Effects of Hyperandrogenemia on Cardiovascular and Metabolic Responses to Chronic Melanocortin‐4 Receptor Blockade in Female SHR

Abstract

Hyperandrogenemia in females has been associated with sympathetic nervous system (SNS) activation and increased blood pressure (BP). We demonstrated that activation of the central nervous system (CNS) melanocortin system contributes to increases in SNS activity and BP in male spontaneously hypertensive rats (SHRs). We examined if chronic antagonism of melanocortin‐4 receptors (MC4R) attenuates elevated BP in female SHRs treated with dihydrostestosterone (DHT, 7.5 mg/90 days). Cardiovascular and metabolic effects of MC4R antagonism were assessed in female DHT‐treated SHR (n=8) and control untreated SHRs (n=7). At 15 weeks of age, the rats were implanted with telemetry probes to measure BP and heart rate (HR), and an intracerebroventricular (ICV) cannula was placed into the lateral ventricle for infusions. After control measurements, the MC4R antagonist (SHU‐9119) was infused (1 nmol/h, ICV) for 10 days followed by a 5‐day recovery period. MC4R 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). No changes were observed in blood glucose. Compared to controls, DHT‐treated SHRs had slightly higher BP, but lower HR (146±3 vs. 142±4 mmHg and 316±2 vs. 363±4 bpm). Chronic SHU‐9119 infusion reduced BP and HR in DHT‐treated SHR (‐12±2 mmHg and ‐14±4 bpm) and control SHR (‐19±2 mmHg and ‐21±6 bpm). These results indicate that MC4R antagonism reduces BP and HR despite marked increases in food intake and body weight in hyperandrogenemic and control female SHR, although the reductions in BP and HR were slightly attenuated in hyperandrogenemic SHR. (NHLBI‐PO1HL51971, NIGMS‐ P20GM104357 and AHA SDG5680016)