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.

journal_name

J Cardiovasc Pharmacol

authors

Harnish DC,Liu X,Kenney T,Winneker RC,Chadwick C,Friedrichs GS,Kilbourne EJ

doi

10.1097/01.fjc.0000211793.60528.f7

subject

Has Abstract

pub_date

2006-06-01 00:00:00

pages

788-95

issue

6

eissn

0160-2446

issn

1533-4023

pii

00005344-200606000-00010

journal_volume

47

pub_type

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