EFFECTS OF REPEATED DOSES AND CONTINUOUS INFUSIONS OF THE GROWTH HORMONE-RELEASING PEPTIDE HEXARELIN IN CONSCIOUS MALE RATS

We have previously shown that hexarelin, a novel GH-releasing peptide (GHRP), is able to elicit GH release when administered i.v., s.c. or b y mouth and that it is a more potent GH secretagogue than GHRP-6. In t he current study, we investigated the effects of hexarelin administere d as repeated doses at 2h intervals or as a continuous 6, 30 or 174 h infusion to conscious male rats. In the first experiment, adult male S prague-Dawley rats were prepared with dual indwelling jugular catheter s. On the day of experimentation, these animals received three 25 mu g /kg i.v. boluses of hexarelin at 2 h intervals with blood sampling at 5, 10, 15, 30, 60, 90 and 120 min after each dose. The mean peak GH re sponse and the mean area under the GH response curve (AUC) for the 30 min after each administration were calculated and are reported as the mean +/- S.E.M. For both the peak and AUC results there was a signific ant (P<0.05) difference in the GH response noted between the first (pe ak 301 +/- 37 ng/ml; AUC 5585 +/- 700 ng/ml per 30 min) and second (pe ak 149 +/- 47 ng/ml; AUC 3056 +/- 908 ng/ml per 30 min) injections of hexarelin, but not between the first and third (peak 214 +/- 49 ng/ml; AUC 3862 +/- 844 ng/ml per 30 min). In a second series of experiments , adult male Sprague-Dawley rats received continuous infusions (100 mu g/h) of hexarelin or saline (1 ml/h) for 6, 30 or 174 h. Blood sample s were collected every 20 min for the duration of the 6 h infusion and for the last 6 h of the two longer hexarelin infusions. Plasma GH con centrations peaked within 40 min of the initiation of infusion, but so on returned to basal levels. Mean plasma GH concentrations did not dif fer between any of the treatment groups, nor did any of the parameters of pulsatile hormone release analyzed. No significant differences in plasma corticosterone concentrations were noted between any of the tre atment groups. On the other hand, while neither the 6 h (941 +/- 70 ng /ml) nor the 30 h (954 +/- 70 ng/ml) hexarelin infusions resulted in a significant increase in the plasma IGF-I concentrations over those no ted in the saline controls (935 +/- 65 ng/ml), a 174 h hexarelin infus ion did elicit a significant increase (1289 +/- 42 ng/ml; P<0.05). Thu s it appears that, while continuous exposure to hexarelin does not dis rupt normal GH cycling, it may (after up to 174 h of exposure) alter o ther components of the growth axis. In addition, since the character o f pulsatile GH release remained unaltered in response to the hexarelin infusion, it appears that this GHRP may not act by suppression of fun ctional somatostatin tone as has been suggested previously.