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Ezio Ghigo - One of the best experts on this subject based on the ideXlab platform.

  • hexarelin a synthetic gh releasing peptide is a powerful stimulus of gh secretion in pubertal children and in adults but not in prepubertal children and in elderly subjects
    Journal of Endocrinological Investigation, 1998
    Co-Authors: J Bellone, Emanuela Arvat, Romano Deghenghi, E Bartolotta, C Sgattoni, Gianluca Aimaretti, S Bellone, Ezio Ghigo
    Abstract:

    GH-releasing peptides (GHRPs) and their non-peptidyl mimetics are synthetic molecules which possess marked, dose-related and reproducible GH-releasing effect even after oral administration. Their potent stimulatory effect on GH secretion suggested that GHRP could be useful as provocative test on the diagnosis of GH deficiency. We compared the GH response to the maximal effective dose of Hexarelin (2 µg/kg iv), an hexapeptide belonging to GHRP family, with that of GHRH (1 µ/kg iv) alone and combined with arginine (ARG, 0.5 g/kg iv), which likely acts via inhibition of hypothalamic Somatostatin Release. We studied 6 prepubertal (4 boys and 2 girls, age 2.6–12.2 yr) and 6 pubertal children with normal short stature (3 boys and 3 girls, age 10.3–14.4 yr) as well as 12 normal young adults (6 males and 6 females, age 22–30 yr) and 12 normal elderly subjects (6 males and 6 females, age 53–79 yr). In prepubertal children, the GH response to HEX (19.0±4.6 µg/l; 611.5±121.4 µg/l/h) was lower than that to GHRH (27.4±12.7 µg/l; 1209.0±590.9 µg/l/h) but this difference did not attain statistical significance. Both these responses were, in turn, lower (p<0.05) than that to ARG+GHRH (57.9±15.1 µg/l; 2483.6±696.6 µg/l/h). In pubertal children, the GH response to HEX (67.6±12.7 µg/l; 2755.3±547.3 µg/l/h) was higher than that to ARG+GHRH (49.1±8.9 µg/l; 2554.1±356.6 µg/l/h) but this difference did not attain statistical significance; both these responses were, in turn, clearly higher (p<0.05) than that to GHRH alone (23.1±7.9 µg/l; 1004.8±214.3 µg/l/h). In young adults, the GH response to HEX 60.9±8.0 µg/l; 2401.0±376.2 µg/l/h) was similar to that to ARG+GHRH (68.9±11.7 µg/l; 3035.7±466.6 µg/l/h) and both were clearly higher (p<0.001) than that to GHRH alone (21.6±3.6 µg/l; 790.0±137.0 µg/l/h). In elderly subjects, the GH response to HEX (22.4±4.9; 855.0±199.0 µg/l/h) was higher (p<0.01) than that to GHRH (3.6±0.8 µg/l; 151.8±24.6 µg/l/h) but lower (p<0.05) than that to ARG+GHRH (48.1±4.6 µg/l; 1758.2±149.1 µg/l/h). In conclusion, GHRPs are a powerful stimulus of GH secretion in pubertal children and young adults only. On the other hand, the age-related variations in the GH response to GHRPs probably limit their reliability for the evaluation of GH releasable pool in prepubertal children and elderly subjects.

  • reduction of the somatotrope responsiveness to ghrh and hexarelin but not to arginine plus ghrh in hyperprolactinemic patients
    Journal of Endocrinological Investigation, 1997
    Co-Authors: Silvia Grottoli, Emanuela Arvat, F. Camanni, P Razzore, S E Oleandri, R Rossetto, E Ciccarelli, Ezio Ghigo
    Abstract:

    Aim of the present study was to verify the maximal secretory capacity of somatotrope cells in patients with pathological hyperprolactinemia (HPRL) comparing it with that in normal age-matched women (NW). To this goal in 12 HPRL normal weight patients (age 28.6±2.6 yr, BMI 23.1 ±1.1 kg/m2) and 8 NW (27.2±0.8 yr, 22.8±0.8 kg/m2) we studied the GH response to GHRH (1µg/kg iv), GHRH plus arginine (ARG, 0.5 g/kg iv), an amino acid probably acting at the hypothalamic level inhibiting Somatostatin Release, and Hexarelin (HEX, 2 µg/kg iv), a synthetic hexapeptide belonging to GHRP family, which acts concomitantly at the pituitary and the hypothalamic level. IGF-I levels in HPRL were similar to those in NW (179.2±16.5 µg/l and 218.5±30.8 µg/l). In NW the GH response to GHRH (AUC: 1299.5±186.9 µg.90 min/l) was lower (p<0.02) than those to GHRH+ARG (5252.7±846.3 µg.90 min/l) and HEX (3216.6±462.3 µg.90 min/l) which, in turn, were similar. In HPRL the GH response to GHRH (894.7±242.4 µg.90 min/l) was lower (p<0.03) than that to HEX (1586.5±251.3 µg.90 min/l) and both were lower (p<0.03) than that to GHRH+ARG (4468.8±941.7 µg.90 min/l). In HPRL the GH responses to GHRH and HEX were lower than those that in NW (p<0.03) while that to GHRH+ARG was similar in both groups. These results demonstrate that the somatotrope responsiveness to GHRH and HEX is clearly reduced in patients with pathological hyperprolactinemia. On the other hand, in this condition the GH response to GHRH+ARG is normal. As arginine likely acts via inhibition of hypothalamic Somatostatin Release, these findings show that the maximal secretory capacity of somatotrope cells in hyperprolactinemia is preserved and indicate that partial refractoriness of somatotrope cells to GHRH and HEX could be due to Somatostatinergic hyperactivity.

  • low hexarelin dose and pyridostigmine have additive effect and potentiate to the same extent the ghrh induced gh response in man
    Clinical Endocrinology, 1997
    Co-Authors: Emanuela Arvat, J Ramunni, F. Camanni, Romano Deghenghi, L Di Vito, L Gianotti, Roberta Giordano, Ezio Ghigo
    Abstract:

    OBJECTIVES: Hexarelin (HEX) is a synthetic hexapeptide belonging to the growth hormone-releasing peptide (GHRP) family. The exact mechanism underlying the strong GH-releasing activity of GHRPs is still unclear, though it has been shown that they act both at the pituitary and the hypothalamic level, where they have specific receptors. To clarify the influence of the cholinergic system on the GH-releasing activity of GHRPs in man, we investigated the effects of pyridostigmine, a cholinergic agonist which stimulates GH secretion by inhibiting Somatostatin Release, on the GH response to various HEX doses. DESIGN: We studied the GH Release induced by various HEX doses (0.25, 0.5 and 2.0 micrograms/kg i.v.) and pyridostigmine (PD, 120 mg po), both alone and coadministered. The interactions between the lowest HEX dose or PD and the maximally effective GHRH dose (1.0 microgram/kg i.v.) were also studied. SUBJECTS: Six normal male volunteers, aged 24-30 years, were studied. MEASUREMENTS: Serum GH was measured in duplicate by immunoradiometric assay. RESULTS: The GH response to HEX administration was dose-dependent. In fact, the GH response to 0.25 microgram/kg HEX (AUC, mean +/- SEM: 816.4 (235.6 mU/l/120 min) was lower, although not significantly, than that to 0.5 microgram/kg HEX (2154.6 +/- 491.6 mU/l/120 min), which, in turn, was lower (p < 0.05) than that after 2.0 micrograms/kg HEX (4819.2 +/- 668.0 mU/l/120 min). The GH rise after GHRH (1299.2 +/- 222.8 mU/l/120 min) was lower (P < 0.05) than that after 2.0 micrograms/kg HEX, but not different from the responses to either 0.25 or 0.5 microgram/kg HEX. PD induced a significant GH rise (559.0 +/- 129.8 mU/l/120 min, P < 0.05 vs saline), similar to that after 0.25 microgram/kg HEX, and lower than those after both 0.5 and 2.0 micrograms/kg HEX (P < 0.05 and p < 0.01, respectively) and GHRH (p < 0.05). PD pretreatment enhanced the GH response to the lowest HEX dose (1961.4 +/- 253.8 mU/l/120 min, p < 0.05) in an additive way, but failed to modify the GH response to either 0.5 or 2.0 micrograms/kg HEX (2753.6 +/- 444.6 and 5179.0 +/- 770.8 mU/l/120 min, respectively). Notably, the GH response to 0.25 microgram/kg HEX + PD was still lower (P < 0.05) than that to 2.0 micrograms/kg HEX. PD pretreatment as well as 0.25 microgram/kg HEX truly potentiated the GH response to GHRH to the same extent (4926.6 +/- 912.8 mU/l/120 min, p < 0.05 and 5958.8 +/- 750.0 mU/l/120 min, p < 0.05 respectively). The GH responses to PD + GHRH and 0.25 microgram/kg HEX + GHRH were similar to that after 2.0 micrograms/kg HEX alone. CONCLUSIONS: Our results demonstrate that pyridostigmine is able to enhance the GH response only to a very low dose Hexarelin which, in turn, potentiates the GHRH-induced GH rise to the same extent as pyridostigmine. As there is evidence that GHRPs do not inhibit hypothalamic Somatostatin Release, these findings are consistent with the hypothesis that they act by antagonizing Somatostatin activity and/or through unknown factors. On the other hand, though there is evidence showing that GHRH activity is needed for GHRP action, our findings indicate that GHRPs act, at least partially, independently of GHRH.

  • influence of beta adrenergic agonists and antagonists on the gh releasing effect of hexarelin in man
    Journal of Endocrinological Investigation, 1996
    Co-Authors: Emanuela Arvat, J Ramunni, Lori Divito, Laura Gianotti, F. Camanni, Romano Deghenghi, Ezio Ghigo
    Abstract:

    Beta-adrenergic receptors mediate the inhibitory influence of cathecolamines on GH secretion, probably via the stimulation of hypothalamic Somatostatin Release. Accordingly, beta-adrenergic agonists and antagonists inhibit and increase, respectively, the GH response to many stimuli, including GHRH, in man. Aim of the present study was to verify the effect, if any, of beta-adrenergic drugs on the GH response to Hexarelin, a synthetic GH-releasing hexapeptide. Interestingly, the GH-releasing effect of Hexarelin has been reported to be partially refractory to neuroendocrine manipulations known to strongly enhance or abolish the GHRH-induced GH Release. In 6 normal male volunteers (aged 22–27 yr) we studied the interaction of the maximally effective iv dose of Hexarelin (HEX, 2 μg/kg iv at 0 min) with atenolol (100 mg po at −60 min) or salbutamol (0.08 mg/kg po at - 60 min), which are beta-adrenergic antagonist and agonist, respectively. HEX induced a marked GH rise(AUC, mean ± SE: 4573.2±588.8 μg.min/L), which was unchanged by atenolol (4706.2±928.2 μg.min/L) but blunted by salbutamol (2792.8±618.0 μg.min/L, p<0.03). In conclusion, present data show that, in man, the GH-releasing effect of Hexarelin is not enhanced by beta-adrenergic blockade while is only blunted by the activation of beta receptors. According to other data, these results indicate that the potent GH-releasing activity of Hexarelin is, at least partially, refractory to beta-adrenergic-mediated manipulations of Somatostatinergic activity.

  • in obesity the somatotrope response to either growth hormone releasing hormone or arginine is inhibited by Somatostatin or pirenzepine but not by glucose
    The Journal of Clinical Endocrinology and Metabolism, 1995
    Co-Authors: Mauro Maccario, F. Camanni, Silvia Grottoli, P Razzore, S E Oleandri, M Procopio, Ezio Ghigo
    Abstract:

    It is known that spontaneous and stimulated GH secretion is reduced in obesity. On the other hand, it has been recently reported that, in obese subjects, plasma GH levels did not change during a hyperglycemic clamp. To further study the sensitivity of somatotrope cells to inhibitory influences in obesity, we studied the effect of Somatostatin, pirenzepine, or glucose on the GH response to GHRH or arginine in 32 obese patients and 30 controls. Basal GH levels were lower in obese than in normal subjects (1.0 +/- 0.6 vs. 4.8 +/- 0.7 micrograms/L, P < 0.05), while insulin-like growth factor-I levels were similar in both groups (137.3 +/- 13.2 vs. 138.8 +/- 12.2 micrograms/L). In obese as well as in control subjects pirenzepine abolished the GH response to either GHRH (AUC0-120: 43.7 +/- 9.6 vs. 258.3 +/- 59.9 micrograms/L/h, P < 0.04 and 113.0 +/- 75.0 vs. 870.5 +/- 255 micrograms/L.h, P < 0.01, respectively) or arginine (6.5 +/- 2.5 vs. 118.7 +/- 55.9 micrograms/L.h, P < 0.05 and 47.7 +/- 7.3 vs. 334.0 +/- 157.5 micrograms/L.h, P < 0.01, respectively). Differently from pirenzepine, glucose blunted the GH response to either GHRH or arginine in control subjects (260.8 +/- 38.3 vs. 479.5 +/- 83.9 micrograms/L.h, P < 0.03 and 294.8 +/- 46.3 vs. 625.1 +/- 139.1 micrograms/L.h, P < 0.05, respectively), but failed to modify it in obese patients (193.7 +/- 39.4 vs. 172.4 +/- 33.6 micrograms/L.h and 121.1 +/- 43.4 vs. 155.1 +/- 39.7 micrograms/L.h, respectively). On the other hand, Somatostatin deeply blunted the GHRH-induced GH Release in obese patients (58.5 +/- 25.4 vs. 548.7 +/- 196.6 micrograms/L.h, P < 0.05) as well as in controls (181.4 +/- 44.4 vs. 759.7 +/- 46.6 micrograms/L.h, P < 0.04). In conclusion, our results show that, in obesity, the stimulated GH Release is refractory to the inhibitory effect of glucose but not of pirenzepine, in spite of their likely common mechanism of action, i.e. increase of hypothalamic Somatostatin Release. Exogenous Somatostatin is able to abolish GH secretion both in normal and obese subjects. These data suggest the existence of a peculiar inhability of hyperglycemia to trigger Somatostatinergic Release in obesity.

Mauro Maccario - One of the best experts on this subject based on the ideXlab platform.

  • in obesity the somatotrope response to either growth hormone releasing hormone or arginine is inhibited by Somatostatin or pirenzepine but not by glucose
    The Journal of Clinical Endocrinology and Metabolism, 1995
    Co-Authors: Mauro Maccario, F. Camanni, Silvia Grottoli, P Razzore, S E Oleandri, M Procopio, Ezio Ghigo
    Abstract:

    It is known that spontaneous and stimulated GH secretion is reduced in obesity. On the other hand, it has been recently reported that, in obese subjects, plasma GH levels did not change during a hyperglycemic clamp. To further study the sensitivity of somatotrope cells to inhibitory influences in obesity, we studied the effect of Somatostatin, pirenzepine, or glucose on the GH response to GHRH or arginine in 32 obese patients and 30 controls. Basal GH levels were lower in obese than in normal subjects (1.0 +/- 0.6 vs. 4.8 +/- 0.7 micrograms/L, P < 0.05), while insulin-like growth factor-I levels were similar in both groups (137.3 +/- 13.2 vs. 138.8 +/- 12.2 micrograms/L). In obese as well as in control subjects pirenzepine abolished the GH response to either GHRH (AUC0-120: 43.7 +/- 9.6 vs. 258.3 +/- 59.9 micrograms/L/h, P < 0.04 and 113.0 +/- 75.0 vs. 870.5 +/- 255 micrograms/L.h, P < 0.01, respectively) or arginine (6.5 +/- 2.5 vs. 118.7 +/- 55.9 micrograms/L.h, P < 0.05 and 47.7 +/- 7.3 vs. 334.0 +/- 157.5 micrograms/L.h, P < 0.01, respectively). Differently from pirenzepine, glucose blunted the GH response to either GHRH or arginine in control subjects (260.8 +/- 38.3 vs. 479.5 +/- 83.9 micrograms/L.h, P < 0.03 and 294.8 +/- 46.3 vs. 625.1 +/- 139.1 micrograms/L.h, P < 0.05, respectively), but failed to modify it in obese patients (193.7 +/- 39.4 vs. 172.4 +/- 33.6 micrograms/L.h and 121.1 +/- 43.4 vs. 155.1 +/- 39.7 micrograms/L.h, respectively). On the other hand, Somatostatin deeply blunted the GHRH-induced GH Release in obese patients (58.5 +/- 25.4 vs. 548.7 +/- 196.6 micrograms/L.h, P < 0.05) as well as in controls (181.4 +/- 44.4 vs. 759.7 +/- 46.6 micrograms/L.h, P < 0.04). In conclusion, our results show that, in obesity, the stimulated GH Release is refractory to the inhibitory effect of glucose but not of pirenzepine, in spite of their likely common mechanism of action, i.e. increase of hypothalamic Somatostatin Release. Exogenous Somatostatin is able to abolish GH secretion both in normal and obese subjects. These data suggest the existence of a peculiar inhability of hyperglycemia to trigger Somatostatinergic Release in obesity.

  • metabolic modulation of the growth hormone releasing activity of hexarelin in man
    Metabolism-clinical and Experimental, 1995
    Co-Authors: Mauro Maccario, Michael Procopio, Vincent Lenaerts, Laura Gianotti, Bruno Pietro Imbimbo, Emanuela Arvat, F. Camanni, Silvia Grottoli, Romano Deghenghi, Ezio Ghigo
    Abstract:

    Hexarelin (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) is a new potent synthetic growth hormone (GH)-releasing hexapeptide. The mechanism of action of hexarelin in man has never been evaluated. Hexarelin may act directly on specific pituitary receptors and indirectly on the hypothalamus. To elucidate its mechanism of action in man, we studied the interaction of hexarelin with glucose and free fatty acids (FFA), two metabolic factors known to inhibit both basal and GH-releasing hormone (GHRH) stimulated GH secretion. Glucose is thought to inhibit GH secretion via stimulation of endogenous Somatostatin Release, whereas FFA could also act directly on somatotrope cells. Therefore, we investigated the effect of oral glucose (100 g) and lipid-heparin infusion (250 mL of a 10% lipid solution + 2,500 U heparin) on the GH response to a maximal dose (2 μg/kg intravenously [IV]) of hexarelin or GHRH in six normal men. Hexarelin elicited a clear-cut GH response (mean ± SEM; peak, 62.6 ± 8.0 μg/L) that was higher (P < .01) than that observed after GHRH (peak, 19.8 ± 2.4 μg/L). Although similar increases in plasma glucose were observed with the two peptides, oral glucose almost abolished the GH response to GHRH (peak, 5.6 ± 0.9 μg/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 38.4 ± 7.9 μg/L, P < .05). Similarly, lipid-heparin infusion nearly abolished the GH response to GHRH (peak, 4.9 ± 1.0 μg/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 34.2 ± 4.5 μg/L, P < .05). This study shows that hexarelin Releases more GH than GHRH and that it is more resistant than GHRH to the inhibitory effect of glucose or FFA. Its resistance to inhibitory influences could be due to antagonism of Somatostatinergic activity within the hypothalamus or directly at the pituitary level, although unknown mechanisms cannot be ruled out.

  • metabolic modulation of the growth hormone releasing activity of hexarelin in man
    Metabolism-clinical and Experimental, 1995
    Co-Authors: Mauro Maccario, Michael Procopio, Vincent Lenaerts, Bruno Pietro Imbimbo, Emanuela Arvat, F. Camanni, Silvia Grottoli, Romano Deghenghi, L Gianotti, Ezio Ghigo
    Abstract:

    Hexarelin (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) is a new potent synthetic growth hormone (GH)-releasing hexapeptide. The mechanism of action of hexarelin in man has never been evaluated. Hexarelin may act directly on specific pituitary receptors and indirectly on the hypothalamus. To elucidate its mechanism of action in man, we studied the interaction of hexarelin with glucose and free fatty acids (FFA), two metabolic factors known to inhibit both basal and GH-releasing hormone (GHRH) stimulated GH secretion. Glucose is thought to inhibit GH secretion via stimulation of endogenous Somatostatin Release, whereas FFA could also act directly on somatotrope cells. Therefore, we investigated the effect of oral glucose (100 g) and lipid-heparin infusion (250 mL of a 10% lipid solution + 2,500 U heparin) on the GH response to a maximal dose (2 μg/kg intravenously [IV]) of hexarelin or GHRH in six normal men. Hexarelin elicited a clear-cut GH response (mean ± SEM; peak, 62.6 ± 8.0 μg/L) that was higher (P < .01) than that observed after GHRH (peak, 19.8 ± 2.4 μg/L). Although similar increases in plasma glucose were observed with the two peptides, oral glucose almost abolished the GH response to GHRH (peak, 5.6 ± 0.9 μg/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 38.4 ± 7.9 μg/L, P < .05). Similarly, lipid-heparin infusion nearly abolished the GH response to GHRH (peak, 4.9 ± 1.0 μg/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 34.2 ± 4.5 μg/L, P < .05). This study shows that hexarelin Releases more GH than GHRH and that it is more resistant than GHRH to the inhibitory effect of glucose or FFA. Its resistance to inhibitory influences could be due to antagonism of Somatostatinergic activity within the hypothalamus or directly at the pituitary level, although unknown mechanisms cannot be ruled out.

F. Camanni - One of the best experts on this subject based on the ideXlab platform.

  • reduction of the somatotrope responsiveness to ghrh and hexarelin but not to arginine plus ghrh in hyperprolactinemic patients
    Journal of Endocrinological Investigation, 1997
    Co-Authors: Silvia Grottoli, Emanuela Arvat, F. Camanni, P Razzore, S E Oleandri, R Rossetto, E Ciccarelli, Ezio Ghigo
    Abstract:

    Aim of the present study was to verify the maximal secretory capacity of somatotrope cells in patients with pathological hyperprolactinemia (HPRL) comparing it with that in normal age-matched women (NW). To this goal in 12 HPRL normal weight patients (age 28.6±2.6 yr, BMI 23.1 ±1.1 kg/m2) and 8 NW (27.2±0.8 yr, 22.8±0.8 kg/m2) we studied the GH response to GHRH (1µg/kg iv), GHRH plus arginine (ARG, 0.5 g/kg iv), an amino acid probably acting at the hypothalamic level inhibiting Somatostatin Release, and Hexarelin (HEX, 2 µg/kg iv), a synthetic hexapeptide belonging to GHRP family, which acts concomitantly at the pituitary and the hypothalamic level. IGF-I levels in HPRL were similar to those in NW (179.2±16.5 µg/l and 218.5±30.8 µg/l). In NW the GH response to GHRH (AUC: 1299.5±186.9 µg.90 min/l) was lower (p<0.02) than those to GHRH+ARG (5252.7±846.3 µg.90 min/l) and HEX (3216.6±462.3 µg.90 min/l) which, in turn, were similar. In HPRL the GH response to GHRH (894.7±242.4 µg.90 min/l) was lower (p<0.03) than that to HEX (1586.5±251.3 µg.90 min/l) and both were lower (p<0.03) than that to GHRH+ARG (4468.8±941.7 µg.90 min/l). In HPRL the GH responses to GHRH and HEX were lower than those that in NW (p<0.03) while that to GHRH+ARG was similar in both groups. These results demonstrate that the somatotrope responsiveness to GHRH and HEX is clearly reduced in patients with pathological hyperprolactinemia. On the other hand, in this condition the GH response to GHRH+ARG is normal. As arginine likely acts via inhibition of hypothalamic Somatostatin Release, these findings show that the maximal secretory capacity of somatotrope cells in hyperprolactinemia is preserved and indicate that partial refractoriness of somatotrope cells to GHRH and HEX could be due to Somatostatinergic hyperactivity.

  • low hexarelin dose and pyridostigmine have additive effect and potentiate to the same extent the ghrh induced gh response in man
    Clinical Endocrinology, 1997
    Co-Authors: Emanuela Arvat, J Ramunni, F. Camanni, Romano Deghenghi, L Di Vito, L Gianotti, Roberta Giordano, Ezio Ghigo
    Abstract:

    OBJECTIVES: Hexarelin (HEX) is a synthetic hexapeptide belonging to the growth hormone-releasing peptide (GHRP) family. The exact mechanism underlying the strong GH-releasing activity of GHRPs is still unclear, though it has been shown that they act both at the pituitary and the hypothalamic level, where they have specific receptors. To clarify the influence of the cholinergic system on the GH-releasing activity of GHRPs in man, we investigated the effects of pyridostigmine, a cholinergic agonist which stimulates GH secretion by inhibiting Somatostatin Release, on the GH response to various HEX doses. DESIGN: We studied the GH Release induced by various HEX doses (0.25, 0.5 and 2.0 micrograms/kg i.v.) and pyridostigmine (PD, 120 mg po), both alone and coadministered. The interactions between the lowest HEX dose or PD and the maximally effective GHRH dose (1.0 microgram/kg i.v.) were also studied. SUBJECTS: Six normal male volunteers, aged 24-30 years, were studied. MEASUREMENTS: Serum GH was measured in duplicate by immunoradiometric assay. RESULTS: The GH response to HEX administration was dose-dependent. In fact, the GH response to 0.25 microgram/kg HEX (AUC, mean +/- SEM: 816.4 (235.6 mU/l/120 min) was lower, although not significantly, than that to 0.5 microgram/kg HEX (2154.6 +/- 491.6 mU/l/120 min), which, in turn, was lower (p < 0.05) than that after 2.0 micrograms/kg HEX (4819.2 +/- 668.0 mU/l/120 min). The GH rise after GHRH (1299.2 +/- 222.8 mU/l/120 min) was lower (P < 0.05) than that after 2.0 micrograms/kg HEX, but not different from the responses to either 0.25 or 0.5 microgram/kg HEX. PD induced a significant GH rise (559.0 +/- 129.8 mU/l/120 min, P < 0.05 vs saline), similar to that after 0.25 microgram/kg HEX, and lower than those after both 0.5 and 2.0 micrograms/kg HEX (P < 0.05 and p < 0.01, respectively) and GHRH (p < 0.05). PD pretreatment enhanced the GH response to the lowest HEX dose (1961.4 +/- 253.8 mU/l/120 min, p < 0.05) in an additive way, but failed to modify the GH response to either 0.5 or 2.0 micrograms/kg HEX (2753.6 +/- 444.6 and 5179.0 +/- 770.8 mU/l/120 min, respectively). Notably, the GH response to 0.25 microgram/kg HEX + PD was still lower (P < 0.05) than that to 2.0 micrograms/kg HEX. PD pretreatment as well as 0.25 microgram/kg HEX truly potentiated the GH response to GHRH to the same extent (4926.6 +/- 912.8 mU/l/120 min, p < 0.05 and 5958.8 +/- 750.0 mU/l/120 min, p < 0.05 respectively). The GH responses to PD + GHRH and 0.25 microgram/kg HEX + GHRH were similar to that after 2.0 micrograms/kg HEX alone. CONCLUSIONS: Our results demonstrate that pyridostigmine is able to enhance the GH response only to a very low dose Hexarelin which, in turn, potentiates the GHRH-induced GH rise to the same extent as pyridostigmine. As there is evidence that GHRPs do not inhibit hypothalamic Somatostatin Release, these findings are consistent with the hypothesis that they act by antagonizing Somatostatin activity and/or through unknown factors. On the other hand, though there is evidence showing that GHRH activity is needed for GHRP action, our findings indicate that GHRPs act, at least partially, independently of GHRH.

  • influence of beta adrenergic agonists and antagonists on the gh releasing effect of hexarelin in man
    Journal of Endocrinological Investigation, 1996
    Co-Authors: Emanuela Arvat, J Ramunni, Lori Divito, Laura Gianotti, F. Camanni, Romano Deghenghi, Ezio Ghigo
    Abstract:

    Beta-adrenergic receptors mediate the inhibitory influence of cathecolamines on GH secretion, probably via the stimulation of hypothalamic Somatostatin Release. Accordingly, beta-adrenergic agonists and antagonists inhibit and increase, respectively, the GH response to many stimuli, including GHRH, in man. Aim of the present study was to verify the effect, if any, of beta-adrenergic drugs on the GH response to Hexarelin, a synthetic GH-releasing hexapeptide. Interestingly, the GH-releasing effect of Hexarelin has been reported to be partially refractory to neuroendocrine manipulations known to strongly enhance or abolish the GHRH-induced GH Release. In 6 normal male volunteers (aged 22–27 yr) we studied the interaction of the maximally effective iv dose of Hexarelin (HEX, 2 μg/kg iv at 0 min) with atenolol (100 mg po at −60 min) or salbutamol (0.08 mg/kg po at - 60 min), which are beta-adrenergic antagonist and agonist, respectively. HEX induced a marked GH rise(AUC, mean ± SE: 4573.2±588.8 μg.min/L), which was unchanged by atenolol (4706.2±928.2 μg.min/L) but blunted by salbutamol (2792.8±618.0 μg.min/L, p<0.03). In conclusion, present data show that, in man, the GH-releasing effect of Hexarelin is not enhanced by beta-adrenergic blockade while is only blunted by the activation of beta receptors. According to other data, these results indicate that the potent GH-releasing activity of Hexarelin is, at least partially, refractory to beta-adrenergic-mediated manipulations of Somatostatinergic activity.

  • in obesity the somatotrope response to either growth hormone releasing hormone or arginine is inhibited by Somatostatin or pirenzepine but not by glucose
    The Journal of Clinical Endocrinology and Metabolism, 1995
    Co-Authors: Mauro Maccario, F. Camanni, Silvia Grottoli, P Razzore, S E Oleandri, M Procopio, Ezio Ghigo
    Abstract:

    It is known that spontaneous and stimulated GH secretion is reduced in obesity. On the other hand, it has been recently reported that, in obese subjects, plasma GH levels did not change during a hyperglycemic clamp. To further study the sensitivity of somatotrope cells to inhibitory influences in obesity, we studied the effect of Somatostatin, pirenzepine, or glucose on the GH response to GHRH or arginine in 32 obese patients and 30 controls. Basal GH levels were lower in obese than in normal subjects (1.0 +/- 0.6 vs. 4.8 +/- 0.7 micrograms/L, P < 0.05), while insulin-like growth factor-I levels were similar in both groups (137.3 +/- 13.2 vs. 138.8 +/- 12.2 micrograms/L). In obese as well as in control subjects pirenzepine abolished the GH response to either GHRH (AUC0-120: 43.7 +/- 9.6 vs. 258.3 +/- 59.9 micrograms/L/h, P < 0.04 and 113.0 +/- 75.0 vs. 870.5 +/- 255 micrograms/L.h, P < 0.01, respectively) or arginine (6.5 +/- 2.5 vs. 118.7 +/- 55.9 micrograms/L.h, P < 0.05 and 47.7 +/- 7.3 vs. 334.0 +/- 157.5 micrograms/L.h, P < 0.01, respectively). Differently from pirenzepine, glucose blunted the GH response to either GHRH or arginine in control subjects (260.8 +/- 38.3 vs. 479.5 +/- 83.9 micrograms/L.h, P < 0.03 and 294.8 +/- 46.3 vs. 625.1 +/- 139.1 micrograms/L.h, P < 0.05, respectively), but failed to modify it in obese patients (193.7 +/- 39.4 vs. 172.4 +/- 33.6 micrograms/L.h and 121.1 +/- 43.4 vs. 155.1 +/- 39.7 micrograms/L.h, respectively). On the other hand, Somatostatin deeply blunted the GHRH-induced GH Release in obese patients (58.5 +/- 25.4 vs. 548.7 +/- 196.6 micrograms/L.h, P < 0.05) as well as in controls (181.4 +/- 44.4 vs. 759.7 +/- 46.6 micrograms/L.h, P < 0.04). In conclusion, our results show that, in obesity, the stimulated GH Release is refractory to the inhibitory effect of glucose but not of pirenzepine, in spite of their likely common mechanism of action, i.e. increase of hypothalamic Somatostatin Release. Exogenous Somatostatin is able to abolish GH secretion both in normal and obese subjects. These data suggest the existence of a peculiar inhability of hyperglycemia to trigger Somatostatinergic Release in obesity.

  • metabolic modulation of the growth hormone releasing activity of hexarelin in man
    Metabolism-clinical and Experimental, 1995
    Co-Authors: Mauro Maccario, Michael Procopio, Vincent Lenaerts, Laura Gianotti, Bruno Pietro Imbimbo, Emanuela Arvat, F. Camanni, Silvia Grottoli, Romano Deghenghi, Ezio Ghigo
    Abstract:

    Hexarelin (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) is a new potent synthetic growth hormone (GH)-releasing hexapeptide. The mechanism of action of hexarelin in man has never been evaluated. Hexarelin may act directly on specific pituitary receptors and indirectly on the hypothalamus. To elucidate its mechanism of action in man, we studied the interaction of hexarelin with glucose and free fatty acids (FFA), two metabolic factors known to inhibit both basal and GH-releasing hormone (GHRH) stimulated GH secretion. Glucose is thought to inhibit GH secretion via stimulation of endogenous Somatostatin Release, whereas FFA could also act directly on somatotrope cells. Therefore, we investigated the effect of oral glucose (100 g) and lipid-heparin infusion (250 mL of a 10% lipid solution + 2,500 U heparin) on the GH response to a maximal dose (2 μg/kg intravenously [IV]) of hexarelin or GHRH in six normal men. Hexarelin elicited a clear-cut GH response (mean ± SEM; peak, 62.6 ± 8.0 μg/L) that was higher (P < .01) than that observed after GHRH (peak, 19.8 ± 2.4 μg/L). Although similar increases in plasma glucose were observed with the two peptides, oral glucose almost abolished the GH response to GHRH (peak, 5.6 ± 0.9 μg/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 38.4 ± 7.9 μg/L, P < .05). Similarly, lipid-heparin infusion nearly abolished the GH response to GHRH (peak, 4.9 ± 1.0 μg/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 34.2 ± 4.5 μg/L, P < .05). This study shows that hexarelin Releases more GH than GHRH and that it is more resistant than GHRH to the inhibitory effect of glucose or FFA. Its resistance to inhibitory influences could be due to antagonism of Somatostatinergic activity within the hypothalamus or directly at the pituitary level, although unknown mechanisms cannot be ruled out.

Emanuela Arvat - One of the best experts on this subject based on the ideXlab platform.

  • hexarelin a synthetic gh releasing peptide is a powerful stimulus of gh secretion in pubertal children and in adults but not in prepubertal children and in elderly subjects
    Journal of Endocrinological Investigation, 1998
    Co-Authors: J Bellone, Emanuela Arvat, Romano Deghenghi, E Bartolotta, C Sgattoni, Gianluca Aimaretti, S Bellone, Ezio Ghigo
    Abstract:

    GH-releasing peptides (GHRPs) and their non-peptidyl mimetics are synthetic molecules which possess marked, dose-related and reproducible GH-releasing effect even after oral administration. Their potent stimulatory effect on GH secretion suggested that GHRP could be useful as provocative test on the diagnosis of GH deficiency. We compared the GH response to the maximal effective dose of Hexarelin (2 µg/kg iv), an hexapeptide belonging to GHRP family, with that of GHRH (1 µ/kg iv) alone and combined with arginine (ARG, 0.5 g/kg iv), which likely acts via inhibition of hypothalamic Somatostatin Release. We studied 6 prepubertal (4 boys and 2 girls, age 2.6–12.2 yr) and 6 pubertal children with normal short stature (3 boys and 3 girls, age 10.3–14.4 yr) as well as 12 normal young adults (6 males and 6 females, age 22–30 yr) and 12 normal elderly subjects (6 males and 6 females, age 53–79 yr). In prepubertal children, the GH response to HEX (19.0±4.6 µg/l; 611.5±121.4 µg/l/h) was lower than that to GHRH (27.4±12.7 µg/l; 1209.0±590.9 µg/l/h) but this difference did not attain statistical significance. Both these responses were, in turn, lower (p<0.05) than that to ARG+GHRH (57.9±15.1 µg/l; 2483.6±696.6 µg/l/h). In pubertal children, the GH response to HEX (67.6±12.7 µg/l; 2755.3±547.3 µg/l/h) was higher than that to ARG+GHRH (49.1±8.9 µg/l; 2554.1±356.6 µg/l/h) but this difference did not attain statistical significance; both these responses were, in turn, clearly higher (p<0.05) than that to GHRH alone (23.1±7.9 µg/l; 1004.8±214.3 µg/l/h). In young adults, the GH response to HEX 60.9±8.0 µg/l; 2401.0±376.2 µg/l/h) was similar to that to ARG+GHRH (68.9±11.7 µg/l; 3035.7±466.6 µg/l/h) and both were clearly higher (p<0.001) than that to GHRH alone (21.6±3.6 µg/l; 790.0±137.0 µg/l/h). In elderly subjects, the GH response to HEX (22.4±4.9; 855.0±199.0 µg/l/h) was higher (p<0.01) than that to GHRH (3.6±0.8 µg/l; 151.8±24.6 µg/l/h) but lower (p<0.05) than that to ARG+GHRH (48.1±4.6 µg/l; 1758.2±149.1 µg/l/h). In conclusion, GHRPs are a powerful stimulus of GH secretion in pubertal children and young adults only. On the other hand, the age-related variations in the GH response to GHRPs probably limit their reliability for the evaluation of GH releasable pool in prepubertal children and elderly subjects.

  • reduction of the somatotrope responsiveness to ghrh and hexarelin but not to arginine plus ghrh in hyperprolactinemic patients
    Journal of Endocrinological Investigation, 1997
    Co-Authors: Silvia Grottoli, Emanuela Arvat, F. Camanni, P Razzore, S E Oleandri, R Rossetto, E Ciccarelli, Ezio Ghigo
    Abstract:

    Aim of the present study was to verify the maximal secretory capacity of somatotrope cells in patients with pathological hyperprolactinemia (HPRL) comparing it with that in normal age-matched women (NW). To this goal in 12 HPRL normal weight patients (age 28.6±2.6 yr, BMI 23.1 ±1.1 kg/m2) and 8 NW (27.2±0.8 yr, 22.8±0.8 kg/m2) we studied the GH response to GHRH (1µg/kg iv), GHRH plus arginine (ARG, 0.5 g/kg iv), an amino acid probably acting at the hypothalamic level inhibiting Somatostatin Release, and Hexarelin (HEX, 2 µg/kg iv), a synthetic hexapeptide belonging to GHRP family, which acts concomitantly at the pituitary and the hypothalamic level. IGF-I levels in HPRL were similar to those in NW (179.2±16.5 µg/l and 218.5±30.8 µg/l). In NW the GH response to GHRH (AUC: 1299.5±186.9 µg.90 min/l) was lower (p<0.02) than those to GHRH+ARG (5252.7±846.3 µg.90 min/l) and HEX (3216.6±462.3 µg.90 min/l) which, in turn, were similar. In HPRL the GH response to GHRH (894.7±242.4 µg.90 min/l) was lower (p<0.03) than that to HEX (1586.5±251.3 µg.90 min/l) and both were lower (p<0.03) than that to GHRH+ARG (4468.8±941.7 µg.90 min/l). In HPRL the GH responses to GHRH and HEX were lower than those that in NW (p<0.03) while that to GHRH+ARG was similar in both groups. These results demonstrate that the somatotrope responsiveness to GHRH and HEX is clearly reduced in patients with pathological hyperprolactinemia. On the other hand, in this condition the GH response to GHRH+ARG is normal. As arginine likely acts via inhibition of hypothalamic Somatostatin Release, these findings show that the maximal secretory capacity of somatotrope cells in hyperprolactinemia is preserved and indicate that partial refractoriness of somatotrope cells to GHRH and HEX could be due to Somatostatinergic hyperactivity.

  • low hexarelin dose and pyridostigmine have additive effect and potentiate to the same extent the ghrh induced gh response in man
    Clinical Endocrinology, 1997
    Co-Authors: Emanuela Arvat, J Ramunni, F. Camanni, Romano Deghenghi, L Di Vito, L Gianotti, Roberta Giordano, Ezio Ghigo
    Abstract:

    OBJECTIVES: Hexarelin (HEX) is a synthetic hexapeptide belonging to the growth hormone-releasing peptide (GHRP) family. The exact mechanism underlying the strong GH-releasing activity of GHRPs is still unclear, though it has been shown that they act both at the pituitary and the hypothalamic level, where they have specific receptors. To clarify the influence of the cholinergic system on the GH-releasing activity of GHRPs in man, we investigated the effects of pyridostigmine, a cholinergic agonist which stimulates GH secretion by inhibiting Somatostatin Release, on the GH response to various HEX doses. DESIGN: We studied the GH Release induced by various HEX doses (0.25, 0.5 and 2.0 micrograms/kg i.v.) and pyridostigmine (PD, 120 mg po), both alone and coadministered. The interactions between the lowest HEX dose or PD and the maximally effective GHRH dose (1.0 microgram/kg i.v.) were also studied. SUBJECTS: Six normal male volunteers, aged 24-30 years, were studied. MEASUREMENTS: Serum GH was measured in duplicate by immunoradiometric assay. RESULTS: The GH response to HEX administration was dose-dependent. In fact, the GH response to 0.25 microgram/kg HEX (AUC, mean +/- SEM: 816.4 (235.6 mU/l/120 min) was lower, although not significantly, than that to 0.5 microgram/kg HEX (2154.6 +/- 491.6 mU/l/120 min), which, in turn, was lower (p < 0.05) than that after 2.0 micrograms/kg HEX (4819.2 +/- 668.0 mU/l/120 min). The GH rise after GHRH (1299.2 +/- 222.8 mU/l/120 min) was lower (P < 0.05) than that after 2.0 micrograms/kg HEX, but not different from the responses to either 0.25 or 0.5 microgram/kg HEX. PD induced a significant GH rise (559.0 +/- 129.8 mU/l/120 min, P < 0.05 vs saline), similar to that after 0.25 microgram/kg HEX, and lower than those after both 0.5 and 2.0 micrograms/kg HEX (P < 0.05 and p < 0.01, respectively) and GHRH (p < 0.05). PD pretreatment enhanced the GH response to the lowest HEX dose (1961.4 +/- 253.8 mU/l/120 min, p < 0.05) in an additive way, but failed to modify the GH response to either 0.5 or 2.0 micrograms/kg HEX (2753.6 +/- 444.6 and 5179.0 +/- 770.8 mU/l/120 min, respectively). Notably, the GH response to 0.25 microgram/kg HEX + PD was still lower (P < 0.05) than that to 2.0 micrograms/kg HEX. PD pretreatment as well as 0.25 microgram/kg HEX truly potentiated the GH response to GHRH to the same extent (4926.6 +/- 912.8 mU/l/120 min, p < 0.05 and 5958.8 +/- 750.0 mU/l/120 min, p < 0.05 respectively). The GH responses to PD + GHRH and 0.25 microgram/kg HEX + GHRH were similar to that after 2.0 micrograms/kg HEX alone. CONCLUSIONS: Our results demonstrate that pyridostigmine is able to enhance the GH response only to a very low dose Hexarelin which, in turn, potentiates the GHRH-induced GH rise to the same extent as pyridostigmine. As there is evidence that GHRPs do not inhibit hypothalamic Somatostatin Release, these findings are consistent with the hypothesis that they act by antagonizing Somatostatin activity and/or through unknown factors. On the other hand, though there is evidence showing that GHRH activity is needed for GHRP action, our findings indicate that GHRPs act, at least partially, independently of GHRH.

  • influence of beta adrenergic agonists and antagonists on the gh releasing effect of hexarelin in man
    Journal of Endocrinological Investigation, 1996
    Co-Authors: Emanuela Arvat, J Ramunni, Lori Divito, Laura Gianotti, F. Camanni, Romano Deghenghi, Ezio Ghigo
    Abstract:

    Beta-adrenergic receptors mediate the inhibitory influence of cathecolamines on GH secretion, probably via the stimulation of hypothalamic Somatostatin Release. Accordingly, beta-adrenergic agonists and antagonists inhibit and increase, respectively, the GH response to many stimuli, including GHRH, in man. Aim of the present study was to verify the effect, if any, of beta-adrenergic drugs on the GH response to Hexarelin, a synthetic GH-releasing hexapeptide. Interestingly, the GH-releasing effect of Hexarelin has been reported to be partially refractory to neuroendocrine manipulations known to strongly enhance or abolish the GHRH-induced GH Release. In 6 normal male volunteers (aged 22–27 yr) we studied the interaction of the maximally effective iv dose of Hexarelin (HEX, 2 μg/kg iv at 0 min) with atenolol (100 mg po at −60 min) or salbutamol (0.08 mg/kg po at - 60 min), which are beta-adrenergic antagonist and agonist, respectively. HEX induced a marked GH rise(AUC, mean ± SE: 4573.2±588.8 μg.min/L), which was unchanged by atenolol (4706.2±928.2 μg.min/L) but blunted by salbutamol (2792.8±618.0 μg.min/L, p<0.03). In conclusion, present data show that, in man, the GH-releasing effect of Hexarelin is not enhanced by beta-adrenergic blockade while is only blunted by the activation of beta receptors. According to other data, these results indicate that the potent GH-releasing activity of Hexarelin is, at least partially, refractory to beta-adrenergic-mediated manipulations of Somatostatinergic activity.

  • metabolic modulation of the growth hormone releasing activity of hexarelin in man
    Metabolism-clinical and Experimental, 1995
    Co-Authors: Mauro Maccario, Michael Procopio, Vincent Lenaerts, Laura Gianotti, Bruno Pietro Imbimbo, Emanuela Arvat, F. Camanni, Silvia Grottoli, Romano Deghenghi, Ezio Ghigo
    Abstract:

    Hexarelin (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) is a new potent synthetic growth hormone (GH)-releasing hexapeptide. The mechanism of action of hexarelin in man has never been evaluated. Hexarelin may act directly on specific pituitary receptors and indirectly on the hypothalamus. To elucidate its mechanism of action in man, we studied the interaction of hexarelin with glucose and free fatty acids (FFA), two metabolic factors known to inhibit both basal and GH-releasing hormone (GHRH) stimulated GH secretion. Glucose is thought to inhibit GH secretion via stimulation of endogenous Somatostatin Release, whereas FFA could also act directly on somatotrope cells. Therefore, we investigated the effect of oral glucose (100 g) and lipid-heparin infusion (250 mL of a 10% lipid solution + 2,500 U heparin) on the GH response to a maximal dose (2 μg/kg intravenously [IV]) of hexarelin or GHRH in six normal men. Hexarelin elicited a clear-cut GH response (mean ± SEM; peak, 62.6 ± 8.0 μg/L) that was higher (P < .01) than that observed after GHRH (peak, 19.8 ± 2.4 μg/L). Although similar increases in plasma glucose were observed with the two peptides, oral glucose almost abolished the GH response to GHRH (peak, 5.6 ± 0.9 μg/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 38.4 ± 7.9 μg/L, P < .05). Similarly, lipid-heparin infusion nearly abolished the GH response to GHRH (peak, 4.9 ± 1.0 μg/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 34.2 ± 4.5 μg/L, P < .05). This study shows that hexarelin Releases more GH than GHRH and that it is more resistant than GHRH to the inhibitory effect of glucose or FFA. Its resistance to inhibitory influences could be due to antagonism of Somatostatinergic activity within the hypothalamus or directly at the pituitary level, although unknown mechanisms cannot be ruled out.

M C Aguila - One of the best experts on this subject based on the ideXlab platform.

  • growth hormone releasing factor increases Somatostatin Release and mrna levels in the rat periventricular nucleus via nitric oxide by activation of guanylate cyclase
    Proceedings of the National Academy of Sciences of the United States of America, 1994
    Co-Authors: M C Aguila
    Abstract:

    Abstract Previous work has shown that growth hormone-releasing factor (GRF) stimulates cGMP production and Somatostatin [somatotropin (growth hormone)-Release-inhibiting factor, SRIF] Release without altering cAMP accumulation by fragments of median eminence incubated in vitro. Therefore, this study was undertaken to evaluate the effect of GRF and cGMP on SRIF mRNA and SRIF Release in the periventricular nuclei of male rats in vitro. SRIF mRNA levels were determined in explants of periventricular nuclei incubated for 6 hr in Waymouth's medium in the presence of various substances. Steady-state levels of SRIF mRNA were measured by an S1 nuclease protection assay using a 32P-labeled rat SRIF RNA probe. SRIF Release and cGMP formation were measured at 30 min and 6 hr by RIA. SRIF mRNA levels and SRIF Release were significantly (P < 0.025) increased (approximately 2-fold) by 1 microM dibutyryl cGMP, whereas sodium butyrate had no effect. This augmentation was not influenced by cycloheximide, an inhibitor of protein synthesis. Sodium nitroprusside (10 microM), an activator of the guanylate cyclase pathway via its Release of nitric oxide, augmented (P < 0.001) SRIF mRNA levels and significantly increased (P < 0.05) SRIF Release. GRF (1 nM) increased SRIF mRNA (P < 0.001) and stimulated the Release of SRIF at 30 min (P < 0.05) and 6 hr (P < 0.01). This stimulation was abolished by 10 microM NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthase, but not by NG-monomethyl-D-arginine (D-NMMA, the inactive isomer). GRF also increased cGMP formation. This effect was completely blocked by incubation with L-NMMA but not D-NMMA. These results indicate that GRF Releases nitric oxide. The nitric oxide diffuses to the adjacent SRIF neurons, where it activates guanylate cyclase, leading to increased formation of cGMP. This cGMP increases SRIF mRNA and SRIF Release in the periventricular nuclei of male rats.

  • the influence of interleukin 2 on the Release of Somatostatin and growth hormone releasing hormone by mediobasal hypothalamus
    Neuroendocrinology, 1993
    Co-Authors: Sharada Karanth, M C Aguila, S M Mccann
    Abstract:

    Interleukin-2 (IL-2), which plays a major role in the bidirectional intercellular communication between the neuroendocrine and immune systems, suppressed the Release of GH from anterior pituitary halves at femtomolar concentrations. It is well established that the Release of GH from the anterior pituitary is regulated by growth hormone releasing hormone (GRH) and growth hormone Release-inhibiting hormone (Somatostatin). Consequently, we studied the possible effect of IL-2 on the Release of Somatostatin and GRH from the mediobasal hypothalamus (MBH) in vitro. Single MBHs were incubated with fresh Krebs-Ringer bicarbonate (KRB) buffer alone or KRB containing different concentrations of IL-2 (10–15–10–10M) for 30 min. After collection of the media, the MBHs were incubated with KRB containing high potassium (high K+ = 56 mM) without IL·2 for a period of 30 min to study the effect of pretreatment with IL-2 on depolarization-induced Somatostatin and GRH Release. Experiments were also undertaken to study the effect of IL-2 in the presence of high K+ or IL·2 in the presence of DA (60 µM), a potent stimulator of Somatostatin and GRH Release. The minimal effective dose of IL-2 which significantly stimulated the Release of Somatostatin was 10–14M. Depolarization-induced Release of Somatostatin was reduced significantly by prior treatment with all the concentrations of IL-2 tested (10–13–10–10M). Basal Release of GRH was unaltered by the different concentrations of IL-2 but the depolarization-induced Release of GRH was significantly lowered by IL-2 (10–13–10–10M). Simultaneous incubation with IL-2 plus high K+ resulted in a significant decrease in GRH Release without modifying the Release of Somatostatin. DA stimulated the Release of both Somatostatin and GRH; however, when IL-2 was added to DA, it significantly attenuated both DA-induced Somatostatin and GRH Release. The results demonstrate the ability of IL-2 to (1) stimulate Somatostatin Release without affecting GRH Release; (2) suppress depolarization induced Somatostatin Release; (3) suppress depolarization-induced GRH Release; and (4) block DA-induced stimulation of both Somatostatin and GRH Release, which suggests the possible involvement of a dopaminergic pathway in the mechanism of action of IL-2.