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Biomedical subjects

E E Müller

Publications and source records attributed to E E Müller.

At least 19 recordsLinked to original sources
PubMed1998

Protectant activity of hexarelin or growth hormone against postischemic ventricular dysfunction in hearts from aged rats.

The ability of hexarelin, a recently synthesized hexapeptide with a strong growth hormone (GH)-releasing activity, or of GH itself to display a protectant activity against postischemic ventricular dysfunction in senescent hearts was studied in 24-month-old male rats. Heart preparations from control (saline-treated) senescent rats, subjected to moderate ischemia, showed at reperfusion: (a) a low recovery of postischemic left ventricular developed pressure (LVDP; 37% of the preischemic values; from 90 +/- 5.7 to 33.5 +/- 3.8 mm Hg; p < 0.01; n = 10) coupled to a substantial increase in coronary perfusion pressure (CPP; 71% over baseline; from 68.3 +/- 5.2 to 116.8 +/- 4.6 mm Hg; p < 0.01; n = 10); (b) a marked increase of creatine kinase (CK) released in the perfusates (6.6-fold increase over preischemic values; from 45 +/- 4 to 298 +/- 25 mU/min/g wet tissue; p < 0.001; n = 10). In vivo administration of hexarelin (80 microg/kg, b.i.d., s.c.) for 21 days resulted in a striking heart protection against reperfusion stunning. In fact, the recovery of LVDP at reperfusion was almost complete (90% of the preischemic values; from 93 +/- 5.8 to 83.7 +/- 5.9 mm Hg; p > 0.05; n = 9), and the increase in coronary resistance was minimal (from 67 +/- 5.8 to 79.7 +/- 6.9 mm Hg; p > 0.05; n = 9). Furthermore, the concentration of CK in the perfusates was increased only twofold (from 45.8 +/- 5.5 to 90 +/- 7.2 mU/min/g wet tissue; p < 0.05; n = 9), with a gradual return toward basal values at the end of reperfusion. The protectant activity of hexarelin was divorced from any detectable alteration of the somatotropic function, as assessed by pituitary GH messenger RNA (mRNA) and plasma insulin-like growth factor I levels. In vivo administration of GH (400 microg/kg b.i.d., s.c.) for the same time lapse resulted in only a partial protectant activity: 55% of LVDP recovery (from 91.5 +/- 6.2 to 50 +/- 3.5 mm Hg; p < 0.01; n = 6); 65% increase of coronary resistance (from 68 +/- 4.3 to 112.2 +/- 5.2 mm Hg; p < 0.01; n = 6); 5.3-fold increase of CK concentrations in heart perfusates on reperfusion (from 43.8 +/- 3.8 to 232 +/- 16 mU/min/g wet tissue; p < 0.001; n = 6). Evaluation of the rate of release of 6-keto-prostaglandin F1alpha (PGF1alpha), the stable metabolite of prostacyclin, in heart perfusates, and assessment of the vasopressor activity of angiotensin II on the coronary vasculature, did not show any change in these parameters among the three experimental groups. Collectively these data indicate that hexarelin displays a strong heart-protectant activity against myocardial stunning in senescent rats. The protection afforded by the peptide is likely due to a direct cardiotropic action and is far greater than that of GH. Neither compound appears able to interfere with the endothelium-dependent relaxant mechanism.

6-Ketoprostaglandin F1 alpha↗
PubMed1998

Intra- and postoperative myocardial ischemia without significant coronary artery stenosis.

A 73-year-old man without a history of coronary artery disease had two episodes of significant ST-segment elevation indicative of inferior myocardial ischemia during the resection of an abdominal aortic aneurysm. During the further course, sudden ST-segment elevations occurred and resolved spontaneously without preceding hemodynamic instability. The patient sustained two episodes of cardiac arrest due to ventricular fibrillation and intermittent third-degree atrioventricular block with ventricular asystole. On cardiac catheterization, coronary arteries had a right dominant pattern. The right coronary artery was entirely patent on multiple injections. Thus, right coronary artery spasm is the only possible explanation for these observations.

Aged↗
PubMed1998

Unexpected activation of pituitary-adrenal axis in healthy young and elderly subjects during somatostatin infusion.

In this study we explored, in man, the effect of acute attenuation of growth hormone (GH) release induced by somatostatin (SRIH) on ACTH and cortisol plasma levels. Sixteen young (8 women, aged 23-32 years, and 8 men, aged 18-27 years) and 14 elderly (8 women, aged 65-82 years, and 6 men, aged 65-70 years) healthy subjects volunteered to participate in this investigation. Each subject was tested on two separate occasions by: (1) a 90-min i.v. infusion of SRIH given in 50 ml 0.9% saline delivered at a rate of 9 microg/kg/h, and (2) a 90-min i.v. infusion of isovolumetric amounts of 0.9% saline. Plasma GH, ACTH, cortisol and glucose concentrations were determined prior and up to 180 min after SRIH or saline infusion. SRIH induced a significant (p < 0.05) decrease in plasma GH levels from basal values of 0.6 +/- 0.15 and 0.5 +/- 0.15 microg/l to nadir values 0.25 +/- 0.1 and 0.2 +/- 0.1 microg/l in young and elderly subjects, respectively. The administration of SRIH was associated with a clear-cut increase in plasma ACTH levels both in young (peak, 10.6 +/- 1.6 pmol/l; AUC, 558.6 +/- 147.5 pmol/l/h) and in elderly (peak, 21.3 +/- 5.6 pmol/l; AUC, 841.9 +/- 153.8 pmol/l/h) subjects with a significant (p < 0.01) difference as compared to saline infusion. Consistent with these results, SRIH infusion resulted in an unequivocal rise in plasma cortisol levels both in young (peak, 394.8 +/- 36.4 nmol/l; AUC, 18,591.62 +/- 1,372.45 nmol/l/h) and in elderly (peak, 585.6 +/- 51.5 nmol/l; AUC, 24,871.05 +/- 1,837.03 nmol/l/h) subjects. The ACTH and cortisol responses to SRIH were significantly (p < 0.05 and p < 0.01) higher in elderly than in young subjects. No sex-related differences occurred in the SRIH-induced activation of hypothalamic-pituitary-adrenocortical (HPA) axis. We conclude that (1) infusion of SRIH, at a dose that inhibited basal GH secretion, was associated with an activation of HPA axis, and (2) this response was higher in elderly individuals compared with younger adults. The reason for this novel and unexpected SRIH effect is presently unclear; however, the latter may be mediated, at least in part, by some central nervous system ACTH-releasing mechanisms activated by SRIH-induced decrease in GH secretion.

Adolescent↗
PubMed1998

Growth hormone responses to growth hormone-releasing hormone and hexarelin in fed and fasted dogs: effect of somatostatin infusion or pretreatment with pirenzepine.

Using unanesthetized young male and female beagle dogs, before and after a 2-day fast, we studied the effect of an i.v. infusion of 0.9% saline (5 ml/h), somatostatin (SS, 4 or 8 micrograms/kg/h), or pretreatment with pirenzepine (PZ, 0.6 mg/kg i.v.), a muscarinic cholinergic antagonist which allegedly releases SS, on the GH release evoked by acute administration of GHRH (2 micrograms/kg i.v.), hexarelin (HEXA), a member of the GH-releasing peptide family (250 micrograms/kg i.v.) or GHRH plus HEXA. In fasted dogs, GHRH delivered during saline infusion induced a clear-cut rise in plasma GH levels, significantly higher than that which it induced in fed dogs. In contrast, HEXA, although very effective in causing the release of GH, only slightly increased GH secretion in fasted dogs over that which it induced in fed dogs. Co-administration of GHRH plus HEXA into fed dogs induced a synergic GH response that further increased with fasting. The action of GHRH in fed dogs was abolished by the lower dose of SS, whereas SS at either dose was ineffective in suppressing the GH-releasing effect during fasting. Infusion of the lower dose of SS failed to counter the action of HEXA, either before or during fasting, whilst the higher SS dose partially reduced it in both conditions. In contrast to SS, PZ reduced the GH-releasing effect of GHRH and HEXA, both in the fed state and, though to a lesser extent, during fasting. Pirenzepine only slightly reduced the robust GH rise elicited by GHRH plus HEXA in fed dogs. The suppressive effect of PZ on the GH response to combined administration of the peptides was lowest in fasted dogs. These data show that: (1) fasting augmented the GH response to GHRH and (to a lesser degree) to HEXA; (2) SS inhibited the GH response to GHRH in the fed state, but not in the fasted state; (3) only the higher dose of SS partially reduced the GH stimulation by HEXA in either the fed or the fasted state; (4) PZ lowered the GH response to GHRH and to HEXA in both the fed and (to a lesser degree) the fasted state; (5) PZ did not modify the GH release due to the combined administration of GHRH and HEXA. It is suggested that: (1) during fasting the greatly enhanced GH response to GHRH alone or GHRH plus HEXA probably reflects an augmented GHRH secretion; (2) somatotrope refractoriness to SS may contribute to the enhanced GH secretion in states of calorie deprivation; (3) in contrast to a general belief, muscarinic cholinergic antagonists, e.g. PZ, do not act exclusively via release of SS, but probably also through inhibition of GHRH function.

Analysis of Variance↗
PubMed1997

Cardiac ischemia and impairment of vascular endothelium function in hearts from growth hormone-deficient rats: protection by hexarelin.

The ability of hexarelin, an effective growth hormone (GH)-releasing hexapeptide, to reverse the worsening of cardiac dysfunction in GH-deficient animals was studied in young male rats passively immunized by administration of an anti-GH-releasing hormone (GHRH) serum. Heart preparations from anti-GHRH serum-treated rats, undergoing low-flow ischemia and reperfusion, showed: (1) a progressive increase of left ventricular end-diastolic pressure during the ischemic period and a poor recovery of contractility at reperfusion with a consistent decrease of the left ventricular-developed pressure; (2) a decreased rate of formation of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), a stable metabolite of prostacyclin, in perfusates from preischemic and reperfusion periods; (3) an increased vasopressor activity of angiotensin II. Hexarelin (80 microg/kg, bid, s.c.), administered for 15 days to anti-GHRH serum-treated rats, restored to normal the impaired somatotropic function and counteracted the ischemic damage, improving postischemic left ventricular developed pressure to values higher than those of controls. Furthermore, both the generation of 6-keto-PGF1alpha and the vasopressor activity of angiotensin II reverted to those of control preparations. Administration of hexarelin to control rats induced a considerable improvement of postischemic ventricular function of the perfused hearts which was similar to that present in preparations from anti-GHRH serum-treated rats given hexarelin. This protective activity was divorced from any further stimulation of somatotropic function. Collectively, these data indicate that, in GH-deficient rats, hexarelin is capable of restoring somatotropic function and has a beneficial effect in myocardial ischemia and reperfusion damage. In addition, the increased responsiveness of the coronary vasculature to angiotensin II and the decreased generation of prostacyclin in hearts from GH-deficient rats would indicate that for prevention of injury and dysfunction of the vascular endothelium a normal somatotropic function is mandatory.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Effect of long-term administration of Hexarelin on the somatotrophic axis in aged rats.

The growth hormone-releasing peptide Hexarelin (Hexa; 80 micrograms/kg-1, s.c.) was administered for 30 and 60 days to old rats. The GH-releasing effect of Hexa was maintained during chronic treatment. At the end of the treatment, old rats were administered once with Hexa which elicited a greater GH response in rats chronically treated with the peptide than in those receiving a placebo. Pituitary GHmRNA concentrations were significantly lower in the older rats than in the younger animals, irrespective of Hexa treatment, while the GH protein content was similar in all the groups studied. The same was true for hypothalamic GHRH, whose synthesis was reduced in all the older animals but not in the young, in the presence of maintained concentrations of the peptide. Somatostatin mRNA concentrations were significantly higher in the hypothalami of older rats and administration of Hexa for 30 or 60 days brought the concentrations of somatostatin mRNA of aged rats to 'young' levels. Treatments with Hexa failed to alter the circulating levels of IGF-1. The data reported in this article indicate that long-term treatment with Hexa normalized some biological indices of somatotrophic function in aged rats.

Aging↗
PubMed1997

Effects of GH and IGF-I administration on GHRH and somatostatin mRNA levels: I. A study on ad libitum fed and starved adult male rats.

The individual role played by GH and IGF-I in the regulation of hypothalamic GHRH and SRIF gene expression is still object of debate. We have investigated the effect of exogenously administered recombinant hGH (rhGH) and recombinant hIGF-I (rhIGF-I) in ad libitum fed control and starved rats, the latter an animal model which is characterized by low circulating levels of endogenous GH and IGF-I. Adult male rats were fed ad libitum (C) or food-deprived (S) for 72 hours; rats in either C or S groups were treated with systemic administration of rhGH and rhIGF-I for 3 days. GHRH, SRIF and GH mRNA levels were evaluated by Northern and slot blot hybridization. Administration of rhGH (250 micrograms/kg/twice daily, sc) induced a significant inhibition of GHRH and a significant stimulation of SRIF mRNA levels in C rats; GH treatment was, however, ineffective on both neuropeptide mRNA levels in the S group. Continuous infusion of rhIGF-I (300 micrograms/kg/day, sc) induced a significant increase of SRIF levels in both C and S rats but did not modify GHRH mRNA levels in either group. In the pituitary, GH mRNA levels followed a pattern very similar to that of GHRH. These results provide evidence for a direct role of GH in the inhibition of GHRH mRNA levels; IGF-I appears more involved in the direct stimulation of SRIF mRNA levels.

Animals↗
PubMed1997

Effects of GH and IGF-I administration on GHRH and somatostatin mRNA levels: II. A study in the infant rat.

It is generally accepted that growth hormone influences its own secretion by modulating the activity of GHRH and SRIF neurons. To investigate if GH feedback mechanisms are already operating in the early postnatal life of the rat, we have studied in 10-day-old pups the effects of rhGH and rhIGF-I administration on GHRH and somatostatin mRNA levels. The same experiment was also performed in pups passively immunized with an anti-GHRH antiserum from the day of birth. The latter animal model had been previously characterized for presenting reduced levels of circulating GH and IGF-I. In control pups, neither rhGH (250 micrograms/kg, b.i.d., sc) nor rhIGF-I (150 micrograms/kg, b.i.d., sc) administration induced significant changes of GHRH and SRIF gene expression. The passive immunization against GHRH induced per se a trend toward an increase and a reduction of GHRH and SRIF mRNA levels, respectively. Also in these rats the treatment for 3 days with rhGH and rhIGF-I did not further modify the GHRH and SRIF mRNA levels. Based on these results, we conclude that in the 10-day-old rat GH feedback mechanisms are poorly operative, though a direct ultra-short loop mechanism involving the GHRH and SRIF systems seems already operating.

Animals↗
PubMed1997

[Reproducibility and validity of a new automatic method of specular microscopy analysis of corneal endothelium].

PURPOSE: This prospective study was designed to test the reproducibility of a new automated technique for analyzing the corneal endothelium and to assess the validity of the technique by comparing it with a standard method. SUBJECTS AND METHODS: We used a contact specular microscope combined with a video camera (Tomey EM-1000) and a computer (IBM compatible PC, 486DX33) with suitable software (Tomey EM-1100, version 0.94). Video images of the corneal endothelium (area: 0.312 mm2) were passed directly into the computer input by means of a frame grabber and were automatically processed. The area to be analyzed could be varied by location and size (5580-135,150 microns2), depending on the quality of the image. Healthy corneas of 67 volunteers (age: 30.9 +/- 8.6 years) were examined. One examiner measured cell density three times in each of 42 eyes (retest-stability); three different examiners made one measurement in each of 25 eyes (objectivity). We evaluated the cell density determined by the computer after automated analysis and assessed the corrected cell density. This second result was obtained after the examiner had corrected the processed image by drawing in cell boundaries that the computer had not recognized or erasing cell boundaries the computer had sketched in by mistake. Additionally, a photograph of the corneal endothelium (specular microscope Bio Optics LSM 2000 A) was obtained from 40 volunteers to be used for manual cell counting applying a "fixed-frame" technique (validity). RESULTS: The corrected values showed a high retest-stability (reliability coefficient r = 0.943) and a high objectivity (r = 0.904). The values obtained by the automated method (2415 +/- 214 cells/mm2) did not differ significantly from those obtained by manual cell counting (2431 +/- 228 cells/mm2) (P = 0.898). The uncorrected values (2252 +/- 190 cells/mm2) were on average 7.2 +/- 2.6% lower than the corrected ones (177 +/- 69 cells/mm2). Retest-stability (r = 0.856) and objectivity (r = 0.737) of the uncorrected values were satisfactory. The uncorrected value was significantly lower than the value of manual cell counting (P < 0.001). The size of the analyzed area (range 12,750-84,708 microns2; average 31,438 +/- 10,655 microns2) had no significant effect on cell density (Spearman's correlation coefficient k = -0.150, P = 0.093). CONCLUSION: The automated method for analyzing the corneal endothelium quickly produces valid, reproducible results in normal corneas, provided that the correction mode of the software is applied.

Endothelium, Corneal↗
PubMed1997

Hypothalamo-pituitary-IGF-1 axis in female rats made obese by overfeeding.

A gender-related impairment of the somatotrophic axis is present in obese Zucker rats, female rats being better preserved than males. We showed that another animal model of obesity, i.e., male rats made obese by feeding a hypercaloric diet had a reduced function of somatotrophic axis which was likely related to impairment of gonadal function. Aim of this work was that of studying the function of somatotrophic axis in female overfed rats and comparing it to that of male rats of the previous study. Sprague-Dawley female rats were fed an energy-rich palatable diet for seven months. At the end of overfeeding, according to the degree of overweight, rats were divided into overtly obese (Obese), overweight (Overweight) and Non-Obese, i.e. rats whose weights were similar to those of controls. Rats fed ad libitum with the standard pellet chow served as controls (Controls). Acute administration of a supramaximal dose of GHRH (2 microg/rat, iv) elicited a plasma GH rise similar to that of Controls in all the groups, except in Obese which had a lower GH response. Growth hormone responses after GHRH administration were inversely related to plasma levels of free fatty acids (FFA). Pituitary GH content and gene expression as well as hypothalamic GHRH and SS mRNA content, were similar in all experimental groups and in Controls and the same was true for plasma concentrations of free IGF-I. These results indicate that, similarly to obese female Zucker rats, also overfed female rats had a better preservation of the somatotrophic axis than their male counterparts. In diet-induced obese rats, also the etiology of the impairment of somatotrophic axis seems to be gender-related i.e. due to a reduction of gonadal function in males and to an elevation of FFA in females.

Animals↗
PubMed1997

Hexarelin stimulation of growth hormone release and mRNA levels in an infant and adult rat model of impaired GHRH function.

Hexarelin, a GH-releasing peptide, is an effective GH secretagogue in man and a variety of experimental animals. In the present study, we sought to characterize the effects of short-term Hexarelin treatment on GH release and GH mRNA levels in infant and young-adult rats and in rats of either age passively immunized with an antiserum against GHRH (GHRH-Ab). Hexarelin (80 micrograms/kg, b.i.d. s.c.), administered for 3, 5 or 10 days to 8-, 6- and 1-day-old rats, respectively, induced a progressive enhancement of the plasma GH rise elicited by a subsequent acute Hexarelin (80 micrograms/kg s.c) challenge when pups were 10 days old. As expected, GHRH-Ab treatment decreased GH concentrations in 10-day-old pups. In GHRH-Ab-treated pups, Hexarelin administration for 3-10 days significantly enhanced the GH response to the acute Hexarelin injection, though the mean plasma GH values remained significantly lower than in the respective control group. Hexarelin treatment did not alter GH mRNA levels in control pups. In GHRH-Ab-treated pups Hexarelin treatment for 3 and 5 days, but not 10 days, restored GH mRNA levels to control values. In young-adult male rats, regardless of antiserum treatment, Hexarelin administration for 5 or 10 days significantly suppressed the GH response to a subsequent acute challenge with the peptide. Yet, 5-10 days of Hexarelin treatment did not alter GH mRNA in control young-adult rats. In adult rats GHRH-Ab also decreased GH mRNA levels, but 10 days of Hexarelin treatment were necessary to return GH mRNA back to normal levels. These results indicate that: (1) the effects of Hexarelin on GH release and GH mRNA levels may be unrelated events; (2) deprivation of GHRH function discloses the ability of Hexarelin to stimulate GH mRNA levels; (3) age plays a crucial role in setting the pituitary responsiveness to short-term Hexarelin treatment, and (4) the different ability of Hexarelin to stimulate GH release and GH synthesis in neonatal and young-adult rats may have clinical relevance in the chronic administration of the peptide.

Aging↗
PubMed1997

Defective hypothalamic growth hormone (GH)-releasing hormone activity may contribute to declining GH secretion with age in man.

There is evidence that withdrawal of SRIH infusion in man promotes a rebound GH response that allegedly has been proposed to be related to the function of GHRH-producing neurons. In the present study we have evaluated whether a reduction in endogenous GHRH activity contributes to the decreased GH secretion of the elderly. Sixteen young (8 women, aged 23-32 yr, and 8 men, aged 18-27 yr) and 13 elderly (8 women, aged 65-82 yr, and 5 men, aged 65-70 yr) healthy subjects volunteered to participate in this investigation. Each subject was tested on 2 separate occasions: 1) a 90-min iv infusion of SRIH was given in 50 mL 0.9% saline delivered at a rate of 9 micrograms/kg.h; and 2) a 90-min iv infusion of isovolumetric amounts of 0.9% saline was given. Plasma GH levels were determined before and up to 180 min after SRIH or saline infusion, whereas plasma insulin-like growth factor I, estradiol, and testosterone levels were measured in basal samples. In elderly women, the mean maximum (delta) GH peak (2 +/- 0.7 micrograms/L) after withdrawal of SRIH infusion was significantly (P < 0.02) lower than that in young women (7.3 +/- 2 micrograms/L). In elderly men, the mean delta GH peak (2.9 +/- 0.6 micrograms/L) after withdrawal of SRIH infusion was lower than that in young men (6.3 +/- 1.6 micrograms/L), although the difference failed to achieve statistical significance. Baseline insulin-like growth factor I levels were significantly lower in elderly compared to young subjects in both men and in women. In women, both age and basal plasma estradiol and testosterone levels significantly correlated with delta GH peak after SRIH withdrawal (r = -0.61, r = 0.61, and r = 0.66, respectively), whereas in men they did not. These findings are compatible with the view that an age-related decrease in endogenous GHRH function may contribute to the defective GH secretion of the elderly. Alterations in plasma concentrations of sex steroids may have important implications in the observed changes.

Adolescent↗
PubMed1997

Hexarelin, a growth hormone-releasing peptide, discloses protectant activity against cardiovascular damage in rats with isolated growth hormone deficiency.

The ability of hexarelin, a recently synthesized hexapeptide with a remarkable growth hormone (GH)-releasing activity, to reverse signs of cardiovascular dysfunction in GH-deficient animals was studied in young male rats made GH deficient by the administration of an anti-GH-releasing hormone serum (GHRH-Ab) for 20 days. Heart preparations from GHRH-Ab treated rats, subjected to low-flow ischemia and reperfusion, showed: a progressive increase of left ventricular end-diastolic pressure during the ischemic period and a poor recovery of contractility at reperfusion as compared to control hearts; a decreased rate of formation of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin, in perfusates of both preischemic and reperfusion period; an increased vasopressor activity of angiotensin II on the coronary vasculature. The endothelium-dependent relaxing function in GH-deficient rats was also evaluated in aortic ring preparations, which showed: a decreased rate of formation of 6-keto-PGF1 alpha, an hyperreactivity to endothelin-1, a markedly reduced vasopressor response to NG-monomethyl-L-arginine (the nitric oxide synthase inhibitor) and a decreased vasodilator response to acetylcholine of precontracted aortic tissue. Hexarelin (80 micrograms/kg, s.c. twice daily), administered for 15 days to GHRH-Ab-treated rats, fully restored the somatotropic function and reversed all the signs of cardiac and endothelial dysfunction. In fact, in heart preparations from rats treated with hexarelin the trend of the ischemic damage was similar to that observed in control rats and both the rate of formation of 6-keto-PGF1 alpha and the vasopressor activity of angiotensin II were reverted to control levels. Furthermore, all the parameters of endothelial function were in the normal range. These results indicate that GH deficiency in rats is responsible for an impairment of cardiac function that is associated with a damage of the endothelium-dependent relaxing function not limited to coronary vessels but widespread in the circulation. These alterations are fully reverted by an in vivo treatment with hexarelin.

Animals↗
PubMed1996

Aspects of the neuroendocrine control of somatotropic function in calorically restricted dogs and patients with eating disorders: studies with cholinergic drugs.

A series of studies was devised in both an experimental model of food deprivation, i.e., beagle dogs undergoing a progressive reduction of calorie intake and adolescent females with anorexia nervosa (AN) in the acute and recovery phase, and in patients with atypical eating disorders. The studies were aimed at ascertaining whether the alleged function of the hypothalamic system inhibitory to growth hormone (GH) secretion, i.e., the somatostatinergic, may account for at least some of the abnormalities of GH secretion present in AN patients (e.g., elevated basal GH levels, paradoxical GH rise after glucose or thyrotropin releasing hormone, etc). Caloric restricted dogs or patients with eating disorders were given an intravenous injection of the physiologic GH-releasing peptide GHRH alone or preceded by pirenzepine, a muscarinic cholinergic antagonist reportedly capable of eliciting hypothalamic release of somatostatin (SS), or pyridostigmine, a muscarinic cholinergic agonist which, conversely, would restrain hypothalamic release of SS. In addition, dogs were challenged with acute administration of glucose or thyrotropin-releasing hormone, compounds also thought to act via somatostatinergic influences. Data obtained in dogs under caloric restriction or in AN patients in the acute phase of the disease with drugs affecting cholinergic transmission suggest that the latter is increased in both conditions (only partial suppression of the GHRH-induced GH rise with pirenzepine, failure of pyridostigmine to further enhance the GH response to GHRH). Instead, in the same AN patients in the acute phase tested during recovery, in AN patients during the recovery phase, and in patients with atypical eating disorders, pirenzepine completely suppressed the GH response to GHRH, as it did in controls. Finally, data obtained on basal and GHRH-stimulated GH release in dogs given glucose or thyrotropin-releasing hormone and in AN patients given arginine, another compound thought to act via inhibition of somatostatinergic influences, do not support the view that somatostatinergic function is impaired in states of food deprivation.

Adolescent↗
PubMed1996

Sixteen weeks of hexarelin therapy in aged dogs: effects on the somatotropic axis, muscle morphology, and bone metabolism.

Hexarelin (HEXA; 500 micrograms/kg/die, s.c.) was administered for 16 weeks to six old beagle dogs. The treatment consisted of three on-drug periods spaced by two off-drug periods. During each on period, the growth hormone (GH) peak response to HEXA initially increased and then dropped to pretreatment values. Each time, a wash-out interval restored the same pattern of GH responsiveness. HEXA significantly augmented the indices of spontaneous pulsatility of GH, but plasma insulin-like growth factor I levels did not change during treatment. HEXA apparently reduced bone resorption since it significantly decreased the urinary concentration of lysylpyridinoline, a bone matrix component. Bone formation apparently was not affected since unchanged levels of alkaline phosphatase were recorded. In three of six old dogs, HEXA induced an improvement of some morphological and biochemical muscular indices, evaluated in muscle specimens that, instead, remained unchanged in a group of young untreated controls. These findings indicate that HEXA effectively releases GH and primes the pituitary of old dogs, and strengthen the view that in aging, GH secretion may be restored by pharmacological means. It would also appear that HEXA-induced GH release improves some indices of body composition in old dogs.

Animals↗
PubMed1996

Somatostatin withdrawal as generator of pulsatile GH release in the dog: a possible tool to evaluate the endogenous GHRH tone?

Reportedly, somatostatin (SS) withdrawal is an effective generator of pulsatile GH release in mammals and it has been proposed that the amplitude of the GH bursts is related to the functional activity of GHRH-producing neurons. Our study was designed to test this hypothesis in the unanesthetized dog, under different conditions of endogenous GHRH function. First, we evaluated the ability of withdrawal of SS infusion to induce a GH secretory burst under basal conditions when GHRH function is thought to be enhanced, i.e. in young (2- to 3-year-old) dogs under sustained (30 days) caloric restriction (CR) or a 2-day fast. Secondly, we performed experiments in aged (11- to 17-year-old) dogs, in which hypothalamic GHRH secretion is thought to be reduced. Old dogs were evaluated under basal conditions, after a 2-day fast and after a 10-day administration of GHRH alone or followed by fasting. Both before and 14 h after the end of each experimental period, young and old dogs underwent a 3-hour (from 10.00 to 13.00 h) intravenous SS infusion (4 micrograms.kg-1.h-1). The secretory profile of GH was generated by 15-min sampling from 09.00 to 15.00 h. Under baseline conditions, SS withdrawal induced a significant burst of GH in young but not in old dogs. After CR, termination of SS infusion was followed in young dogs by a robust GH burst, significantly higher than that observed when dogs were fed ad libitum. In this instance, reduction of plasma IGF-I concentrations was unlikely to be responsible for the higher GH burst; the same pattern was present in the young dogs after a 2-day fast, when circulating IGF-I was unaltered. In old dogs, SS withdrawal did not modify baseline GH levels even after fasting, but induced a significant GH increase after GHRH priming. When GHRH priming was followed by fasting, SS withdrawal resulted in a GH burst higher than that occurring after fasting or GHRH alone. Altogether, these data support the view that the rebound rise in GH induced by withdrawal of SS is related to the endogenous GHRH tone. It is suggested that extrapolation of these findings to humans might permit probing, albeit inferentially, the endogenous GHRH tone under different physiologic or pathologic conditions.

Animals↗