The pathogenesis of acute renal failure (ARF) in sepsis is multifactorial. The role of nitric oxide (NO) in septic ARF has been a source of controversy. We hypothesized that endotoxaemia-induced exacerbation of inducible nitric oxide synthase (iNOS)-related NO release impairs renal oxygenation and contributes to ARF in anaesthetized rats. In the present study, rats received lipopolysaccharide (2.5 mg/kg) for 30 min. Two hours later, fluid resuscitation was started (HES130; 5 mL/kg per h after a 5 mL/kg bolus) supplemented either by the NO donor nitroglycerin (NTG; 0.5 μg/kg per min after a 2 μg/kg bolus), the selective iNOS inhibitor 1400W (3 mg/kg per h after a 3 mg/kg bolus) or both. Systemic haemodynamics and renal microvascular P o2 (μP o2) were recorded continuously. Furthermore, creatinine clearance, plasma NOx (nitrate + nitrite + S-nitrosothiols) levels and the expression of iNOS mRNA were measured. Endotoxaemia reduced renal blood flow, decreased mean arterial pressure, resulted in anuria and was associated with an increase in plasma NOx levels and renal iNOS expression. Renal μP o2 deteriorated gradually during endotoxaemia and there was a significant decrease in renal O2 delivery and consumption. Manipulation of NO levels had no beneficial effect on systemic haemodynamics, renal μP o2 or creatinine clearance over standard fluid resuscitation. The application of 1400W+NTG significantly reduced plasma NO x levels compared with fluid resuscitation and NTG alone. Neither iNOS inhibition, NO donation nor a combination of both showed beneficial effects on systemic haemodynamics, renal oxygenation and renal function compared with fluid resuscitation alone. Our results question the proposed key role of NO in the pathogenesis of septic ARF in rats.

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Clinical and Experimental Pharmacology & Physiology
Erasmus MC: University Medical Center Rotterdam

Johannes, T., Mik, E., Klingel, K., Goedhart, P., Zanke, C., Nohé, B., … Ince, C. (2009). Effects of 1400w and/or nitroglycerin on renal oxygenation and kidney function during endotoxaemia in anaesthetized rats. Clinical and Experimental Pharmacology & Physiology, 36(9), 870–879. doi:10.1111/j.1440-1681.2009.05204.x