title: Atorvastatin reduces endotoxin-induced microvascular inflammation via NOSII.
abstract: In a lipopolysaccharide (LPS)-induced rat model of sepsis (endotoxaemia), we previously demonstrated that pravastatin reduced microvascular inflammation via increased endothelial nitric oxide synthase III (NOSIII). This study aimed to determine whether atorvastatin, the most commonly used statin for lowering cholesterol, exerted beneficial pleiotropic effects via a similar mechanism. The mesenteric microcirculation of anaesthetised male Wistar rats (308 ± 63 g, n = 54) was prepared for fluorescent intravital microscopy. Over 4 h, animals received intravenous (i.v.) administration of either saline, LPS (150 μg kg(-1) h(-1)) or LPS + atorvastatin (200 μg kg(-1) s.c., 18 and 3 h before LPS), with/without the non-specific NOS inhibitor L-NG-Nitroarginine Methyl Ester (L-NAME) (10 μg kg(-1) h(-1)) or NOSII-specific inhibitor 1400 W (20 μg kg(-1) min(-1)). LPS decreased mean arterial blood pressure (MAP) (4 h, control 113 ± 20 mmHg; LPS 70 ± 23 mmHg), being reversed by atorvastatin (105 ± 3 mmHg) (p < 0.05). LPS also increased macromolecular leak measured after 100 mg kg(-1) of i.v FITC-BSA (arbitrary grey level adjacent to venules), which again was attenuated by atorvastatin (control 1.9 ± 4.0; LPS 12.0 ± 2.4; LPS + atorvastatin 4.5 ± 2.2) (p < 0.05). Furthermore, immunohistochemistry identified that atorvastatin decreased LPS-induced upregulation of endothelial cell NOSII expression, but NOSIII was unchanged in all groups. Atorvastatin improved MAP and reduced microvascular inflammation during endotoxaemia, associated with a reduction of pro-inflammatory NOSII. This differs from previous studies, whereby pravastatin increased expression of NOSIII. Thus preoperative statins have beneficial anti-inflammatory effects during endotoxaemia, but careful consideration must be given to the specific statin being used.
authors: Microcirculation Research Group, Faculty of Medicine, Dentistry and Health, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK, caroline_mcgown@hotmail.com.
authors: Caroline C
authors: CC
authors: McGown
authors: Zoë L S
authors: ZL
authors: Brookes
authors: Paul G
authors: PG
authors: Hellewell
authors: Jonathan J
authors: JJ
authors: Ross
authors: Nicola J
authors: NJ
authors: Brown
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000069059:Atorvastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D019446:Endotoxemia / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D015870:Gene Expression / Q000187:drug effects; D000069416:Intravital Microscopy; D007962:Leukocytes / Q000201:enzymology / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D055806:Microvessels / Q000187:drug effects* / Q000201:enzymology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D017208:Rats, Wistar; D014657:Vasculitis / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D000069059:Atorvastatin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat