Endothelial protective and antishock effects of a selective estrogen receptor modulator in rats

This study investigated whether idoxifene, a selective estrogen receptor mo dulator (SERM), exerted protective effects against ischemia-reperfusion-ind uced shock. Ovariectomized rats were treated with vehicle, idoxifene, or 17 beta -estradiol for 4 days. Rats were subjected to splanchnic artery occlu sion (SAO) followed by reperfusion (SOA/R). In vehicle-treated rats, SAO/R resulted in hypotension, hemoconcentration, increased plasma tumor necrosis factor (TNF)-alpha levels, intestinal neutrophil accumulation, and endothe lial dysfunction. 17 beta -Estradiol treatment increased plasma estradiol c oncentration and reduced SAO/R-induced tissue injury. Idoxifene treatment h ad no effect on plasma estradiol concentration but reduced SAO/R-induced he moconcentration (+8.8 +/- 1.3 vs. +14 +/- 1.3% in the vehicle group, P< 0.0 1), TNF-<alpha> production (98 +/- 3.2 vs. 214 +/- 13 pg/ml, P< 0.01), and neutrophil accumulation (0.025 +/- 0.005 vs. 0.047 +/- 0.005 U/g protein, P < 0.01). It also improved endothelial function, prolonged survival time (17 2 +/- 3.5 vs. 147 +/- 8 min, P< 0.01), and increased survival rate (69 vs. 23%, P< 0.01). Moreover, treatment with 17 beta -estradiol or idoxifene in vivo reduced TNF-alpha -induced endothelial dysfunction in vitro. Taken tog ether, these results demonstrated that idoxifene exerted estrogen-like, end othelial-protective, and antishock effects in ovariectomized rats, suggesti ng that SERMs have therapeutic potential in tissue injury resulting from is chemia-reperfusion.