title: Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injury in rat hearts.
abstract: OBJECTIVE
  Due to reported modulatory effects of statins on nitric oxide synthase (NOS) expression, we tested the hypothesis of protective effects of in vivo chronic treatment with rosuvastatin, a novel 3-hydroxy-3-methyl-glutaryl coenzyme A-reductase inhibitor, on ischemia-reperfusion injury, and investigated mechanisms involved.
  
  
  METHODS
  After 3 weeks of in vivo treatment with rosuvastatin (0.2-20 mg/kg/day) or placebo, excised hearts from Wistar rats were subjected to 15 min global ischemia and 22-180 min reperfusion. We evaluated creatine-phosphokinase and nitrite levels in the coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and the expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) (by reverse-transcription polymerase chain reaction and Western blotting).
  
  
  RESULTS
  Rosuvastatin 0.2 and 2 mg/kg/day significantly reduced myocardial damage and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions. At 2 mg/kg/day, rosuvastatin significantly increased eNOS mRNA and protein compared with untreated hearts, and conversely decreased iNOS mRNA and protein, as well as nitrite production after ischemia-reperfusion. The addition of the NOS inhibitor N(omega)-nitro-L-arginine methylester (L-NAME, 30 micromol/L) significantly reduced cardioprotection against ischemia-reperfusion.
  
  
  CONCLUSIONS
  Chronic treatment with rosuvastatin before ischemia reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte damage by NO-dependent mechanisms.
authors.affiliation: Laboratory of Experimental Cardiology, Department of Clinical Sciences and Bioimaging, and Center of Excellence of Aging, G. d'Annunzio University, Chieti, Italy.
authors.forename: Pericle
authors.initials: P
authors.lastname: Di Napoli
authors.forename: Alfonso Antonio
authors.initials: AA
authors.lastname: Taccardi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Grilli
authors.forename: Maria Anna
authors.initials: MA
authors.lastname: De Lutiis
authors.forename: Antonio
authors.initials: A
authors.lastname: Barsotti
authors.forename: Mario
authors.initials: M
authors.lastname: Felaco
authors.forename: Raffaele
authors.initials: R
authors.lastname: De Caterina
mesh_terms: D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002199:Capillary Permeability; D003402:Creatine Kinase / Q000032:analysis; D004334:Drug Administration Schedule; D005464:Fluorobenzenes / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D009573:Nitrites / Q000032:analysis; D010477:Perfusion; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000627:therapeutic use*
chemical_list: D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009573:Nitrites; D011743:Pyrimidines; D012333:RNA, Messenger; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D019001:Nitric Oxide Synthase; D003402:Creatine Kinase