title: Effects of a nitric oxide synthase inhibitor in humans with septic shock.
abstract: OBJECTIVE
  Studies in animals have indicated that increased production of nitric oxide from an inducible isoform of nitric oxide synthase contributes to the pathophysiology of endotoxic and cytokine induced shock. The aim of this study was to determine the role of nitric oxide in septic shock in humans.
  
  
  METHODS
  The study was a randomised, double blind, placebo controlled investigation of the effects of the nitric oxide synthase inhibitor NG monomethyl-L-arginine (L-NMMA) in 12 patients with severe sepsis associated with hypotension. Measurements of haemodynamic, haematological, and biochemical variables were made.
  
  
  RESULTS
  L-NMMA (0.3 and 1 mg.kg-1) produced a dose dependent increase in mean arterial pressure, systemic vascular resistance, pulmonary vascular resistance, central venous pressure, and pulmonary artery occlusion pressure, and a decrease in cardiac output and heart rate. In response to the highest dose of L-NMMA systemic vascular resistance increased from 547(SEM 92) to 889(143) dyne.s.cm-5, mean arterial blood pressure increased from 80.9(2.9) to 100.5(6.1) mm Hg, and cardiac output decreased from 11.2(2.1) to 8.9(1.9) litres.min-1. Continuous infusion of L-NMMA (1 mg.kg-1 x h-1) produced sustained haemodynamic changes. Platelet numbers decreased during the course of the study in both the L-NMMA and the placebo group and did not differ significantly between the groups.
  
  
  CONCLUSIONS
  Low doses of L-NMMA cause a widespread increase in vascular tone and raise blood pressure in patients with septic shock. Overproduction of nitric oxide appears to be an important mechanism in septic shock in patients, and inhibition of nitric oxide synthesis might provide a novel therapeutic approach to this condition. However, L-NMMA produced a fall in cardiac output and it is possible that this would worsen tissue perfusion. Larger studies examining the effects of L-NMMA on mortality and morbidity are now required.
authors.affiliation: St George's Hospital and Medical School, London, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Petros
authors.forename: G
authors.initials: G
authors.lastname: Lamb
authors.forename: A
authors.initials: A
authors.lastname: Leone
authors.forename: S
authors.initials: S
authors.lastname: Moncada
authors.forename: D
authors.initials: D
authors.lastname: Bennett
authors.forename: P
authors.initials: P
authors.lastname: Vallance
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004311:Double-Blind Method; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase; D012772:Shock, Septic / Q000188:drug therapy*; D014655:Vascular Resistance / Q000187:drug effects; D019323:omega-N-Methylarginine
chemical_list: D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases