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See detailBM-573 inhibits the development of early atherosclerotic lesions in Apo E deficient mice by blocking TP receptors and thromboxane synthase.
Cherdon, Céline ULg; Rolin, Stephanie; Hanson, Julien ULg et al

in Prostaglandins & Other Lipid Mediators (2011)

Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which thromboxane A(2) (TXA(2)) and 8-iso-PGF(2() have recently ... [more ▼]

Atherosclerosis is the principal cause of mortality in industrialized countries. Its development is influenced by several mediators of which thromboxane A(2) (TXA(2)) and 8-iso-PGF(2() have recently received a lot of attention. This study aimed to investigate the effect of a dual thromboxane synthase inhibitor and thromboxane receptor antagonist (BM-573) and ASA on lesion formation in apolipoprotein E-deficient mice. The combination of ASA and BM-573 was also studied. Plasma measurements demonstrated that the treatments did not affect body weight or plasma cholesterol levels. BM-573, but not ASA, significantly decreased atherogenic lesions as demonstrated by macroscopic analysis. Both treatments alone inhibited TXB(2) synthesis but only BM-573 and the combination therapy were able to decrease firstly, plasma levels of soluble intracellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) and secondly, the expression of these proteins in the aortic root of Apo E. These results were confirmed in endothelial cell cultures derived from human saphenous vein endothelial cells (HSVECs). In these cells, BM-573 also prevented the increased mRNA expression of ICAM-1 and VCAM-1 induced by U-46619 and 8-iso-PGF(2(). Our results show that a molecule combining receptor antagonism and thromboxane synthase inhibition is more efficient in delaying atherosclerosis in Apo E(-/-) mice than sole inhibition of TXA(2) formation. [less ▲]

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See detailBM-520, an original TXA(2) modulator, inhibits the action of thromboxane A(2) and 8-iso-prostaglandin F-2 alpha in vitro and in vivo on human and rodent platelets, and aortic vascular smooth muscles from rodents
Rolin, S.; Hanson, Julien ULg; Vastersaegher, C. et al

in Prostaglandins & Other Lipid Mediators (2007), 84(1-2), 14-23

Thromboxane A(2) (TXA(2)) and 8-iso-PGF(2 alpha). are two prostanoid agonists of the thromboxane A(2) receptor (TP), whose activation has been involved in platelet aggregation and atherosclerosis. Agents ... [more ▼]

Thromboxane A(2) (TXA(2)) and 8-iso-PGF(2 alpha). are two prostanoid agonists of the thromboxane A(2) receptor (TP), whose activation has been involved in platelet aggregation and atherosclerosis. Agents able to counteract the actions of these agonists are of great interest in the treatment and prevention of cardiovascular events. Here, we investigated in vitro and in vivo the pharmacological profile of BM-520, a new TP antagonist. In our experiments, this compound showed a great binding affinity for human washed platelets TP receptors, and prevented human platelet activation and aggregation induced by U-46619, arachidonic acid and 8-iso-PGF(2 alpha). The TP receptor antagonist property of BM-520 was confirmed by its relaxing effect on rat aorta smooth muscle preparations precontracted with U-46619 and 8-iso-PGF(2 alpha). Further, its TP antagonism was also demonstrated in vivo in guinea pig after a single intravenous injection (10 mg kg(-1)). We conclude that this novel TP antagonist could be a promising therapeutic tool in pathologies such as atherosclerosis where an increased production of TXA(2) and 8-iso-PGF2., as well as TP activation are well-established pathogenic events. (c) 2007 Elsevier Inc. All rights reserved. [less ▲]

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See detailEvaluation of BM-573, a novel TXA(2) synthase inhibitor and receptor antagonist, in a porcine model of myocardial ischemia-reperfusion
Kolh, Philippe ULg; Rolin, S.; Tchana-Sato, Vincent ULg et al

in Prostaglandins & Other Lipid Mediators (2006), 79(1-2), 53-73

Aims: To investigate whether BM-573 (N-tert-butyl-N'-[2-(4'-methylphenylam\ino)-5-nitro-benzenesulfonyl]urea), an original combined thromboxane A(2) synthase inhibitor and receptor antagonist, prevents ... [more ▼]

Aims: To investigate whether BM-573 (N-tert-butyl-N'-[2-(4'-methylphenylam\ino)-5-nitro-benzenesulfonyl]urea), an original combined thromboxane A(2) synthase inhibitor and receptor antagonist, prevents reperfusion injury in acutely ischemic pigs. Methods: Twelve animals were randomly divided in two groups: a control group (n = 6) intravenously infused with vehicle, and a BM-573-treated group (n = 6) infused with BM-573 (10 mg kg(-1) h(-1)). In both groups, the left anterior descending (LAD) coronary artery was Occluded for 60 min and reperfused for 240 min. Either vehicle or BM-573 was infused 30 min before LAD occlusion and throughout the experiment. Platelet aggregation induced by arachidonic acid ex vivo measured was prevented by BM-573. Results: In both groups, LAD occlusion decreased cardiac output, ejection fraction, slope of stroke work-end-diastolic volume relationship, and induced end-systolic pressure-volume relationship (ESPVR) rightward shift, while left ventricular afterload increased. Ventriculo-arterial coupling and mechanical efficiency decreased. In both groups, reperfusion further decreased cardiac output and ejection fraction, while ESPVR displayed a further rightward shift. Ventriculo-arterial coupling and mechanical efficiency remained impaired. Area at risk, evidenced with Evans blue, was 33.2 +/- 3.4% of the LV mass (LVM) in both groups, and mean infarct size, revealed by triphenyltetrazolium chloride (TTC), was 27.3 +/- 2.6% of the LVM in the BM-573-treated group (NS). Histological examination and immunohistochemical identification of desmin revealed necrosis in the anteroseptal region similar in both groups, while myocardial ATP dosages and electron microscopy also showed that BM-573 had no cardioprotective effect. Conclusions: These data suggest that BM-573 failed to prevent reperfusion injury in acutely ischemic pigs. (C) 2005 Elsevier Inc. All rights reserved. [less ▲]

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See detailEffects of BM-573, a thromboxane A(2) modulator on systemic hemodynamics perturbations induced by U-46619 in the pig
Tchana-Sato, Vincent ULg; Dogné, Jean-Michel ULg; Lambermont, Bernard ULg et al

in Prostaglandins & Other Lipid Mediators (2005), 78(1-4), 82-95

The aim of our study was to evaluate the effects of thromboxane A(2) (TXA(2)) agonist, U-46619, on systemic circulatory parameters in the pigs before and after administration of a novel TXA(2) receptor ... [more ▼]

The aim of our study was to evaluate the effects of thromboxane A(2) (TXA(2)) agonist, U-46619, on systemic circulatory parameters in the pigs before and after administration of a novel TXA(2) receptor antagonist and synthase inhibitor (BM-573). Twelve anesthetized pigs were randomly assigned in two groups: in Ago group (n=6), the animals received six consecutive injections of U-46619 at 30 min interval, while in Anta group (n = 6) they received an increasing dosage regimen of BM-573 10 min before each U-46619 injection. The effects of each dose of BM-573 on ex vivo platelet aggregation induced by arachidonic acid, collagen or ADP were also evaluated. Vascular properties such as characteristic impedance, peripheral resistance, compliance, arterial elastance were estimated using a windkessel model. Intravenous injections of 0.500 mg/ml of BM-573 and higher doses resulted in a complete inhibition of platelet aggregation induced by arachidonic acid. In the same conditions, BM-573 completely blocked the increase of arterial elastance, and stabilized both mean aortic blood pressure and mean systemic blood flow. In conclusion, BM-573 could therefore be a promising therapeutic approach in pathophysiological states where TXA(2) plays it main role in the increase of vascular resistance like in pathologies such as systemic hypertension. (c) 2005 Published by Elsevier Inc. [less ▲]

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