terutroban and rofecoxib

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.. Prospective, randomized, control trial.. Research laboratory.. Hyperlipidemic APOE*3Leiden transgenic mice.. 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.. 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.. 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).

Topics: Animals; Apolipoprotein E3; Cyclooxygenase 2 Inhibitors; Hyperlipidemias; Immunohistochemistry; Lactones; Male; Mice; Mice, Transgenic; Myocardial Infarction; Myocardial Reperfusion Injury; Naphthalenes; Propionates; Random Allocation; Receptors, Thromboxane; Sulfones; Ventricular Function, Left; Ventricular Pressure

Topics: Animals; Cyclooxygenase 2 Inhibitors; Hemodynamics; Hyperlipidemias; Lactones; Mice; Myocardial Infarction; Myocardial Reperfusion Injury; Naphthalenes; Propionates; Receptors, Thromboxane; Sulfones; Ventricular Function, Left; Ventricular Pressure

Thromboxane (Tx) A2 is a vasoconstrictor and platelet agonist. Aspirin affords cardioprotection through inhibition of TxA2 formation by platelet cyclooxygenase (COX-1). Prostacyclin (PGI2) is a vasodilator that inhibits platelet function. Here we show that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PGI2 receptor (IP) but are depressed in mice genetically deficient in the TxA2 receptor (TP) or treated with a TP antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI2 modulates platelet-vascular interactions in vivo and specifically limits the response to TxA2. This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit PGI2 but not TxA2.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Carotid Artery Injuries; Carotid Artery, Common; Cell Division; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Endothelium, Vascular; Epoprostenol; Humans; Isoenzymes; Lactones; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Muscle, Smooth, Vascular; Naphthalenes; Platelet Activation; Platelet Aggregation; Propionates; Prostaglandin-Endoperoxide Synthases; Receptors, Epoprostenol; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfones; Tetrahydronaphthalenes; Thromboxane A2; Tunica Intima