Eptastigmine augments basal and GHRH-stimulated growth hormone release in young and old dogs

Abstract

The aim of the present work was to evaluate the effect on the growth hormone (GH) secretion of eptastigmine, a new long-acting cholinesterase inhibitor, in unanesthetized beagle dogs. In a first study, 5 young dogs were given single doses (0.5, 1.0, and 2.0 mg/kg, i.m.) of the drug or saline in a randomized cross-over manner. Blood samples were collected immediately before and, at regular intervals, until 150 min after drug injection. GH plasma concentrations were determined by radioimmunoassay. Plasma cholinesterase activity was measured with a potentiometric method. There was a significant logistic relationship (r = 0.601, P<0.01) between the administered dose of eptastigmine and the log-transformed areas under the GH plasma concentration-time curve (AUC) with a calculated ED 50 for eptastigmine of 0.63±0.36 mg/kg. There was also a significant linear relationship (r = 0.630, P<0.01) between log-transformed AUC of GH levels and AUC of plasma cholinesterase activity. In a second study we evaluate the ability of eptastigmine (2.0 mg/kg, i.m.) to potentiate the GH-releasing effect of the GH-releasing hormone (GHRH, 2.0 μg/kg, i.v.) in young and old dogs. Eptastigmine was administered 45 min before GHRH and blood collected every 15 min until 90 min after GHRH injection. In young dogs, maximum GH plasma levels (C max) were 6.1±1.0 ng/ml after GHRH compared to 22.5±2.3 ng/ml after GHRH preceded by eptastigmine (P<0.01). In old animals, C max were 4.6±1.4 ng/ml after GHRH vs 13.2±7.4 ng/ml after combined administration of GHRH and eptastigmine (P<0.05). These data indicate that eptastigmine is very effective in augmenting basal and stimulated GH secretion in old dog. The good activity also shown in old animals suggests a potential use of this drug to reverse the age-dependent decline in GH secretion responsible for many involutional changes of aging.