SYSTEMIC AND UTERINE RESPONSES TO CHRONIC INFUSION OF ESTRADIOL-17-BETA

Human and ovine pregnancies are associated with increases in plasma levels of estrogens and angiotensin II (ANG II), cardiac output (CO), blood volume (BV), and uterine blood flow (UBF), as well as attenuated ANG II pressor responses. We hypothesized that, in nonpregnant animals, prolonged estradiol-17beta (E2beta) treatment would reproduce these endocrine and hemodynamic alterations. Nonpregnant ovariectomized ewes (n = 5) received 5 mug E2beta/kg iv followed by 220 mug/day for 14 days. Plasma E2beta increased from 36 +/- 6 to 269 +/- 79 (SE) pg/ml (P < 0.05) during E2beta treatment, returning to control values 4 days posttreatment. By 3 days of E2beta, mean arterial pressure (MAP) and systemic vascular resistance (SVR) fell 9 +/- 1 and 29 +/- 1%, whereas heart rate (HR) and CO increased 20 +/- 5 and 26 +/- 1% (P < 0.05). Stroke volume (SV), BV, and plasma volume were unchanged until 7 days of E2beta, with values rising 17 +/- 5, 13 +/- 3, and 14 +/- 4, respectively (P < 0.05). Although MAP remained similarly depressed (-11 +/- 1%) during week 2 of E2beta, SVR decreased further (-37 +/- 3%) and was associated with additional increases (P < 0.05) in CO to 44 +/- 5%, reflecting rises in SV (21 +/- 2%) but not HR. Increases in BV correlated with rises in CO (r = 0.55) and SV (r = 0.64) but not HR (r = -0.04). Although UBF increased 396 +/- 131% 120 min after the E2beta bolus (P < 0.05), values returned to control levels by 7 days of E2beta treatment. ANG II and plasma renin activity (PRA) increased maximally by 3 days of E2beta, from 12 +/- 2 pg/ml and 1.28 +/- 0.18 ng . ml-1 . h-1 to 56 +/- 29 and 2.75 +/- 0.54, respectively (P < 0.05), and returned to control levels at greater-than-or-equal-to 7 days. Pressor responses to infused ANG II (0.11511. 5 mug/min) decreased during E2beta treatment, and, despite subsequent decreases in plasma E2beta, ANG II, and PRA 2 wk post-E2beta, responses remained attenuated (P < 0.05). Prolonged E2beta treatment reproduces many cardiovascular alterations associated with pregnancy, including systemic vasodilation and attenuated pressor responses to infused ANG II, but does not maintain elevations in UBF. Furthermore, activation of the renin-angiotensin system via vascular ''underfilling'' was reversed after BV expansion.