title: The pathway-selective estrogen receptor ligand WAY-169916 reduces infarct size after myocardial ischemia and reperfusion by an estrogen receptor dependent mechanism.
abstract: Previous studies have shown that estrogen treatment protects the heart from reperfusion injury. The adverse effects of long-term estrogen treatment limit its clinical use and emphasize the need for the development of specific pharmacological interventions such as pathway-selective estrogen receptor (ER) ligands. Pathway-selective ER ligands are compounds that retain estrogen's anti-inflammatory ability, but they are devoid of conventional estrogenic action. In the present study, the pathway-selective ER ligand WAY-169916 was assessed for its cardioprotective potential in an in vivo model of ischemia-reperfusion injury. Anesthetized, ovariectomized rabbits were administered WAY-169916 (1 mg/kg), 17beta-estradiol (E2; 20 microg/rabbit), or vehicle intravenously 30 minutes before a 30-minute occlusion and 4 hours of reperfusion. Acute treatment with either WAY-169916 or E2 resulted in a decrease in infarct size, expressed as a percent of area at risk (WAY-169916, 21.2 +/- 3.3; P < 0.001 and E2, 18.8 +/- 1.7; P < 0.001) compared with vehicle 59.4 +/- 5.4). Pretreatment with estrogen receptor antagonist ICI 182,780 significantly limited the infarct size sparing effect of both WAY-169916 and E2 when expressed as a percent of the risk region (WAY 169916, 47.4 +/- 4.4; E2, 53.01 +/- 5.0). The results demonstrate that WAY-169916 protects the heart against ischemia-reperfusion injury through an ER-dependent mechanism.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0632, USA. boothea@umich.edu
authors.forename: Erin A
authors.initials: EA
authors.lastname: Booth
authors.forename: Marta
authors.initials: M
authors.lastname: Marchesi
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Knittel
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kilbourne
authors.forename: Benedict R
authors.initials: BR
authors.lastname: Lucchesi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D008024:Ligands; D009203:Myocardial Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D004965:Estrogen Antagonists; D008024:Ligands; D011720:Pyrazoles; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; C499198:WAY-169916; D000077267:Fulvestrant; D004958:Estradiol