Nitric oxide modulation of the growth hormone-releasing activity of Hexarelin in young and old dogs

The growth hormone (GH)-releasing activity of Hexarelin, a potent GH-releas ing peptide (GHRP) analog, was evaluated in eight young (aged 1 to 6 years) and five old (10 to 16 years) beagle dogs pretreated with erythrityl tetra nitrate, a liposoluble nitric oxide (NO) donor, and/or indomethacin, an inh ibitor of cyclooxygenase enzymes, and N-nitro-L- or N-nitro-D-arginine meth ylester (L-NAME and D-NAME), active and inactive NO synthase (NOS) inhibito rs, respectively, Erythrityl tetranitrate (0.3 mg . kg(-1) oral [PO]) strik ingly potentiated Hexarelin-stimulated GH secretion (31.25 mu g . kg(-1) in travenous [IV]) in both young (area under the time-concentration curve at 0 to 90 minutes AUC(0.90)] 878.50 +/- 267.02 v 1,994.04 +/- 434.20 ng . mL(- 1) . h, P < .01) and aged animals (314.82 +/- 117.11 v 1,314.12 +/- 484.75 ng . mL(-1) . h, P < .01). The NO donor alone did not modify baseline GH le vels in either young dogs (188.68 +/- 85.24 ng . mL(-1) . h) or old dogs (1 20.49 +/- 22.03 ng . mL(-1) . h). L-NAME (5 mg . hg(-1) x 2 IV) suppressed GH release induced by the peptide in young dogs (1,367.68 +/- 251.87 v 411. 12 +/- 68.49 ng . mL(-1) . h, P < .01), but potentiated it in old dogs (314 .73 +/- 117.10 v 1,103.97 +/- 374.11 ng . mL(-1) . h, P < .01). D-NAME (5 m g . kg(-1) x 2 IV) did not affect the GH response to Hexarelin in either yo ung (1,328.68 +/- 433.54 ng . mL(-1) . h) or aged (342.32 +/- 84.82 ng . mL (-1) . h) dogs. Indomethacin (1.5 mg . kg(-1) IM) abolished the NO-donor po tentiation of the GH response induced by Hexerelin in both young dogs (1,62 7.25 +/- 260.90 v 1,163.37 +/- 334.84 ng . mL(-1) . h, P < .05) and old dog s (1,061.47 +/- 210.38 v 365.69 +/- 79.27 ng . mL(-1) . h, P < .01) without affecting the plasma GH peak evoked by the peptide alone (young dogs, 786. 04 +/- 153.44 v 960.04 +/- 444.44 ng . mL(-1) . h, P = NS; old dogs, 474.55 +/- 47.30 v 490.82 +/- 144.86 ng . mL(-1) . h, P = NS). In conclusion, (1) NO donors are capable to further increase the strong GH-releasing activity of Hexarelin in both young and old dogs, although the site(s) and mechanis m(s) of action of NO is still obscure; (2) the different GH response to the peptide after NOS inhibition in young and old dogs signifies in the latter an alteration of the somatotrope function; and (3) prostaglandins are the downstream effecters of the chain of events triggered by activation of the NO-ergic system. Copyright (C) 1999 by W.B. Saunders Company.