title: Effect of selective inhibition of renal inducible nitric oxide synthase on renal blood flow and function in experimental hyperdynamic sepsis.
abstract: OBJECTIVE
  Nitric oxide plays an important role in the control of renal blood flow and renal function. In sepsis, increased levels of inducible nitric oxide synthase produce excessive nitric oxide, which may contribute to the development of acute kidney injury. We, therefore, examined the effects of intrarenal infusion of selective inducible nitric oxide synthase inhibitors in a large animal model of hyperdynamic sepsis in which acute kidney injury occurs in the presence of increased renal blood flow.
  
  
  METHODS
  Prospective crossover randomized controlled interventional studies.
  
  
  METHODS
  University-affiliated research institute.
  
  
  METHODS
  Twelve unilaterally nephrectomized Merino ewes.
  
  
  METHODS
  Infusion of a selective (1400W) and a partially selective inducible nitric oxide synthase inhibitor (aminoguanidine) into the renal artery for 2 hrs after the induction of sepsis, and comparison with a nonselective inhibitor (Nω-nitro-L-arginine methyl ester).
  
  
  RESULTS
  In sheep with nonhypotensive hyperdynamic sepsis, creatinine clearance halved (32 to 16 mL/min, ratio [95% confidence interval] 0.51 [0.28-0.92]) despite increased renal blood flow (241 to 343 mL/min, difference [95% confidence interval] 102 [78-126]). Infusion of 1400W did not change renal blood flow, urine output, or creatinine clearance, whereas infusion of Nω-nitro-L-arginine methyl ester and a high dose of aminoguanidine normalized renal blood flow, but did not alter creatinine clearance.
  
  
  CONCLUSIONS
  In hyperdynamic sepsis, intrarenal infusion of a highly selective inducible nitric oxide synthase inhibitor did not reduce the elevated renal blood flow or improve renal function. In contrast, renal blood flow was reduced by infusion of a nonselective NOS inhibitor or a high dose of a partially selective inducible nitric oxide synthase inhibitor. The renal vasodilatation in septic acute kidney injury may be due to nitric oxide derived from the endothelial and neural isoforms of nitric oxide synthase, but their blockade did not restore renal function.
authors.affiliation: Howard Florey Institute, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Paolo
authors.initials: P
authors.lastname: Calzavacca
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Bellomo
authors.forename: Michael
authors.initials: M
authors.lastname: Bailey
authors.forename: Clive N
authors.initials: CN
authors.lastname: May
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006439:Hemodynamics / Q000502:physiology; D007261:Infusions, Intra-Arterial; D007668:Kidney / Q000201:enzymology / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000502:physiology; D012077:Renal Artery / Q000503:physiopathology; D012079:Renal Circulation / Q000187:drug effects* / Q000502:physiology; D018805:Sepsis / Q000150:complications / Q000503:physiopathology*; D012756:Sheep
chemical_list: D006146:Guanidines; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester