title: Effects of BM-573 on Endothelial Dependent Relaxation and Increased Blood Pressure at Early Stages of Atherosclerosis.
abstract: Endothelial dysfunction is considered to be an early event in atherosclerosis and plays a pivotal role in the development, progression and clinical complications of atherosclerosis. Previous studies have shown the beneficial effects of combined inhibition of thromboxane synthase and antagonism of thromboxane receptors by BM-573 on atherosclerosis; however our knowledge about the beneficial effects of BM-573 on endothelial function and increased blood pressure related to early stage of atherosclerosis is limited. In the present study, we investigated the effects of short-term (3 μM, 1 hour) and chronic (10 mg/L, 8 weeks) treatments with BM-573 on vasodilatory function, nitric oxide (NO) bioavailability, oxidative stress and systolic blood pressure in 15 weeks old apolipoprotein E-deficient (ApoE-KO) mice. ApoE-KO mice showed a reduced endothelium-derived relaxation. In addition, NO bioavailability was reduced and oxidative stress and blood pressure were increased in ApoE-KO mice versus wild-type mice. BM-573 treatments were able to improve the relaxation profile in ApoE-KO mice. Short-term effects of BM-573 were mainly mediated by an increased phosphorylation of both eNOS and Akt, whereas BM-573 in vivo treatment also reduced oxidative stress and restored NO bioavailability. In addition, chronic administration of BM-573 reduced systolic blood pressure in ApoE-KO mice. In conclusion, pharmacological modulation of TxA2 biosynthesis and biological activities by dual TP antagonism/TxAS inhibition with BM-573, already known to prevent plaque formation, has the potential to correct vasodilatory dysfunction at the early stages of atherosclerosis.
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institute of Experimental & Clinical Research (IREC), Université Catholique de Louvain (UCL) Medical School, Brussels, Belgium.
authors.forename: Miguel
authors.initials: M
authors.lastname: Romero
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institute of Experimental & Clinical Research (IREC), Université Catholique de Louvain (UCL) Medical School, Brussels, Belgium.
authors.forename: Elvira
authors.initials: E
authors.lastname: Leon-Gomez
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institute of Experimental & Clinical Research (IREC), Université Catholique de Louvain (UCL) Medical School, Brussels, Belgium.
authors.forename: Irina
authors.initials: I
authors.lastname: Lobysheva
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institute of Experimental & Clinical Research (IREC), Université Catholique de Louvain (UCL) Medical School, Brussels, Belgium.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Rath
authors.affiliation: Department of Pharmacy, University of Namur, Namur, Belgium.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dogné
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institute of Experimental & Clinical Research (IREC), Université Catholique de Louvain (UCL) Medical School, Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institute of Experimental & Clinical Research (IREC), Université Catholique de Louvain (UCL) Medical School, Brussels, Belgium.
authors.forename: Chantal
authors.initials: C
authors.lastname: Dessy
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000378:metabolism; D013453:Sulfonylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001057:Apolipoproteins E; C475768:N-terbutyl-N'-(2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl)urea; D017382:Reactive Oxygen Species; D017482:Receptors, Thromboxane; D013453:Sulfonylurea Compounds; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt