Genetically obese male Zucker rats have an impaired secretion of GH, coupled to
hyperinsulinemia,
hyperlipidemia and
glucose intolerance. The aim of this study was to evaluate whether a chronic treatment with
hexarelin, a synthetic
enkephalin-derived hexapeptide with a potent GH-releasing activity, might be able to ameliorate the somatotropic function and reverse some metabolic alterations associated with
obesity in male obese Zucker rats. Furthermore, 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 Zucker rats. Obese and lean male rats of the Zucker strain were treated with
hexarelin (80 microgram/kg, b.i.d., s.c.) or saline (1 ml/kg, b.i.d., s.c.) for 30 days. An acute
hexarelin injection (80 microgram, s.c.) at the 28th day of treatment elicited a rise in plasma GH levels in ! lean but not in obese rats (pretreated or not with
hexarelin); lean rats chronically treated with
hexarelin showed a greater increase in plasma GH as compared with control counterparts. At the end of the experiment, pituitary GH
mRNA levels were significantly reduced in obese rats and
hexarelin administration failed to increase pituitary GH
mRNA and
IGF-I concentrations in plasma and heart. Chronic treatment with
hexarelin increased insulinemia and
blood glucose levels in obese but not in lean rats, left unaltered the high
triglyceride levels but significantly 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 recovery of postischemic left ventricular developed pressure (LVDP), coupled to a substantial increase in coronary perfusion pressure, and b) a marked increase in
creatine kinase released in the perfusates. Hexare! lin administration for 30 days counteracted the heart ischemic damage both in lean and obese Zucker rats. In fact, the recovery of LVDP at reperfusion was significantly higher than in controls and the increase in coronary resistance was minimal. Collectively, these data indicate that a 30-day treatment with
hexarelin was unable to improve somatotropic function in male obese Zucker rats but was successful in decreasing plasma
cholesterol concentrations.
Hexarelin exerted a cardioprotective effect in both lean and obese rats. The heart-protective activity afforded by the
peptide was divorced from any stimulation of the GH axis and is probably exerted through activation of specific cardiac receptors.