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

Abstract

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.

• Authors: Douglas C Harnish, Xiaorong Liu, Thomas Kenney, Richard C Winneker, Chris Chadwick, Gregory S Friedrichs, Edward J Kilbourne
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 47 Issue 6 Pg. 788-95 (Jun 2006) ISSN: 0160-2446 [Print] United States
• PMID: 16810080 (Publication Type: Journal Article)

Chemical References

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

Topics

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