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
17 beta-estradiol resulted in a comparable dose-dependent vasorelaxation (maximal relaxation: 75.3 +/- 4.9 and 71 +/- 4.7%, respectively). Treatment of the rings with
N(omega)-nitro-L-arginine methyl ester completely blocked
idoxifene- and
17 beta-estradiol-induced vasorelaxation. In vitro incubation of SMA rings with
TNF alpha significantly reduced vasorelaxation to an endothelium-dependent
vasodilator,
acetylcholine (maximal relaxation: 73 +/- 3.7 versus 95 +/- 2.9% pre-
TNF alpha, P <.01).
Idoxifene, but surprisingly not
17 beta-estradiol, prevented
TNF alpha-induced endothelial dysfunction (maximal relaxation: 86 +/- 2.6% in
idoxifene-treated rings and 77 +/- 5.1% in 17beta-
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 NaNO(2) (95 +/- 3.2%). Treatment with
idoxifene at either 1 or 2 mg/kg/day, or 17beta-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
TNF alpha- 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.