title: Negative effects of rofecoxib treatment on cardiac function after ischemia-reperfusion injury in APOE3Leiden mice are prevented by combined treatment with thromboxane prostanoid-receptor antagonist S18886 (terutroban).
abstract: OBJECTIVE
  Selective cyclooxygenase-2 inhibition by rofecoxib was associated with increased risk of cardiovascular events. We hypothesized that concomitant treatment with thromboxane prostanoid receptor antagonist S18886 might ameliorate possible negative effects. We evaluated the effects of S18886, rofecoxib, and the interaction of both compounds in a combined treatment on myocardial infarct (MI) size and cardiac function after experimental ischemia/reperfusion injury in hyperlipidemic APOE*3Leiden transgenic mice.
  
  
  METHODS
  Prospective, randomized, control trial.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Hyperlipidemic APOE*3Leiden transgenic mice.
  
  
  METHODS
  After four weeks of feeding an atherogenic diet, MI was induced by a 30-min ligation of the left anterior descending coronary artery, followed by reperfusion. Oral compound treatment was initiated 90 mins before MI, and continued daily by gavage for seven days. Four treatment groups (n = 12, each) were studied: solvent (Control), S18886, rofecoxib, and S18886 plus rofecoxib.
  
  
  RESULTS
  One week after MI, the mice were anesthetized and cardiac function was quantified by left ventricular (LV) pressure-volume relationships obtained by miniature pressure-conductance catheters. The ischemic area was measured by morphometry and expressed as percentage of LV area. No significant differences in infarct size were found between groups. Compared with control, treatment with S18886 did not affect heart function whereas the rofecoxib group had significantly lower cardiac output (4.5 +/- 0.8 vs. 3.2 +/- 1.1 mL/min, p < 0.01), lower ejection fraction (40 +/- 8 vs. 27 +/- 11%, p < 0.005), and increased end-systolic volume (18.6 +/- 5.7 vs. 28.6 +/- 9.0 muL, p < 0.05). The group with combined (S18886+rofecoxib) treatment was not different from control. Statistical analysis showed significant interactive effects between S18886 and rofecoxib indicating that negative effects of rofecoxib on cardiac function were prevented by S18886 treatment.
  
  
  CONCLUSIONS
  Rofecoxib treatment reduced global and systolic LV function after ischemia-reperfusion injury in APOE*3Leiden mice. These negative effects are prevented by combined treatment with thromboxane prostanoid-receptor antagonist S18886 (terutroban).
authors.affiliation: TNO BioSciences, Leiden, The Netherlands.
authors.forename: José W
authors.initials: JW
authors.lastname: van der Hoorn
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: Marian E
authors.initials: ME
authors.lastname: Bekkers
authors.forename: Hans M
authors.initials: HM
authors.lastname: Princen
authors.forename: Stefano
authors.initials: S
authors.lastname: Corda
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: Emeis
authors.forename: Paul
authors.initials: P
authors.lastname: Steendijk
mesh_terms: D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics*; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects*; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy; D007150:Immunohistochemistry; D007783:Lactones / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D011422:Propionates / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000009:adverse effects*; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D053318:Apolipoprotein E3; D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D009281:Naphthalenes; D011422:Propionates; D017482:Receptors, Thromboxane; D013450:Sulfones; C116926:rofecoxib; C501362:terutroban