Abstract

Estrogen is known to stimulate endothelial nitric oxide production and attenuate endothelial dysfunction after ischemia and reperfusion. However, estrogen therapy increases the risk of breast and endometrial cancer. The present study was designed to determine whether idoxifene, a selective estrogen receptor modulator without adverse effects on reproductive organs, may stimulate nitric oxide release and protect endothelial function. In U-46619 precontracted superior mesenteric arterial (SMA) segments isolated from ovariectomized rats, idoxifene and 17β-estradiol resulted in a comparable dose-dependent vasorelaxation (maximal relaxation: 75.3 ± 4.9 and 71 ± 4.7%, respectively). Treatment of the rings withN^ω-nitro-l-arginine methyl ester completely blocked idoxifene- and 17β-estradiol-induced vasorelaxation. In vitro incubation of SMA rings with TNFα significantly reduced vasorelaxation to an endothelium-dependent vasodilator, acetylcholine (maximal relaxation: 73 ± 3.7 versus 95 ± 2.9% pre-TNFα, P < .01). Idoxifene, but surprisingly not 17β-estradiol, prevented TNFα-induced endothelial dysfunction (maximal relaxation: 86 ± 2.6% in idoxifene-treated rings and 77 ± 5.1% in 17β-estrogen-treated rings). In vivo ischemia and reperfusion resulted in significant endothelial dysfunction as evidenced by decreased vasorelaxation to acetylcholine (maximal relaxation: 48 ± 5.5 versus 92 ± 3.9% in normal SMA rings), but a normal relaxation response to an endothelium-independent vasodilator, acidified NaNO₂(95 ± 3.2%). Treatment with idoxifene at either 1 or 2 mg/kg/day, or 17β-estrogen at 1 mg/kg/day for 4 days significantly preserved endothelial function (P < .01 versus vehicle). Taken together, these results demonstrate that idoxifene is an endothelium-dependent vasodilator and exerts significant endothelial protective effects against TNFα- and ischemia-reperfusion-induced endothelial injury. These results suggest that selective estrogen receptor modulators have therapeutic potential in diseases where endothelial dysfunction plays an important role.