Oestrogen-mediated cardioprotection following ischaemia and reperfusion is mimicked by an oestrogen receptor (ER)alpha agonist and unaffected by an ER beta antagonist

Oestrogen protects the heart from ischaemic injury. The current study aims to characterise two novel oestrogen receptor (ER) ligands, an ERa agonist ERA-45 and an ERb antagonist ERB-88, and then use them to investigate the roles of ERa and ERb 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 (nZ48) were ovariectomised and implanted with 17b-oestradiol (17bE2) 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. TheERa agonist ERA-45 showed more than 35-fold selectivity for ERa compared with ERb gene transactivation. In vitro, the ERb antagonist ERB-88 inhibited transactivation by 17bE2 via ERb with 46-fold selectivity relative to inhibition via ERa. In vivo, 17bE2 significantly reduced neutrophil infiltration, oxidant stress and necrosis following ischaemia and reperfusion. Cardioprotection by 17bE2 was not inhibited by ERB-88 but was completely reproduced by ERA-45. In conclusion, protection of the rat heart after ischaemia–reperfusion by 17bE2 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 ERa. Journal of Endocrinology (2008) 197, 493–501