Mechanisms responsible for endothelial dysfunction associated with acute estrogen deprivation in normotensive women

Background-The goal of this study was to evaluate whether endothelial dysfu nction associated with acute estrogen deprivation is caused by an alteratio n 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 Fe rtile women with leiomyoma (age, 44.5 +/- 5.1 years), we studied forearm bl ood flow (strain-gauge plethysmography) changes induced by intrabrachial ac etylcholine (0.15, 0.45, 1.5, 4.5, or 15 mu g.100 mL(-1).min(-1)) or sodium nitroprusside (1, 2, or 4 mu g.100 mL(-1).min(-1)), an endothelium-depende nt or -independent vasodilator, respectively. The NO pathway was evaluated by repeating acetylcholine during L-arginine (200 mu g.100 mL(-1).min(-1); 13 control subjects and 9 patients) or N-G-monomethyl-L- arginine (L-NMMA; 100 mu g.100 mL(-1).min(-1); 13 control subjects and 9 patients); productio n of cyclooxygenase-derived vasoconstrictors was assessed by repeating acet ylcholine during indomethacin (50 mu g.100 mL(-1).min(-1): 13 control subje cts and 9 patients) or vitamin C (8 mg.100 mL(-1).min(-1); 13 control subje cts and 9 patients). Patients repeated the study within I month after ovari ectomy and again after 3 months of estrogen replacement therapy (ERT; 17 be ta-estradiol TTS, 50 mu g/d). Basally, vasodilation to acetylcholine was po tentiated and inhibited by L-arginine and L-NMMA, respectively (P<0.05), bu t was unaffected by indomethacin or vitamin C. After ovariectomy, the modul ating 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 prevent ed 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.