Abstract 249: Modulation of Angiotensin II-Induced Hypertension by Cytochrome P450 1B1 Metabolites of Estrogen in Female Mice

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Abstract

Pre-menopausal females are less susceptible to increases in blood pressure (BP) compared to males in various models of experimental hypertension, and this protection is lost following ovariectomy (OVX). We reported that in male rodents, cytochrome P450 (CYP) 1B1, via generation of reactive oxygen species, contributes to angiotensin (Ang) II- and DOCA-salt-induced hypertension and in SHR. Recently it has been shown that dexfenfluramine causes pulmonary arterial hypertension by a CYP1B1-dependent mechanism in female, but not male mice. Whether sex differences exist in the contribution of CYP1B1 to systemic hypertension is not known. Since CYP1B1 has a high affinity for estrogen, and estrogen and its metabolites exert both pro- and anti-proliferative effects, this study was conducted to determine the contribution of CYP1B1, estrogen, and its metabolites in the development of Ang II-induced hypertension in 8 weeks old female Cyp1b1+/+ and Cyp1b1-/- mice. Mice were infused with Ang II (700 ng/kg/min) or vehicle with or without 2-hydroxyestradiol (2-OHE), 4-OHE (1.5 mg/kg/day, i.p.), or the CYP1B1 inhibitor, 2,4,3′5′-tetramethoxystilbene (TMS, 300 μg/kg, every 3rd day, i.p.), for 2 weeks, and BP was measured twice weekly by tail cuff. Ang II increased BP to a greater degree in Cyp1b1-/- than in Cyp1b1+/+ mice (119 ± 3 to 171 ± 11 mmHg vs. 120 ± 4 to 149 ± 4 mmHg, respectively, P < 0.05). The increase in BP produced by Ang II in Cyp1b1-/- mice was reduced by treatment with 2-OHE (171 ± 11 vs. 140 ± 8 mmHg, P < 0.05). However, treatment with 4-OHE in Cyp1b1+/+ mice enhanced the hypertensive effect of Ang II (190 ± 4 vs. 149 ± 4 mmHg, P < 0.05), as did TMS (187 ± 5 vs. 149 ± 4 mmHg, P < 0.05). These agents did not affect basal BP in Cyp1b1+/+ or Cyp1b1-/- mice. Furthermore, our preliminary data show that OVX increased the hypertensive effect of Ang II after 7 days of infusion in Cyp1b1+/+ mice (171 ± 10 vs. 140 ± 4 mmHg, P < 0.05) but not Cyp1b1-/- mice (167 ± 8 vs. 169 ± 7 mmHg, P > 0.05). These data suggest that estrogen metabolites of CYP1B1 exert both anti- (2-OHE) and pro-hypertensive (4-OHE) effects, and that the low pressor effect of Ang II in female mice is most likely mediated by the latter. Moreover, agents that inhibit CYP1B1 activity could promote development of systemic hypertension in female mice.

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