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Cardiovascular and metabolic responses to chronic central MC3/4R antagonism in obese Zucker rats

We examined if obese Zucker rats have elevated endogenous melanocortin system activation, independent of leptin's actions, which could contribute to elevated blood pressure in this model. The long‐term cardiovascular and metabolic effects of melanocortin‐3/4 receptor (MC3/4R) antagonism were assessed in lean and obese Zucker rats with leptin receptor mutations. Lean (n=6) and obese (n=5) Zucker rats were implanted with telemetry to measure blood pressure (BP) and heart rate (HR) 24‐hrs/day, and an intracerebroventricular (ICV) cannula was placed in the lateral ventricle. After control measurements, MC3/4R antagonist (SHU‐9119, 1 nmol/h, ICV) was infused for 10 days followed by a 5‐day recovery period. Chronic central MC3/4R antagonism caused significant increases in food intake and body weight in lean (20±1 to 45±2 g and 373±11 to 432±14 g) and obese (25±2 to 35±2 g and 547±10 to 604±11 g) Zucker rats. No significant changes were observed in plasma glucose levels in lean (97±4 to 103±6 mg/dl) or obese (105±3 to 111±5 mg/dl) Zucker rats. Chronic SHU‐9119 infusion in obese Zucker rats reduced MAP and HR by 6±1 mmHg and 24±5 bpm while in lean rats SHU‐9119 infusion only reduced HR by 31±9 bpm without altering MAP. These results suggest that obese Zucker rat have elevated endogenous melanocortin tone, independent of leptin receptor activation, which appear to contribute to their elevated blood pressure.