(Circulation. 2000;101:2258.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Mechanisms Responsible for Endothelial Dysfunction Associated With Acute Estrogen Deprivation in Normotensive Women
From the Departments of Internal Medicine (A.V., L.G., S.P., S.B., S.T., A.S.) and Obstetrics and Gynecology (M.L., A.G.), University of Pisa, and Department of Obstetrics and Gynecology, University of Udine (F.P.), Udine, Italy.
Correspondence to Agostino Virdis, MD, Department of Internal Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy.
Background—The goal of this study was to evaluate whether endothelial dysfunction associated with acute estrogen deprivation is caused by an alteration in the L-arginine–nitric oxide (NO) pathway and oxidative stress.
Methods and Results—In 26 healthy women (age, 45.7±5.4 years) and 18 fertile women with leiomyoma (age, 44.5±5.1 years), we studied forearm blood flow (strain-gauge plethysmography) changes induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, or 15 µg · 100 mL-1 · min-1) or sodium nitroprusside (1, 2, or 4 µg · 100 mL-1 · min-1), an endothelium-dependent or -independent vasodilator, respectively. The NO pathway was evaluated by repeating acetylcholine during L-arginine (200 µg · 100 mL-1 · min-1; 13 control subjects and 9 patients) or NG-monomethyl-L-arginine (L-NMMA; 100 µg · 100 mL-1 · min-1; 13 control subjects and 9 patients); production of cyclooxygenase-derived vasoconstrictors was assessed by repeating acetylcholine during indomethacin (50 µg · 100 mL-1 · min-1; 13 control subjects and 9 patients) or vitamin C (8 mg · 100 mL-1 · min-1; 13 control subjects and 9 patients). Patients repeated the study within 1 month after ovariectomy and again after 3 months of estrogen replacement therapy (ERT; 17 ß-estradiol TTS, 50 µg/d). Basally, vasodilation to acetylcholine was potentiated and inhibited by L-arginine and L-NMMA, respectively (P<0.05), but was unaffected by indomethacin or vitamin C. After ovariectomy, the modulating effect of L-arginine and L-NMMA disappeared, whereas indomethacin and vitamin C potentiated the response to acetylcholine (P<0.05). ERT restored L-arginine and L-NMMA effects on vasodilation to acetylcholine but prevented the potentiation caused by indomethacin or vitamin C. Response to sodium nitroprusside was unaffected by either ovariectomy or ERT.
Conclusions—Endothelial dysfunction secondary to acute endogenous estrogen deprivation is caused by reduced NO availability. Cyclooxygenase-dependent production of oxidative stress could be responsible for this alteration.
Key Words: endothelium • nitric oxide • estrogen • antioxidants
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