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).
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).
van der Hoorn
José W
JW
TNO BioSciences, Leiden, The Netherlands.
Jukema
J Wouter
JW
Bekkers
Marian E
ME
Princen
Hans M
HM
Corda
Stefano
S
Emeis
Jeff J
JJ
Steendijk
Paul
P
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
D053318:Apolipoprotein E3; D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D009281:Naphthalenes; D011422:Propionates; D017482:Receptors, Thromboxane; D013450:Sulfones; C116926:rofecoxib; C501362:terutroban