title: Nitric oxide-donating atorvastatin attenuates neutrophil recruitment during vascular inflammation independent of changes in plasma cholesterol.
abstract: OBJECTIVE
  Polymorphonuclear neutrophils, the first leukocytes to infiltrate the inflamed tissue, can make important contributions to vascular inflammatory processes driving the development of atherosclerosis. We herein investigated the effects of atorvastatin and NCX 6560 (a nitric oxide (NO)-donating atorvastatin derivative that has completed a successful phase 1b study) on neutrophilic inflammation in carotid arteries of normocholesterolemic rabbits subjected to perivascular collar placement.
  
  
  METHODS
  Atorvastatin or NCX 6560 were administered orally (5 mg/kg/day or equimolar dose) to New Zealand White rabbits for 6 days, followed by collar implantation 1 h after the last dose. Twenty-four hours later carotids were harvested for neutrophil quantification by immunostaining.
  
  
  RESULTS
  Treatment with NCX 6560 was associated with a lower neutrophil infiltration (-39.5 %), while atorvastatin did not affect neutrophil content. The result was independent of effects on plasma cholesterol or differences in atorvastatin bioavailability, which suggests an important role of NO-related mechanisms in mediating this effect. Consistent with these in vivo findings, in vitro studies showed that NCX 6560, as compared to atorvastatin, had greater inhibitory activity on processes involved in neutrophil recruitment, such as migration in response to IL-8 and IL-8 release by endothelial cells and by neutrophils themselves. Pretreatment with NCX 6560, but not with atorvastatin, reduced the ability of neutrophil supernatants to promote monocyte chemotaxis, a well-known pro-inflammatory activity of neutrophils.
  
  
  CONCLUSIONS
  Experimental data suggest a potential role of NO-releasing statins in the control of the vascular inflammatory process mediated by polymorphonuclear neutrophils.
authors: Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. roberta.baetta@unimi.it
authors: Roberta
authors: R
authors: Baetta
authors: Agnese
authors: A
authors: Granata
authors: Daniela
authors: D
authors: Miglietta
authors: Francesca
authors: F
authors: Oliva
authors: Lorenzo
authors: L
authors: Arnaboldi
authors: Alessandra
authors: A
authors: Bonomo
authors: Nicola
authors: N
authors: Ferri
authors: Ennio
authors: E
authors: Ongini
authors: Stefano
authors: S
authors: Bellosta
authors: Alberto
authors: A
authors: Corsini
mesh_terms: D000208:Acute Disease; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000069059:Atorvastatin; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D002784:Cholesterol / Q000097:blood*; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology; D008297:Male; D015394:Molecular Structure; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000276:immunology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits
chemical_list: D006538:Heptanoic Acids; D016209:Interleukin-8; C524539:NCX 6560; D020030:Nitric Oxide Donors; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin