Early Inhibition of Angiotensin Converting Enzyme Abolishes the Androgen‐Mediated Blood Pressure Increase in a Model of PCOS

Abstract

Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in women, is characterized by androgen‐excess and ovarian dysfunction. PCOS is frequently associated with components of metabolic syndrome and increased blood pressure (BP). We previously characterized a rat experimental model in which chronic androgen‐excess initiated before puberty resembles many cardiometabolic abnormalities observed in PCOS women such as increased food intake (FI), body weight (BW), BP and activation of the intrarenal Renin Angiotensin System (RAS). In the present study, we tested the hypothesis that early RAS inhibition abolishes the androgen‐mediated BP increase in this model of PCOS.Female SD rats, 4 week‐old, were randomized to be implanted with DHT (dihydrotestosterone, 7.5 mg/90 days) or control pellets (n=5–8/group). Enalapril (ENA, 250mg/L), an angiotensin‐converting enzyme (ACE) inhibitor, was administered in the drinking water. Experiment 1 (Early RAS inhibition): a set of rats was randomized into control, DHT or DHT plus ENA (DHT+ENA) groups. ENA treatment was initiated at the time of DHT pellet implantation and continued for 3 months. Experiment 2 (Late RAS inhibition): a second set of rats was randomized into DHT and control groups for 6 months and co‐treated with ENA (DHT+ENA) for the last 2 weeks. FI, BW and BP (by radiotelemetry in conscious freely moving animals) were measured throughout the studies.Early RAS inhibition: DHT‐treated rats had increased daily FI (20 ± 1 vs 16 ± 1 g, p<0.05), BW (267 ± 3 vs 216 ± 2g, p<0.0001), and BP (115 ± 3 vs 98 ± 5 mmHg, p<0.0001) compared to controls. DHT+ENA ameliorated androgen‐mediated increase in FI (17 ± 1 vs 20 ± 1 g, p<0.05), BW (251 ± 2 vs 267 ± 3 g, p<0.0001), and abolished androgen‐mediated increase in BP (83 ± 1 vs 115 ± 3 mmHg, p<0.0001). Late RAS inhibition: DHT‐treated rats had increased BW (347 ± 14 vs 255 ± 7 g, p<0.0001) and BP (114 ± 1 vs 108 ± 0.5 mmHg, p<0.0001) than controls. ENA did not have effect on BW and caused a similar BP reduction in control and DHT‐treated rat; thereby, BP remained significantly higher in PCOS rats compared to controls (86 ± 1 vs 91 ± 1 mmHg, p<0.0001).In summary, early RAS inhibition exhibited beneficial effects on androgen‐induced obesity and abolished the androgen‐mediated increase in BP observed in this model of PCOS. In contrast, RAS inhibition after chronic androgen‐exposure had no effect on BW and failed to completely normalize BP in this experimental model of PCOS. Androgen‐induced activation of the RAS plays a major role in mediating increased BP in PCOS. This study shows that increased BP after chronic androgen‐excess becomes partially RAS independent. BP normalization in PCOS subjects should not be delayed to prevent the progression of androgen‐induced cardiovascular complications.Support or Funding InformationAHA 0830239N and 12SDG8980032, EFFERG, and NIH R21 DK‐113500 and P20 GM‐121334This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.