Effects of 1400W and/or nitroglycerin on renal oxygenation and kidney function during endotoxaemia in anaesthetized rats.
1. 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. 2. 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 1400 W (3 mg/kg per h after a 3 mg/kg bolus) or both. Systemic haemodynamics and renal microvascular Po2 (µPo(2)) were recorded continuously. Furthermore, creatinine clearance, plasma NO(x) (nitrate + nitrite + S-nitrosothiols) levels and the expression of iNOS mRNA were measured. 3. Endotoxaemia reduced renal blood flow, decreased mean arterial pressure, resulted in anuria and was associated with an increase in plasma NO(x) levels and renal iNOS expression. Renal µPo2 deteriorated gradually during endotoxaemia and there was a significant decrease in renal O(2) delivery and consumption. Manipulation of NO levels had no beneficial effect on systemic haemodynamics, renal µPo(2) or creatinine clearance over standard fluid resuscitation. The application of 1400 W+NTG significantly reduced plasma NO(x) levels compared with fluid resuscitation and NTG alone. 4. 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.
Johannes
Tanja
T
Department of Translational Physiology, AMC, University of Amsterdam, The Netherlands. Tanja.Johannes@uni-tuebingen.de
Mik
Egbert G
EG
Klingel
Karin
K
Goedhart
Peter T
PT
Zanke
Christof
C
Nohé
Boris
B
Dieterich
Hans-Jürgen
HJ
Unertl
Klaus E
KE
Ince
Can
C
D058186:Acute Kidney Injury / Q000097:blood / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000578:Amidines / Q000494:pharmacology*; D000768:Anesthesia, General; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005440:Fluid Therapy; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008070:Lipopolysaccharides; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D013997:Time Factors
D000578:Amidines; D001596:Benzylamines; D015415:Biomarkers; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D009569:Nitric Oxide; D003404:Creatinine; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D005996:Nitroglycerin