Beneficial versus detrimental effects of nitric oxide synthase inhibitors in circulatory shock: lessons learned from experimental and clinical studies.
Septic shock is a physiological derangement of the cardiovascular system characterized by pathological vasodilation. Recent studies have established a role for nitric oxide, previously known as endothelium-derived relaxing factor, in the vascular dysfunction of sepsis. This finding suggests that inhibition of nitric oxide synthase (NOS), the enzyme responsible for nitric oxide production, could be a target for therapeutic intervention. Animal studies have provided conflicting results, demonstrating both beneficial and detrimental effects. We provide here an overview of the preclinical studies of NOS inhibitors and an update of the clinical studies. The low toxicity and marked antihypotensive activity of NOS inhibitors in humans highlight some of the drawbacks of certain animal models and provide important insights into the experimental study of septic shock.
Kilbourn
R G
RG
Rush-Presbyterian-St. Luke's Medical Center, Section of Hematology/Oncology, Chicago, Illinois 60612, USA.
Szabó
C
C
Traber
D L
DL
D000818:Animals; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D004285:Dogs; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology / Q000627:therapeutic use; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats; D012377:Rodentia; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester