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Research ArticleCARDIOVASCULAR

Nitric Oxide Stimulatory and Endothelial Protective Effects of Idoxifene, a Selective Estrogen Receptor Modulator, in the Splanchnic Artery of the Ovariectomized Rat

Xin L. Ma, Feng Gao, Chen-Ling Yao, Jun Chen, Bernard L. Lopez, Theodore A. Christopher, Jyoti Disa, Juan-Li Gu, Eliot H. Ohlstein and Tian-Li Yue
Journal of Pharmacology and Experimental Therapeutics November 2000, 295 (2) 786-792;
Xin L. Ma
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Feng Gao
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Chen-Ling Yao
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Jun Chen
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Bernard L. Lopez
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Theodore A. Christopher
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Jyoti Disa
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Juan-Li Gu
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Eliot H. Ohlstein
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Tian-Li Yue
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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 withNω-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.

Footnotes

  • Send reprint requests to: Xin L. Ma, Division of Emergency Medicine, Jefferson Medical College, 1020 Sansom St., Philadelphia, PA 19107-5004. E-mail: Xin.Ma{at}mail.tju.edu

  • Abbreviations:
    NO
    nitric oxide
    NOS
    nitric-oxide synthase
    SERM
    selective estrogen receptor modulator
    Ovx
    ovariectomy
    TNFα
    tumor necrosis factor-α
    DMSO
    dimethyl sulfoxide
    SMA
    superior mesenteric artery
    K-H
    Krebs-Henseleit buffer solution
    ACh
    acetylcholine
    l-NAME
    Nω-nitro-l-arginine methyl ester
    SI/R
    splanchnic ischemia/reperfusion
    • Received March 16, 2000.
    • Accepted July 7, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 2
1 Nov 2000
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Research ArticleCARDIOVASCULAR

Nitric Oxide Stimulatory and Endothelial Protective Effects of Idoxifene, a Selective Estrogen Receptor Modulator, in the Splanchnic Artery of the Ovariectomized Rat

Xin L. Ma, Feng Gao, Chen-Ling Yao, Jun Chen, Bernard L. Lopez, Theodore A. Christopher, Jyoti Disa, Juan-Li Gu, Eliot H. Ohlstein and Tian-Li Yue
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 786-792;

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Research ArticleCARDIOVASCULAR

Nitric Oxide Stimulatory and Endothelial Protective Effects of Idoxifene, a Selective Estrogen Receptor Modulator, in the Splanchnic Artery of the Ovariectomized Rat

Xin L. Ma, Feng Gao, Chen-Ling Yao, Jun Chen, Bernard L. Lopez, Theodore A. Christopher, Jyoti Disa, Juan-Li Gu, Eliot H. Ohlstein and Tian-Li Yue
Journal of Pharmacology and Experimental Therapeutics November 1, 2000, 295 (2) 786-792;
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