control animals.

CONCLUSIONS:

These data support the hypothesis that iNOS and NO are involved in the pathogenesis of renal I/R injury and suggests that use of iNOS inhibitors may be a valuable therapeutic strategy clinical situations where renal I/R may be prevalent.

• Authors: Lisa A Mark, Ann V Robinson, James A Schulak
• Journal: The Journal of surgical research (J Surg Res) Vol. 129 Issue 2 Pg. 236-41 (Dec 2005) ISSN: 0022-4804 [Print] United States
• PMID: 16140334 (Publication Type: Journal Article)

Chemical References

• Amidines
• Benzylamines
• Endothelins
• Enzyme Inhibitors
• N-(3-(aminomethyl)benzyl)acetamidine
• Nitric Oxide
• 3-nitrotyrosine
• Tyrosine
• Creatinine
• Nitric Oxide Synthase Type II
• Nos2 protein, rat

Topics

• Amidines (pharmacology)
• Animals
• Benzylamines (pharmacology)
• Creatinine (blood)
• Disease Models, Animal
• Endothelins (blood)
• Enzyme Inhibitors (pharmacology)
• Kidney Tubules (blood supply, enzymology)
• Male
• Nitric Oxide (blood)
• Nitric Oxide Synthase Type II (antagonists & inhibitors, metabolism)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (drug therapy, metabolism)
• Tyrosine (analogs & derivatives, metabolism)