title: Aspirin before reperfusion blunts the infarct size limiting effect of atorvastatin.
abstract: We assessed whether aspirin (acetylsalicylic acid, ASA), administered before reperfusion, abrogates the infarct size (IS)-limiting effect of atorvastatin (ATV). Statins reduce IS. This dose-dependent effect is mediated by upregulation of cycloxygenase-2 (COX2) and PGI(2) production. Administration of selective COX2-inhibitors either with ATV for 3 days or immediately before coronary occlusion blocks the IS-limiting effect of ATV. Sprague-Dawley rats received 3-day ATV (10 mg x kg(-1) x day(-1)) or water alone. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion (IS protocol, n=8 in each group), or rats underwent 30 min coronary artery occlusion and 10 min reperfusion (enzyme expression and activity protocol, n=4 in each group). Immediately before reperfusion rats received intravenous ASA (5, 10, or 20 mg/kg) or saline. Area-at-risk (AR) was assessed by blue dye and IS by triphenyltetrazolium chloride. ATV reduced IS (10.1 +/- 1.4% of the AR) compared with controls (31.0 +/- 2.2%). Intravenous ASA alone did not affect IS (29.0 +/- 2.6%); however, ASA dose dependently (5, 10, and 20 mg/kg) attenuated the protective effect of ATV on IS (15.8 +/- 0.9%, 22.0 +/- 1.6%, and 23.7 +/- 3.8%, respectively). ASA dose dependently blocked the upregulation of COX2 by ATV. COX2 activity was as follows: control, 8.93 +/- 0.90 pg/mg; ATV, 75.85 +/- 1.08 pg/mg; ATV + ASA5, 34.39 +/- 1.48 pg/mg; ATV + ASA10, 19.87 +/- 1.10 pg/mg; and ATV + ASA20, 9.36 +/- 0.94 pg/mg. ASA, administered before reperfusion in doses comparable to those used in the clinical setting, abrogates the IS-limiting effect of ATV in a model with mechanical occlusion of the coronary artery. This potential adverse interaction should be further investigated in the clinical setting of acute coronary syndromes.
authors.affiliation: Division of Cardiology, University of Texas Medical Branch, 5,106 John Sealy Annex, 301 Univ. Blvd., Galveston, Texas 77555-0553, USA. yobirnba@utmb.edu
authors.forename: Yochai
authors.initials: Y
authors.lastname: Birnbaum
authors.forename: Yu
authors.initials: Y
authors.lastname: Lin
authors.forename: Yumei
authors.initials: Y
authors.lastname: Ye
authors.forename: Juan D
authors.initials: JD
authors.lastname: Martinez
authors.forename: Ming-He
authors.initials: MH
authors.lastname: Huang
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Lui
authors.forename: Jose R
authors.initials: JR
authors.lastname: Perez-Polo
authors.forename: Barry F
authors.initials: BF
authors.lastname: Uretsky
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001241:Aspirin / Q000008:administration & dosage* / Q000627:therapeutic use; D000069059:Atorvastatin; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D006538:Heptanoic Acids / Q000008:administration & dosage* / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D011758:Pyrroles / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016861:Cyclooxygenase Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D011758:Pyrroles; D015121:6-Ketoprostaglandin F1 alpha; D000069059:Atorvastatin; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D001241:Aspirin