L-canavanine improves organ function and tissue adenosine triphosphate levels in rodent endotoxemia.

Abstract

Overproduction of NO by an inducible NO synthase (iNOS) plays a major role in the pathophysiology of septic shock, and selective inhibition of iNOS in this setting could be of great therapeutic value. In the present study, we evaluated the effects of L-canavanine, a selective iNOS inhibitor, in an animal model of septic shock, with a particular focus on tissue oxidative metabolism and organ functions. Anesthetized rats challenged intravenously with lipopolysacharide (LPS) were treated after 1 h by a continuous infusion of either L-canavanine (20 mg/kg/h; n = 11) or an equivalent volume of saline (2 ml/kg/h; n = 17) given for 4 h. A third group (sham rats; n = 9) did not receive LPS and was treated with a continuous infusion of saline (2 ml/kg/h). At the end of experiments, biopsies were taken from the liver, the kidney, and the small intestine for the measurement of tissue ATP. LPS induced a progressive fall in blood pressure, accompanied by biologic signs of liver and kidney failure, concomitant with a marked decrease in tissue ATP stores. L-canavanine largely prevented hypotension and significantly increased tissue ATP while reducing the signs of organ dysfunction. These effects were associated with a significant improvement in survival during the 5 h of study. We conclude that L-canavanine not only reduces hypotension in endotoxin shock but also largely prevents the detrimental consequences of LPS on tissue oxidative metabolism and major organ functions, allowing a decrease in endotoxin lethality.

Renal cortical hexokinase and pentose phosphate pathway activation through the EGFR/Akt signaling pathway in endotoxin-induced acute kidney injury

“…Patil et al (40) recently demonstrated reduced renal electron transport chain complex I and complex II/III activity occurring as early as 6 h after cecal ligation and puncture in mice. Furthermore, a reduction of renal ATP levels has been observed in rodent models of sepsis-induced AKI which correlated well with renal dysfunction (32,40,49). Taken together, these data provide strong evidence that mitochondrial dysfunction plays a central role in the pathophysiology of sepsis-induced AKI.…”

“…Suppression of mitochondrial mRNAs correlated with renal function as measured by blood urea nitrogen (BUN) (62). LPS-induced mitochondrial dysfunction results in a decline (ϳ50%) in renal ATP content within 5 h of exposure in rodents, likely contributing to changes in renal function in this model of septic AKI (32). Disruption of renal mitochondrial function and ATP production has also been reported in the cecal ligation and puncture model (CLP) of sepsis (40).…”

Comparison of Inflammation, Organ Damage, and Oxidant Stress Induced by Salmonella enterica Serovar Muenchen Flagellin and Serovar Enteritidis Lipopolysaccharide

“…A group of five mice not receiving LPS or flagellin was used for control purposes. The dose of LPS administered in this study was selected on the basis of numerous previous works evaluating the effects of LPS in rodents, where doses in the milligram-per-kilogram range were generally administered (9,17,31,33). Accordingly, we used a similar dose of flagellin.…”

Cardiovascular effects of fentanyl in conscious rats

“…The latter is an index of whole-body production of nitric oxide. Nitrate was determined by a spectrophotometric assay based on the oxidation of NADPH during the enzymatic conversion of nitrate to nitrite by a nitrate reducatase, as previously described [24].…”