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Centre for Cardiovascular Science, University of Edinburgh, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK¹ Organon Laboratories Ltd, Department Pharmacology, Newhouse, Lanarkshire, Scotland ML1 5SH, UK² Department Pharmacology, NV Organon, PO Box 20, 5340 BH Oss, The Netherlands

(Correspondence should be addressed to G A Gray; Email: gillian.gray{at}ed.ac.uk)

The authors declare that there are no conflicts of interest that would prejudice the impartiality of this research.

Oestrogen protects the heart from ischaemic injury. The current study aims to characterise two novel oestrogen receptor (ER) ligands, an ER agonist ERA-45 and an ERβ antagonist ERB-88, and then use them to investigate the roles of ER and ERβ in mediating the cardioprotection by E from ischaemia–reperfusion injury in the rat. The ER ligands were characterised by gene transactivation assay using ER-transfected Chinese hamster ovary (CHO) cells and in bioavailability studies in vivo. Female rats (n=48) were ovariectomised and implanted with 17β-oestradiol (17βE₂) releasing or placebo pellets. ERA-45, ERB-88 or vehicle was administered for 5 days prior to ischaemia–reperfusion studies. Necrosis, neutrophil infiltration (myeloperoxidase activity) and oxidant stress production (electron paramagnetic resonance) from the area-at-risk were measured to assess reperfusion injury. The ER agonist ERA-45 showed more than 35-fold selectivity for ER compared with ERβ gene transactivation. In vitro, the ERβ antagonist ERB-88 inhibited transactivation by 17βE₂ via ERβ with 46-fold selectivity relative to inhibition via ER. In vivo, 17βE₂ significantly reduced neutrophil infiltration, oxidant stress and necrosis following ischaemia and reperfusion. Cardioprotection by 17βE₂ was not inhibited by ERB-88 but was completely reproduced by ERA-45. In conclusion, protection of the rat heart after ischaemia–reperfusion by 17βE₂ is achieved through the reduction of cardiomyocyte death, neutrophil infiltration and oxygen-free radical availability.The results of this study indicate that these effects are primarily mediated via activation of ER.

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