title: Beneficial microvascular and anti-inflammatory effects of pravastatin during sepsis involve nitric oxide synthase III.
abstract: BACKGROUND
  Sepsis induces microvascular inflammation and production of the vasodilator nitric oxide (NO) via endothelial and inducible nitric oxide synthase (eNOS or NOS III and iNOS or NOS II). Statins are cholesterol-lowering drugs; however, they also attenuate inflammation. This study aimed to determine whether pravastatin protected against sepsis-induced hypotension, loss of vascular tone, and microvascular inflammation via NOS pathways.
  
  
  METHODS
  Male Wistar rats (n=18) were anaesthetized and the mesentery prepared for fluorescent intravital microscopy. Animals received either lipopolysaccharide (LPS; n=6); LPS+pravastatin (18 and 3 h before LPS; n=6), or saline as a control, for 4 h.
  
  
  RESULTS
  Mean arterial pressure decreased in LPS-treated animals (P<0.05), but not in those also receiving pravastatin. Acetylcholine-induced relaxation of venules was abolished by LPS but improved by pravastatin. Pravastatin also reduced the increase in nitrite concentration and macromolecular leak from venules induced by LPS (P<0.05). The increased leucocyte adhesion seen in LPS-treated rats was also reduced in those also treated with pravastatin. Immunohistochemical analysis showed that pravastatin increased endothelial cell expression of NOS III during sepsis, but had no effect on LPS-induced up-regulation of NOS II.
  
  
  CONCLUSIONS
  Pravastatin improved NOS III-mediated vessel relaxation and exerted anti-inflammatory effects within the microcirculation after LPS administration in rats. Pravastatin therefore appears to have beneficial effects during sepsis, as a result of increased microvascular expression and function of NOS III.
authors.affiliation: Microcirculation Research Group, Department of Cardiovascular Sciences, University of Sheffield, Faculty of Medicine, Dentistry and Health, Beech Hill Road, Sheffield S10 2RX, UK.
authors.forename: C C
authors.initials: CC
authors.lastname: McGown
authors.forename: N J
authors.initials: NJ
authors.lastname: Brown
authors.forename: P G
authors.initials: PG
authors.lastname: Hellewell
authors.forename: C S
authors.initials: CS
authors.lastname: Reilly
authors.forename: Z L S
authors.initials: ZL
authors.lastname: Brookes
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D019446:Endotoxemia / Q000150:complications* / Q000503:physiopathology; D007962:Leukocytes / Q000201:enzymology / Q000502:physiology; D008070:Lipopolysaccharides; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000502:physiology*; D017035:Pravastatin / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D014657:Vasculitis / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D052250:Nitric Oxide Synthase Type III; D017035:Pravastatin