Abstract P134: Hypertension in Postmenopausal Women: Role of Renin-angiotensin System and Eicosanoids

Abstract

Hyperandrogenemic postmenopausal women have elevated blood pressure (BP) and the mechanisms responsible for it have not been elucidated. We tested the hypothesis that activated renin-angiotensin system (RAS) in combination with cytochrome P450 (CYP 450) arachidonic acid metabolites in renal microvasculature contribute to the elevated BP in post-estrous cycling hyperandrogenemic female (PMHAF) rats. Female SD rats were implanted with DHT (7.5mg/90d) or placebo pellets (n=12/grp) beginning at 6 wks of age; pellets were changed every 85 d. At 14 months of age, baseline mean arterial pressure (MAP, telemetry) was measured in control and PMHAF rats. Each group was then divided into two groups, one group received non-specific CYP 450 inhibitor, 1-aminobenzotriazole (1-ABT; 100mg/kg/day, i.p.), and the other received Losartan (40mg/kg/day, P.O.) for 10 days. For the following 10 days all rats received both drugs. Baseline BP was significantly higher in PMHAF than controls (112±3 vs 126±3 mmHg, p=0.008). 1-ABT alone had no effect on BP in either control or PMHAF rats. Losartan alone reduced MAP in both groups (112±3 vs 97±3 mmHg, p<0.05 in control and 126±3 vs 100±3 mmHg, p<0.05 in PMHAF). In control rats first given 1-ABT, losartan had no effect on BP (112±3 vs 113±2 mmHg, p=NS). In control rats first given losartan, BP continued to decrease over the next 10 days (97±3 vs 87±2 mmHg, p=0.046). Just as in control rats, in PMHAF rats given 1-ABT first, losartan had no further effect on BP (130±2 vs 126±4 mmHg, P=NS). Unlike in control rats, PMHAF rats given 1-ABT after losartan, the BP increased to back to baseline levels (126±3 vs 116±5 mmHg, p=NS). This data suggests that BP in aging female control rats is mediated by the RAS and likely greater vasoconstrictor to vasodilator ratios of eicosanoids. BP control in PMHAF rats is more complex with the RAS playing a major role. Data suggests that vasodilators (EETs) in the renal microvasculature and 20-HETE in the tubules contribute to BP control which would explain the increase in BP back to baseline with 1-ABT + losartan. Future studies will be necessary to determine exact mechanisms responsible for the hypertension in PMHAF rats, and may explain why in hyperandrogenemic women BP is difficult to control to normotensive levels. PO1HL51971.