title: Low arginine/asymmetric dimethylarginine ratio deteriorates systemic hemodynamics and organ blood flow in a rat model.
abstract: OBJECTIVE
  Both arginine and asymmetric dimethylarginine (ADMA) play a crucial role in the arginine-nitric oxide pathway. Low arginine and high ADMA levels can be found in critically ill patients after major surgery. The aim of this study was to evaluate the effects of low arginine plasma concentrations in combination with high ADMA plasma concentrations on hemodynamics and organ blood flow.
  
  
  METHODS
  Randomized, placebo-controlled animal laboratory investigation.
  
  
  METHODS
  Male Wistar rats (n = 21), anesthetized.
  
  
  METHODS
  Rats were randomly assigned to three groups: a control group, an ADMA group, or an arginase (ASE)/ADMA group. In the control group, rats received (at t = 0) an intravenous (IV) infusion of 1.5 mL 0.9% NaCl during a 20-minute period. After 60 minutes (t = 60), rats received an IV bolus of 1.0 mL 0.9% NaCl. In the ADMA group, rats received an IV infusion of 1.5 mL 0.9% NaCl during a 20-minute period and at t = 60 an IV bolus of 1.0 mL ADMA (20 mg/kg). In the ASE/ADMA group, rats received an IV infusion of 1.5 mL ASE (3200 IU) solution during a 20-minute period and at t = 60 an IV bolus of 1.0 mL ADMA (20 mg/kg).
  
  
  RESULTS
  Infusion of ADMA (20 mg/kg) and ASE (3200 IU) resulted in increased plasma ADMA levels and decreased arginine levels. During the whole experiment, systemic hemodynamics (heart rate, mean arterial pressure [MAP], and cardiac output) were measured. In addition, organ blood flow was measured at t = 90 and t = 180 minutes, using fluorescent microspheres. Compared with the control group, MAP and systemic vascular resistance were increased after infusion of ADMA. Infusion of ASE in combination with ADMA significantly deteriorated systemic hemodynamics (MAP, cardiac output, stroke volume, and systemic vascular resistance) and organ blood flow through the kidney and spleen. In addition, an initial decrease in arterial flow, followed by a later major increase, and panlobular apoptosis and necrosis of the liver was observed.
  
  
  CONCLUSIONS
  The current study shows that low arginine plasma levels in combination with high ADMA plasma levels deteriorates systemic hemodynamics and reduces blood flow through the kidney and spleen and liver. These data suggest that a diminished nitric oxide production may be involved in the onset of organ failure.
authors.affiliation: Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands. m.richir@vumc.nl
authors.forename: Milan C
authors.initials: MC
authors.lastname: Richir
authors.forename: Anton A
authors.initials: AA
authors.lastname: van Lambalgen
authors.forename: Tom
authors.initials: T
authors.lastname: Teerlink
authors.forename: Willem
authors.initials: W
authors.lastname: Wisselink
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bloemena
authors.forename: Hubert A
authors.initials: HA
authors.lastname: Prins
authors.forename: Theo P G M
authors.initials: TP
authors.lastname: de Vries
authors.forename: Paul A M
authors.initials: PA
authors.lastname: van Leeuwen
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood*; D006439:Hemodynamics; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow
chemical_list: C018524:N,N-dimethylarginine; D001120:Arginine