Endocrine, metabolic and cardioprotective effects of hexarelin in obese Zucker rats

Genetically obese male Zucker rats have an impaired secretion of GH, couple d to hyperinsulinemia, hyperlipidemia and glucose intolerance. The aim of t his study was to evaluate whether a chronic treatment with hexarelin, a syn thetic enkephalin-derived hexapeptide with a potent GH-releasing activity, might be able to ameliorate the somatotropic function and reverse some meta bolic alterations associated with obesity in male obese Zucker rats. Furthe rmore, as decreased GH secretion and insulin resistance are associated with increased cardiovascular risk, we also tested the capacity of hexarelin to prevent postischemic ventricular dysfunction in hearts of male obese Zucke r rats. Obese and lean male rats of the Zucker strain were treated with hex arelin (80 mug/kg, b.i.d., s.c.) or saline (1 ml/kg, b.i.d., s.c.) for 30 d ays. An acute hexarelin injection (80 mug, s.c.) at the 28th day of treatme nt elicited a rise in plasma GH levels in lean but not in obese rats (pretr eated or not with hexarelin); lean rats chronically treated with hexarelin showed a greater increase in plasma GH as compared with control counterpart s. At the end of the experiment, pituitary GH mRNA levels were significantl y reduced in obese rats and hexarelin administration failed to increase pit uitary GH mRNA and IGF-I concentrations in plasma and heart. Chronic treatm ent with hexarelin increased insulinemia and blood glucose levels in obese but not in lean rats, left ullaltered the high triglyceride levels but sign ificantly decreased plasma cholesterol concentrations in obese rats. Heart preparations from lean and obese Zucker rats treated with saline, subjected to low flow ischemia and reperfusion, showed at reperfusion: a) a low reco ver): of postischemic left ventricular developed pressure (LVDP), coupled t o a substantial increase in coronary perfusion pressure, and b) a marked in crease in creatine kinase released in the perfusates. Hexarelin administrat ion for 30 days counteracted the heart ischemic damage both ill lean and ob ese Zucker rats. In fact, the recovery of LVDP at reperfusion was significa ntly higher than in controls and the increase in coronary resistance was mi nimal. Collectively, these data indicate that a 30-day treatment with hexar elin was unable to improve somatotropic function in male obese Zucker rats but was successful in decreasing plasma cholesterol concentrations. Hexarel in exerted a cardioprotective effect in both lean and obese rats. The heart -protective activity afforded by the peptide was divorced from any stimulat ion of the GH axis and is probably exerted through activation of specific c ardiac receptors.