Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, increases survival in stroke-prone rats by preventing systemic inflammation and endothelial dysfunction: comparison with aspirin and rosuvastatin.

Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, Milan, Italy.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.89). 03/2010; 334(1):199-205. DOI: 10.1124/jpet.110.165787
Source: PubMed

ABSTRACT This study investigated the efficacy of terutroban, a specific thromboxane/prostaglandin endoperoxide receptor antagonist, on stroke incidence in spontaneously hypertensive stroke-prone rats (SHRSP). The effects of terutroban were compared with those of aspirin, another antiplatelet agent, and rosuvastatin, known to exert end-organ protection in SHRSP. Salt-loaded male SHRSP were treated orally once a day with vehicle, terutroban (30 mg/kg/day), aspirin (60 mg/kg/day), or rosuvastatin (10 mg/kg/day). Compared with vehicle, and regardless of any effect on blood pressure or serum thromboxane B(2) levels, terutroban significantly increased survival (p < 0.001) as a consequence of a delayed brain lesion occurrence monitored by magnetic resonance imaging (p < 0.001), and a delayed increase of proteinuria (p < 0.001). Terutroban decreased cerebral mRNA transcription of interleukin-1beta, transforming growth factor-beta, and monocyte chemoattractant protein-1 after 6 weeks of dietary treatment. Terutroban also prevented the accumulation of urinary acute-phase proteins at high molecular weight, identified as markers of systemic inflammation, and assessed longitudinally by one-dimensional electrophoresis. Terutroban also has protective effects on the vasculature as suggested by the preservation of endothelial function and endothelial nitric-oxide synthase expression in isolated carotid arteries. These effects are similar to those obtained with rosuvastatin, and superior to those of aspirin. Terutroban increases survival in SHRSP by reducing systemic inflammation as well as preserving endothelial function. These data support clinical development of terutroban in the prevention of cerebrovascular and cardiovascular complications of atherothrombosis.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Un intermédiaire clé chiral de configuration (R) correspondant à la forme biologiquement active du térutroban a été préparé par hydrogénation asymétrique. Les catalyseurs sont formés à partir de complexes du ruthénium aisément accessibles modifiés par des ligands phosphorés chiraux. L’utilisation des ligands chiraux de la famille des catASium®T permet de réaliser cette transformation très efficacement en termes d’activité et d’énantiosélectivité (ee jusqu’à 92 %), avec de hauts rapports substrat/catalyseur.
    Comptes Rendus Chimie 07/2014; 17(7-8). DOI:10.1016/j.crci.2013.11.013 · 1.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Activation of thromboxane prostanoid (TP) receptor on platelets, monocytes/macrophages, endothelial cells (EC) and vascular smooth muscle cells (SMC) plays important roles in regulating platelet activation and vascular tone, and in the pathogenesis of thrombosis and vascular inflammation. Oxidative stress and vascular inflammation increase the formation of TP receptor agonists, which promote initiation and progression of atherogenesis and thrombosis. Furthermore, TP receptor activation promotes angiogenesis and vessel wall constriction. Besides thromboxane A2 (TXA2 ) and its endoperoxide precursors prostaglandin (PG)G2 and PGH2 , also isoprostanes and 20-hydroxyeicosatetraenoic acid (20-HETE) activate TP receptor as autocrine or paracrine ligands. These additional TP activators play a role in pathological conditions such as diabetes, obesity, and hypertension, and their biosynthesis is not inhibited by aspirin, at variance with that of TXA2 . The understanding of TP receptor function increased our current knowledge of the pathogenesis of atherosclerosis and thrombosis, highlighting the great impact that this receptor has in cardiovascular disorders. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 12/2013; 12(2). DOI:10.1111/jth.12472 · 6.08 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The prothrombotic mediator thromboxane A2 is derived from arachidonic acid metabolism through the cyclooxygenase and thromboxane synthase pathways, and transduces its effect through the thromboxane prostanoid (TP) receptor. The aim of this study was to determine the effect of the TP receptor antagonist and thromboxane synthase inhibitor EV-077 on inflammatory markers in human umbilical vein endothelial cells and on human coronary artery smooth muscle cell proliferation. To this end, mRNA levels of different proinflammatory mediators were studied by real time quantitative PCR, supernatants were analyzed by enzyme immune assay, and cell proliferation was assessed using WST-1. EV-077 significantly decreased mRNA levels of ICAM-1 and PTX3 after TNFα incubation, whereas concentrations of 6-Keto PGF1α in supernatants of endothelial cells incubated with TNFα were significantly increased after EV-077 treatment. Although U46619 did not alter coronary artery smooth muscle cell proliferation, this thromboxane mimetic enhanced the proliferation induced by serum, insulin and growth factors, which was significantly inhibited by EV-077. In conclusion, EV-077 inhibited TNFα-induced endothelial inflammation and reduced the enhancement of smooth muscle cell proliferation induced by a thromboxane mimetic, supporting that the thromboxane pathway may be associated with early atherosclerosis in terms of endothelial dysfunction and vascular hypertrophy.
    Biochemical and Biophysical Research Communications 10/2013; DOI:10.1016/j.bbrc.2013.10.078 · 2.28 Impact Factor