Abstract 61: Hypertension in a Rat Model of Postmenopausal Hyperandrogenemia (Polycystic Ovary Syndrome) Roles of the Renin-Angiotensin and Sympathetic Nervous Systems

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Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in premenopausal women. PCOS is characterized by hyperandrogenemia that does not abate after menopause. Hyperandrogenemic postmenopausal women (HA-PMW) are hypertensive, but the mechanisms responsible have not been elucidated. Hypertension in PMW is less well controlled than in age-matched men. We have developed a model, the hyperandrogenemic postcycling female (PMHAF) rat, aged 13-14 mos, that exhibits many of the characteristics found in HA-PMW. In the present studies we tested the hypothesis that the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) contribute to hypertension in PMHAF rats. Female Sprague-Dawley rats were implanted with dihydrotestosterone (7.5mg/90d) or placebo pellets beginning at 4 wks of age, and pellets were changed every 85 d. At 12-13 mos of age, PMHAF rats were obese compared to placebo controls, and CT scans showed that both total adipose (TAF) and visceral adipose (VAF) were increased in PMHAF vs placebo controls (n=4/grp) (TAF: 7.9±0.5 vs 5.46±1.00 AU/g BW, p<0.05; VAF, 4.60±0.30 vs 3.45±0.07 AU/g BW, p<0.05). PMHAF rats (n=3/grp) were implanted with radiotelemetry transmitters, and 2 wks later, baseline MAP was measured for 5 d. Then rats were given losartan (40mg/kg/d) or tap water placebo for 5 days, and then tap water was returned. After additional 5 d and return of MAP to baseline, rats were implanted with minipumps containing terazocin and propranolol (10 mg/kg/d for each drug, sc, for 7 d) or saline vehicle. Baseline MAP in PMHAF rats was (128±9 vs 105±9 mmHg, p<0.05). Losartan reduced MAP more in PMHAF than placebo controls (111±9 vs 95±7 mmHg, p<0.05). Intrarenal angiotensinogen and ACE1 mRNA levels were increased by 8 fold and 2 fold, respectively, in PMHAF rats vs placebo controls (p<0.05). α11,2-Adrenergic blockade reduced MAP by 13% in PMHAF rats, the same level as in placebo controls, and had no effect in placebo controls (110±12 vs 102±5 mmHg, p<0.05 vs baseline MAP). These data suggest that both the RAS and SNS are upregulated in PMHAF rats and contribute to their hypertension. These data also suggest that multiple drug therapy is likely to be necessary to control MAP in PMW with hyperandrogenemia. Supported by PO1HL51971.

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