Role of hypothalamic melanocortin3/4 receptors in mediating chronic cardiovascular, renal and metabolic actions of leptin. Hypertension

Abstract—The present study examined whether blockade of melanocortin receptors subtypes 3 and 4 (MC3/4-R) inhibits chronic cardiovascular and dietary responses to leptin infusion. A cannula was placed in the lateral ventricle of male Sprague-Dawley rats for chronic intracerebroventricular (ICV) infusion via osmotic minipump, and arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) and heart rate (HR) 24 h/d and IV infusions. After a 5-day control period, rats received (1) 0.9 % saline vehicle ICV for 12 days plus leptin (1 g/kg per minute IV, n5) during the final 7 days; (2) MC3/4-R antagonist SHU-9119 (1 nmol/h ICV) for 12 days plus leptin (1 g/kg per minute IV, n6) during the final 7 days; and (3) SHU-9119 (1 nmol/h ICV, n8) for 12 days. Leptin infusion in vehicle-treated rats caused a small increase in MAP (51 mm Hg) despite reduced food intake (231 to 101 g/d) and decreased body weight (6%1%). SHU-9119 infusion completely prevented the cardiovascular and dietary actions of leptin, leading to increased food intake (231 to 494 g/d) and body weight (30%2%), markedly decreased HR (779 bpm), and caused a decrease in MAP (61 mm Hg). Similar results were observed when SHU-9119 was infused alone in vehicle-treated rats. Leptin decreased plasma insulin to 30 % of control values, an effect that was also abolished by SHU-9119 treatment, which caused a 5-fold increase in plasma insulin concentration. Thus, MC3/4-R antagonism completely blocked the chronic cardiovascular, satiety, and metabolic effects of leptin, suggesting that the hypothalamic melanocortin system plays an important role in mediating these actions of leptin. (Hypertension. 2004