title: The impact of intrarenal nitric oxide synthase inhibition on renal blood flow and function in mild and severe hyperdynamic sepsis.
abstract: OBJECTIVE
  In experimental hyperdynamic sepsis, renal function deteriorates despite renal vasodilatation and increased renal blood flow. Because nitric oxide is increased in sepsis and participates in renal blood flow control, we investigated the effects of intrarenal Nω-nitro-L-arginine methyl ester, a nonspecific nitric oxide synthase inhibitor, in mild and severe sepsis.
  
  
  METHODS
  Prospective crossover and randomized control interventional studies.
  
  
  METHODS
  University-affiliated research institute.
  
  
  METHODS
  Thirty-two merino ewes.
  
  
  METHODS
  Examination of responses to intrarenal infusion of Nω-nitro-L-arginine methyl ester for 8 hrs in unilaterally nephrectomized normal sheep and in sheep administered Escherichia coli.
  
  
  RESULTS
  : In normal sheep, Nω-nitro-L-arginine methyl ester decreased renal blood flow (301 ± 30 to 228 ± 26 mL/min) and creatinine clearance (40.0 ± 5.8 to 31.1 ± 2.8 mL/min), whereas plasma creatinine increased, but fractional excretion of sodium was unchanged. In sheep with nonhypotensive hyperdynamic sepsis, plasma creatinine increased and there were decreases in creatinine clearance (34.5 ± 4.6 to 20.1 ± 3.7 mL/min) and fractional excretion of sodium despite increased renal blood flow. Infusion of Nω-nitro-L-arginine methyl ester normalized renal blood flow and increased urine output, but creatinine clearance did not improve and plasma creatinine and fractional excretion of sodium increased. In sheep with severe hypotensive sepsis, creatinine clearance decreased further (31.1 ± 5.4 to 16.0 ± 1.7 mL/min) despite increased renal blood flow. Infusion of Nω-nitro-L-arginine methyl ester restored mean arterial pressure and reduced renal blood flow but did not improve plasma creatinine or creatinine clearance.
  
  
  CONCLUSIONS
  In hyperdynamic sepsis, with or without hypotension, creatinine clearance decreased despite increasing renal blood flow. Intrarenal Nω-nitro-L-arginine methyl ester infusion reduced renal blood flow but did not improve creatinine clearance. These data indicate that septic acute kidney injury is not the result of decreased renal blood flow nor is it improved by nonspecific nitric oxide synthase inhibition.
authors.affiliation: Howard Florey Institute, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Bellomo
authors.forename: Clive N
authors.initials: CN
authors.lastname: May
mesh_terms: D000818:Animals; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000098:blood supply / Q000201:enzymology* / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D012079:Renal Circulation / Q000502:physiology*; D018805:Sepsis / Q000201:enzymology* / Q000503:physiopathology; D012756:Sheep; D014563:Urodynamics / Q000187:drug effects / Q000502:physiology
chemical_list: D003404:Creatinine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester