Chronic MC3/4R activation does not mimic the actions of leptin on baroreceptor sensitivity and heart rate regulation in diabetic rats

Abstract

We recently showed that leptin restores baroreflex sensitivity (BRS), cardiac sympathetic tone (CST) and intrinsic heart rate (IHR) in streptozotocin (STZ) diabetic rats. Since most actions of leptin require functional melanocortin 3 and 4 receptor (MC3/4R) signaling, we tested whether chronic MC3/4R activation with Melanotan II (MTII) mimics the cardiovascular actions of leptin in diabetic rats. After a 5‐day control period, STZ was injected to create diabetes. Seven days after STZ injection, an ICV infusion of MTII (10 ng/hr) was started and maintained for 10 days. MAP and HR (measured by telemetry), cardiac sympathetic‐vagal balance, IHR (measured after propranolol and atropine injections) and BRS (phenylephrine and sodium nitroprusside injections) were determined during control, 7 days after STZ injection and on the 7th day of MTII infusion. Animals were pair‐fed the same amount consumed by leptin treated rats from our previous studies. Chronic MTII infusion plus pair‐feeding failed to normalize blood glucose and the bradycardia caused by diabetes (∼400 mg/dl and −90 bpm) and did not restore IHR (337±6, 276±7 and 272±8 bpm, for control, diabetes, and MTII respectively), CST (−75±8, −47±10, −49±12 bpm) or BRS (−2.6±0.3, −1.7±0.3 and −1.9±0.3 bpm/mmHg) to normal values. These results suggest that chronic MC3/4‐R activation can be offset by compensatory mechanisms normally suppressed by leptin. (NHLBI, AHA