Abstract P170: Cytochrome P450 1b1-Dependent Sex Differences in Norepinephrine-Induced Hypertension

Abstract

Females exhibit a lower pressor response to norepinephrine (NE) than the males. Previously we reported that cytochrome P450 (CYP) 1B1 contributes to the sex difference in angiotensin II-induced hypertension by metabolizing the sex steroids testosterone into 6β-hydroxytestosterone, and estradiol into 2-hydroestradiol which is further metabolized to 2-methoxyestradiol (2-ME) by catechol-O-methyl transferase (COMT). This study was conducted to determine the contribution of CYP1B1 to NE-induced hypertension. Eight weeks old wild-type ( Cyp1b1 +/+ ) and CYP1B1 gene disrupted ( Cyp1b1 -/- ) intact, castrated (Cas) male, and ovariectomized (OVX) female mice were infused with NE (7μg/kg/min, s.c.) or its vehicle (saline) using mini-osmotic pumps for 2 weeks. The systolic blood pressure (SBP, mmHg) was measured by tail-cuff. At the end of 2 weeks, NE increased SBP to a higher level (P<0.05, n=5) in the intact Cyp1b1 +/+ male (159±3 vs. 117±5) than in the female (137±2 vs. 120±5) mice. NE-induced increase in SBP was minimized (P<0.05, n=4) in the Cas Cyp1b1 +/+ (127±6 vs. 116±3), and the intact Cyp1b1 -/- male mice (134±2 vs. 119±3). The increase in SBP by NE was enhanced in the Cyp1b1 +/+ OVX (154±3 vs. 118±4) and Cyp1b1 -/- intact female mice (155±4 vs. 122±4) compared to the intact female Cyp1b1 +/+ mice (p<0.05, n=4-5). The COMT inhibitor, Ro-041-0960 (25 mg/kg, s.c., every 2 nd day) enhanced the NE-induced increase in SBP in Cyp1b1 +/+ intact female (151±2, Δ14) (P<0.05, n=4-5) but not in the OVX (160±5, Δ6) or the intact Cyp1b1 -/- female mice (158±5, Δ3) (n=3-4). Treatment with 2-ME (1.5 mg/kg, i.p., every 3 rd day) minimized the NE-induced increase in SBP in the intact Cyp1b1 -/- female mice (131±1, Δ24) (P<0.05, n=4). These data suggest that sex difference in NE-induced hypertension is dependent on CYP1B1, and the protective effect of E2 in female mice against NE-induced hypertension is mediated via the formation of 2-ME. Therefore, 2-ME could be useful to treat hypertension associated with increased sympathetic activity in postmenopausal females, hypoestrogenemic premenopausal women, and pre- and post-menopausal women with ovarian failure. Moreover, NE used to treat acute hypotensive states could produce deleterious cardiovascular effects in the above conditions.