Abstract 251: 20-HETE Contributes to the Hypertension in a Model of Postmenopausal Polycystic Ovary Syndrome

Abstract

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 (PMW) are hypertensive, but the mechanisms responsible have not been elucidated. Hypertension (HT) in PMW is less well controlled than in age-matched men, which suggests that different mechanisms may be mediating the HT in PMW. We have developed a model, the hyperandrogenemic postcycling female (PMHAF) rat, aged 13-14 mos, that exhibits many of the characteristics found in hyperandrogenemic PMW. In the present study we tested the hypothesis that 20-HETE contributes to the HT 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 13-14 mos of age, preglomerular renal microvessels were isolated from PMHAF and placebo control rats (n=6/grp) and 20-HETE and ω-hydroxylase activity were measured by LC-MS. mRNA for CYP4A enzymes were measured by real time RT-PCR. Basal 20-HETE levels in the renal vasculature increased by 60% in PMHAF vs placebo controls (0.398±0.22 vs 0.245 ±0.68 pmol/mg; p<0.05) and 20-HETE synthesis from arachidonic acid was increased by 17-fold (19.6±5.1 vs 1.18±0.14 pmol/min/mg, p<0.001). CYP4A2 mRNA levels were increased 15-fold and CYP4A8 mRNA levels were decreased by 60% in PMHAF rats compared to placebo controls (n=6/grp; p<0.05, PMHAF compared to placebo controls). In another group of rats, acute infusion of an inhibitor of 20-HETE synthesis, HET-0016 (10 mg/kg bolus and 1 mg/kg/h iv) reduced MAP by about 20 mm Hg in PMHAF rats. These data suggest that synthesis of 20-HETE in the vasculature is upregulated in PMHAF rats and contributes to their hypertension. The studies also suggest that novel mechanisms may be responsible for hypertension in PMW with hyperandrogenemia compared to age-matched men, and as such, novel therapeutic approaches may be necessary to control their blood pressures. Supported by PO1HL51971.