Regulation of Blood Pressure, Appetite, and Glucose by CNS Melanocortin System in Hyperandrogenemic Female SHR

BACKGROUND Hyperandrogenemia in females may be associated with sympathetic nervous system (SNS) activation and increased blood pressure (BP). However the importance of hyperandrogenemia in causing hypertension in females and the mechanisms involved are still unclear. We tested whether chronic hyperandrogenemia exacerbates hypertension in young female spontaneously hypertensive rats (SHR) and whether endogenous melanocortin-3/4 receptor (MC3/4R) activation contributes to the elevated BP. METHODS Cardiovascular and metabolic effects of chronic MC3/4R antagonism were assessed in female SHR treated with dihydrotestosterone (DHT, beginning at 5 weeks of age) and placebo-treated female SHR. BP and heart rate (HR) were measured by telemetry and an intracerebroventricular (ICV) cannula was placed in the lateral ventricle for infusions. After control measurements, the MC3/4R antagonist (SHU-9119) was infused for 10 days (1 nmol/hour, ICV, at 15 weeks of age) followed by a 5-day recovery period. RESULTS MC3/4R antagonism increased food intake and body weight in DHT-treated SHR (14 +/- 1 to 35 +/- 1 g/day and 244 +/- 3 to 298 +/- 8 g) and controls (14 +/- 1 to 34 +/- 2 g/day and 207 +/- 4 to 269 +/- 8 g). Compared to untreated SHR, DHT-treated SHR had similar BP but lower HR (146 +/- 3 vs. 142 +/- 4 mm Hg and 316 +/- 2 vs. 363 +/- 4 bpm). Chronic SHU-9119 infusion reduced BP and HR in DHT-treated SHR (-12 +/- 2 mm Hg and -14 +/- 4 bpm) and control female SHR (-19 +/- 2 mm Hg and -21 +/- 6 bpm). CONCLUSION These results indicate that hyperandrogenemia does not exacerbate hypertension in female SHR. MC3/4R antagonism reduces BP and HR despite marked increases in food intake and body weight in hyperan-drogenemic and control female SHR.