EFFECTS OF HISTAMINERGIC ANTAGONISTS ON THE GH-RELEASING ACTIVITY OF GHRH OR HEXARELIN, A SYNTHETIC HEXAPEPTIDE, IN MAN

The role of histamine in the neural control of GH secretion in man is still unclear, although a stimulatory influence has been hypothesized in man. To clarify this point, in 7 normal young women (23-28 yr) in t heir early follicular phase, we studied the effect of the histaminergi c blockade by diphenhydramine (DPH, 80 mg os at -60 min) on the GH res ponse to GHRH (2 mu g/kg iv) or Hexarelin (HEX, 2 mu g/kg iv), a synth etic hexapeptide with strong GH-releasing effect. In 6 of the 7 women the effect of terfenadine (TRF, 120 mg os at -60 min), another H1-rece ptor antagonist, on the GH response to GHRH or HEX was also studied. A s HEX has also PRL- and ACTH-releasing activity and histamine has been shown to have a stimulatory role in the neural control of these hormo nes, the effects of DPH or IRF on the HEX-induced PRL, ACTH and cortis ol release were also studied. GHRH induced a GH rise (peak, mean+/-SEM : 35.4+/-6.5 vs 2.5+/-1.1 mu g/l, p<0.02, n=7; 34.7+/-7.9 vs 3.9+/-1.5 mu g/l, p<0.02, n=6) lower p<0.05) than that elicited by HEX (49.1+/- 8.5 vs 3.9+/-1.0 mu g/l, p<0.01, n=7; 48.7+/-8.9 vs 3.2+/-0.8 mu g/l, p<0.01, n=6). DPH inhibited the GH response to both GHRH (AUC: 453.9+/ -104.7 vs 1223.7+/-202.6 mu gmin/l, p<0.05) and HEX (922.0+/-215.4 vs 1636.4+/-267.5 mu gmin/l, p<0.05), although the HEX-induced GH rise persisted higher than that induced by GH RH (p<0.05). TRF did not modi fy the GHRH-induced GH rise (950.5+/-369.2 mgmin/l vs 1115.3+/-255.6 mu gmin/l) as well as the somatotrope responsiveness to HEX (1163.2+/ -188.7 vs 1427.3+/-323.3 mgmin/l). HEX also significantly increased P RL (13.9+/-3.1 vs 6.5+/-0.8 mu g/l, p<0.03), ACTH (31.1+/-6.6 vs 16.6/-2.9 pg/ml, p<0.02) and cortisol (96.6+/-6.3 vs 82.2+/-6.2 mu g/L, p< 0.05) levels. PRL, ACTH and cortisol responses to HEX were unaffected by DPH (536.5+/-85.6 vs 599.5+/-129.2 mu gmin/l, 1068.5+/-306.0 vs 12 82.8+/-222.0 pgmin/ml and 4277.4+/-588.4 vs 4738.3+/-355.3 mu g*min/l , respectively) as well as by TRF (621.3+/-110.4 vs 530.3+/-131.4 mu g min/L, 972.4+/-189.6 vs 1060.2+/-224.7 pg*min/ml and 6203.8+/-1329.5 vs 5141.2+/-295.5 mu gmin/l, respectively). In conclusion, our findin gs are against the hypothesis of a major role of H1-receptor-mediated histaminergic influence on GH secretion in humans. In fact, the H1-his taminergic blockade by TRF does not affect the GH response to GHRH or HEX; the inhibitory effect of DPH may probably be due to its intrinsic anticholinergic activity. Our data also confirm that Hexarelin releas es more GH than GHRH and demonstrate that its effect on GH, PRL and AC TH release is not mediated by H1-receptors. (C) 1997, Editrice Kurtis.