Creased thrombin generation (Glutathione Peroxidase drug Freudenberger et al., 2009). Besides MPA, an additional synthetic gestagen, norethisterone acetate (NET-A), is generally utilized in postmenopausal HRT (Koubovec et al., 2005) together with oestrogens. NET-A and MPA differ from each and every other with regard to agonism of other steroid receptors as well as the progesterone receptor. Specifically, in contrast to MPA, which can be identified to possess partial glucocorticoid effects (Wiegratz and Kuhl, 2004), NET-A has been found to exert only minimal glucocorticoid actions (Koubovec et al., 2005). Consequently, further research employing animal models of atherothrombosis will assistance to clarify the atherothrombotic threat distribution of synthetic gestagens and to investigate the underlying mechanisms. Accordingly, the aims in the present work were (i) to evaluate the prothrombotic MPA effect with another synthetic progestin, NET-A, (ii) to decide when the effects of MPA can be antagonized with mifepristone and (iii) to search for underlying mechanisms by comparing aortic gene expression immediately after chronic remedy with MPA versus NET-A to define genes, functional terms and pathways that might potentially beinvolved in thrombotic responses in ovariectomized DNMT1 Accession apolipoprotein E (ApoE)-deficient mice treated with MPA in comparison to these treated with NET-A.MethodsWhere applicable, the drug/molecular target nomenclature complies with Alexander et al. (2013).AnimalsAnimal experiments were performed in line with the guidelines with the `Deutsches Tierschutzgesetz’ and were authorized by the `Landesamt f Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen’ below the reference number Az. 8.87? All studies involving animals are reported in accordance with the ARRIVE recommendations for reporting experiments involving animals (Kilkenny et al., 2010; McGrath et al., 2010). Homozygous female ApoE-deficient mice (Jackson Laboratory, Bar Harbor, ME, USA) were maintained on a 12 h dark/light cycle with unrestricted access to food and water. Animals had been fed a typical chow diet regime (Ssniff, Soest, Germany) until commencement of hormone substitution. From this point on, mice received a Western-type diet plan (Ssniff) as previously described (Freudenberger et al., 2009). Exactly where indicated, anaesthesia was induced employing Ketanest/xylazine [100 mg g? Ketanest (Pfizer, Berlin, Germany), five mg g? xylazine (Bayer, Leverkusen, Germany)]. Anaesthetics were intraperitoneally injected and sufficient anaesthesia was assured by the absence on the blink reflex along with the inter-toe reflex. The number (n) of animals employed for the unique experiments is provided inside the respective figure legends.Ovariectomy and hormone substitutionAt the age of 4 to 5 weeks, mice were bilaterally ovariectomized (OVX) under anaesthesia. Post-operative analgesia was ensured by s.c. application of Carprofen (5 mg g?; Pfizer). Roughly 14 days after OVX, mice were randomly assigned to six various therapy groups, namely placebo forBritish Journal of Pharmacology (2014) 171 5032?048BJPTableT Freudenberger et al.Dose and release parameters of the different pellets implanted s.c.Chemical compound Medroxyprogesterone acetate (MPA) Norethisterone acetate (NET-A) MifepristoneTotal dose (mg)/pellet 2.5 1.2 90.Total time of release (days) 90 90Release ( g)/day 27.7 13.3 1000.mifepristone, mifepristone, placebo for MPA/NET-A, MPA, MPA + mifepristone and NET-A. Soon after anaesthesia, mice were s.c. implanted with slow-release hormone pellets (Revolutionary Analysis of America, Sarasota,.