The pathway-selective estrogen receptor ligand WAY-169916 displays differential activity in ischemia-reperfusion injury models

J Cardiovasc Pharmacol. 2006 Jun;47(6):788-95. doi: 10.1097/01.fjc.0000211793.60528.f7.


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.

MeSH terms

  • Animals
  • Cardiotonic Agents / administration & dosage
  • Cardiotonic Agents / therapeutic use*
  • Cholesterol / blood
  • Disease Models, Animal
  • Estradiol / administration & dosage
  • Estradiol / therapeutic use*
  • Female
  • In Vitro Techniques
  • Ligands
  • Male
  • Myocardial Reperfusion Injury / prevention & control*
  • Pyrazoles / administration & dosage
  • Pyrazoles / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Estrogen
  • Uterus / drug effects


  • Cardiotonic Agents
  • Ligands
  • Pyrazoles
  • Receptors, Estrogen
  • WAY-169916
  • Estradiol
  • Cholesterol