The pathway-selective estrogen receptor ligand WAY-169916 displays differential activity in ischemia-reperfusion injury models.
We previously reported on the development of a pathway-selective estrogen receptor (ER) ligand, WAY-169916, that has ER-dependent antiinflammatory activity and is devoid of classic ER transcriptional activity. In the current study, WAY-169916 and 17beta-estradiol (17beta-E2) were evaluated for protective activity in models of cardiac ischemia-reperfusion injury. In rats subjected to cardiac ischemia-reperfusion injury by occlusion of the left coronary artery, infarct size relative to the area at risk in the left ventricle was significantly attenuated by a single dose of 17beta-E2 (20 microg/kg, SC), and WAY-169916 administered SC (10 mg/kg) or IV (1 mg/kg) during the ischemia phase. In isolated hearts perfused on a Langendorff apparatus and subjected to global ischemia and reperfusion, 17beta-E2 and WAY-169916 both had direct cardioprotective activity when perfused at 1 microM but their effects varied between different end points. Perfusion with 17beta-E2 only improved recovery of left ventricle-developed pressure. Perfusion with WAY-169916 attenuated the elevation in perfusion pressure, diastolic pressure, and release of creatine kinase after ischemia. In contrast to 17alpha-ethinylestradiol, WAY-169916 had no classic estrogen effects on uterine weight or total serum cholesterol in rats treated for 4 days. The data demonstrate that the pathway-selective ER ligand WAY-169916 displays differential activity in vivo on different cardiovascular end points.
Harnish
Douglas C
DC
Women's Health and Musculoskeletal Biology, Wyeth Research, Collegeville, PA 19426-3930, USA.
Liu
Xiaorong
X
Kenney
Thomas
T
Winneker
Richard C
RC
Chadwick
Chris
C
Friedrichs
Gregory S
GS
Kilbourne
Edward J
EJ
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D004958:Estradiol / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen; D014599:Uterus / Q000187:drug effects
D002316:Cardiotonic Agents; D008024:Ligands; D011720:Pyrazoles; D011960:Receptors, Estrogen; C499198:WAY-169916; D004958:Estradiol; D002784:Cholesterol