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D Cocchi

Publications and source records attributed to D Cocchi.

At least 19 recordsLinked to original sources
PubMed1995

Somatotropic dysregulation in old mammals.

In old mammals, including humans, the spontaneous growth hormone (GH) secretory pattern is markedly reduced resulting in lower amounts of GH released over 24 h, and the GH response to administration of GH-releasing hormone (GHRH) is reduced. In agreement with these in vivo findings, an impaired responsiveness to GHRH is evident in the pituitary of old male and female rats in vitro, and this is linked with a diminished stimulation of adenylate cyclase by GHRH. The poor GH responsiveness to GHRH in old mammals, which in the rat is coupled to a defective number of GHRH receptors in the somatotrophs, is likely due to a primary deficiency of GHRH availability, as implied by the diminished GHRH immunoreactivity and gene expression in and GHRH release from the hypothalamus of old rats. Attempts have been made to stimulate the sluggish somatotrophic function in elderly humans and dogs using GHRH; in either species positive results were obtained though, overall, it would seem that the GHRH hypofunction does not entirely account for the GH hyposecretory state during ageing. Concerning somatostatin, although the expression of this peptide decreases with age in the rat hypothalamus, secretion and activity of this hormone is increased, resulting in an altered relationship between GHRH and somatostatin gene expression and secretion. It is likely that defects, especially in catecholaminergic and cholinergic neurons, are instrumental in altering specific peptidergic neurons. Reportedly, catecholamines induce GH release by stimulating GHRH neurons and inhibiting somatostatin-releasing neurons; acetylcholine stimulates GH release via muscarinic receptors, in this way inhibiting the action of somatostatin neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Alterations of adenylyl cyclase-coupled growth hormone-releasing hormone (GHRH) pituitary receptors in different conditions of GHRH deprivation.

Previous studies have clearly shown that the progressive decrease of growth hormone (GH) secretion occurring during ageing is coupled with a reduced responsiveness of pituitary GHRH receptors both in terms of GH secretion and activation of the adenylyl cyclase (AC), in the presence of increased basal values of the enzyme. The mechanism(s) subserving the age-associated alterations of GHRH-sensitive AC is likely related to the progressive decrease of hypothalamic GHRH function occurring with ageing. In this context, in old male rats, short-term administration of GHRH decreased the high basal AC activity and enhanced the GHRH-stimulated AC activity. Along this line, we decided to investigate whether experimentally induced abrogation of GHRH function in adult rats would induce the same alterations of AC-coupled GHRH receptors present in aged rats. Passive immunization of male young-adult rats with supra-maximal doses of GHRH antiserum (Ab-GHRH) significantly reduced the AC responsiveness to GHRH, an effect already evident 5 days post-injection and still present at 10 days. At this time interval, the treatment also evoked a significant increase of basal AC levels and of Gs alpha protein in the pituitary and completely blocked the GH-releasing effect of a bolus injection of GHRH. Furthermore, mechanical disruption of brain-pituitary links by complete stereotaxical ablation of the mediobasal hypothalamus induced a significant increase of basal AC levels and Gs alpha protein in the pituitary and a strikingly lower AC responsiveness to GHRH.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1994

Low doses of either intravenously or orally administered arginine are able to enhance growth hormone response to growth hormone releasing hormone in elderly subjects.

Reportedly, the responsiveness of somatotrope cells to GHRH is reduced in elderly humans but it is totally restored by arginine (ARG) which likely acts by inhibiting hypothalamic release of somatostatin. As this effect was observed after infusion of high doses of the amino acid, in this study, we compared the effect of iv administration of 30, 10 and 5 g ARG(group A, B and C, respectively) as well as oral administration of 8 g ARG(group D) on the GH response to 1 microgram/kg i.v.GHRH in 27 healthy elderly subjects (11 M and 16 F, age 70-86 yr, BMI 21-25 kg/m2). In group A (n = 7) 30 g i.v. ARG strikingly enhanced the GHRH-induced GH rise (peak, mean +/- SE: 41.5 +/- 4.4 vs 11.7 +/- 5.3 micrograms/L, p < 0.05). Similarly, in group B (n = 6) and D (n = 7) 10 g i.v. and 8 g oral ARG enhanced the GH response to GHRH (20.9 +/- 4.7 vs 8.3 +/- 2.8 micrograms/L, p < 0.03 and 31.0 +/- 5.3 vs 11.4 +/- 3.4 micrograms/L, p < 0.03, respectively). In contrast, in group C (n = 7) 5 g i.v. ARG failed to modify the GHRH-induced GH rise (6.0 +/- 1.6 vs 3.5 +/- 0.9 micrograms/L). The GH responses to GHRH alone did not significantly differ amongst groups; the GH responses to GHRH and ARG were not significantly different among groups A, B and D and were greater than the GH response in group C. These results show that the GH response to GHRH in elderly subjects is enhanced even by low iv doses of arginine and by the orally administered amino acid, the lowest effective dose being 8 g. Moreover, they imply that the combined administration of GHRH and arginine may be a useful approach to restore the impaired function of the GH-IGF axis in aging.

Administration, Oral↗
PubMed1994

Glucagon stimulates GH secretion after intramuscular but not intravenous administration. Evidence against the assumption that glucagon per se has a GH-releasing activity.

In order to verify the true GH-releasing effect of glucagon and to explain the mechanism underlying this effect, we studied the effect of glucagon (GLU, 1 mg) administered either iv or im on both basal and GHRH (1 microgram/kg)-induced GH rise in 48 normal short children and adolescents. Moreover, the in vitro effect of GLU on rat anterior pituitary cells was studied. Intravenous administration of GLU induced no significant GH rise. On the other hand, im GLU administration induced a clear-cut GH increase (mean +/- SE GH peak after GLU vs placebo = 25.7 +/- 3.9 vs 10.1 +/- 3.6 micrograms/L, p < 0.01). Intravenous administration of GLU failed to modify the GHRH-induced GH rise either when coadministered with the neurohormone (35.2 +/- 4.1 vs 34.1 +/- 6.0 micrograms/L) or when given 60 min earlier (20.2 +/- 5.8 vs 21.1 +/- 8.3 micrograms/L). Differently from iv GLU, im GLU strikingly potentiated the GH response to GHRH given 90 min later (57.5 +/- 6.3 vs 24.7 +/- 9.1 micrograms/L, p < 0.01). Mean plasma glucose levels increased 30 min after GLU, administered either iv or im, and returned to basal levels 60 min later. GH secretion from dispersed rat pituitary cells was unaffected by incubation with GLU (10(-10)-10(-4) mol/L). Incubation of the cells with 10(-7) mol/L GHRH induced instead a clear-cut stimulation of GH release. In conclusion, our data demonstrate that glucagon per se has not GH-releasing activity as indicated by its uneffectiveness to release GH in vitro and after intravenous administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Neuroendocrine aging: its impact on somatotrophic function.

In this paper, two different aspects of growth hormone neuroregulation during aging were considered. Twenty-month-old male rats had decreased growth hormone-releasing hormone mRNA levels and a slight reduction of somatostatin mRNA levels in the hypothalamus when compared to 8-month-old counterparts. Short-term administration of biosynthetic human growth hormone (125 micrograms rat twice daily, i.p.) to 8-month-old rats reduced hypothalamic growth hormone-releasing hormone mRNA and increased somatostatin mRNA levels. In old rats, growth hormone administration did not significantly change growth hormone-releasing hormone and somatostatin gene expression. Six old beagle dogs received short-term administration of growth hormone-releasing hormone alone or co-administered with clonidine, an alpha 2-adrenoceptor agonist, and the growth hormone secretory pattern was evaluated during a 6 h period by cluster analysis. In dogs given growth hormone-releasing hormone alone twice daily for 10 days, none of the GH secretory indices were modified except for the increase in the mean GH peak amplitude. By contrast, simultaneous administration of growth hormone-releasing hormone and clonidine, both given twice daily, significantly increased GH peak frequency and total peak area. Administration of clonidine (once daily) associated with growth hormone-releasing hormone (twice daily) further increased the GH secretory indices.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Growth hormone administration to aged rats improves membrane electrical properties of skeletal muscle fibers.

Decreased secretion of growth hormone (GH) during aging may play a role in the impairment of muscle performance. To test this hypothesis we evaluated the effects of a chronic treatment with 150 micrograms/kg of GH on membrane electrical properties of extensor digitorum longus muscle of 23-month-old Wistar Kyoto female rats. We found that such treatment could partially but significantly reduce the age-related changes of these parameters. Indeed, with respect to untreated age-matched control rats we found a complete restoration of fiber diameter to the adult value, and a partial improvement of membrane resistance and capacitance values. Furthermore, the GH treatment significantly increased the low total membrane conductance characterizing aged muscle fibers. The increase of total membrane conductance was due to a significant increase toward the adult value of chloride conductance. In addition, the muscles from GH-treated aged rats had values of potassium conductance completely restored down to the adult ones. Accordingly, membrane excitability was also significantly improved by the treatment. The same treatment in adult female rats produced a slight but significant increase of both chloride conductance and potassium conductance, whereas in adult male rats we observed only a significant increase of fiber diameter. Our data show that impairment of GH secretion may contribute to the age-related changes of membrane electrical properties of skeletal muscle and support the potential benefit of GH administration to improve muscle performance in aged subjects.

Aging↗
PubMed1993

Effect of acute and short-term administration of cholinomimetic drugs on corticosterone secretion in the rat.

Centrally acting cholinomimetic drugs have been proposed for the therapy of cognitive disorders in aged subjects. Among the possible adverse side effects of this class of compounds, of great relevance is the stimulatory action on the adrenocortical axis, in view of the toxicity of glucocorticoids for hippocampal neurons and the immune system. The aim of the present study was to evaluate in conscious male rats the effect of acute and short-term administration of three novel cholinomimetic drugs on the release of corticosterone. The potent agonist of muscarinic receptors RU 35963 strikingly increased corticosterone levels after acute but not after short-term (6 days) administration. Similar results were obtained after administration of the reversible inhibitor of cholinesterase, eptastigmine. In contrast to RU 35963 and eptastigmine, acute administration of a choline precursor, L-alpha-glycerylphosphorylcholine, only slightly affected plasma corticosterone concentrations after both acute and short-term administration. It is concluded that activation of adrenocortical function by cholinomimetic drugs is a short-lasting event which does not represent an important side effect of these compounds when given on a long-term basis.

Analysis of Variance↗
PubMed1993

Growth hormone secretion is differently affected in genetically obese male and female rats.

Growth hormone (GH) secretion is markedly blunted in obesity. Reportedly, genetically obese Zucker rats show a reduced GH secretion due to an impaired function of hypothalamic neurons producing the GH-releasing hormone (GHRH). The aim of this work was: (1) to compare the in vitro GH responsiveness to GHRH in genetically obese female versus male Zucker rats and, (2) to evaluate the function of hypothalamic GHRH and somatostatin and of pituitary receptors for these neurohormones as assessed by the effectiveness of GHRH and somatostatin on adenylate cyclase (AC) activity. Baseline GH secretion of pituitaries obtained from male and female obese rats was not different and similar to that present in lean counterparts. Stimulation with 10(-7) M GHRH elicited a significantly lower GH secretion from the pituitaries of obese male rats but induced a similar GH secretion from the pituitaries of lean and obese female rats. In these pituitaries, GH concentration was similar in obese versus lean male and female rats [corrected]. A sex-related difference was also evidenced when plasma concentrations of somatomedin C (IGF-I) were evaluated. Obese male rats had lower IGF-I concentrations than lean counterparts, while this was not the case for obese versus lean female rats. Evaluation of AC activity following GHRH disclosed a lower activation in obese than in lean male rats, whereas in the females the enzyme activation was higher in obese than in lean animals. Conversely, the inhibitory effect of somatostatin on forskolin-stimulated AC was similar in pituitary membranes of obese and lean rats of both sexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1993

Aspects of the neuroendocrine control of growth hormone secretion in ageing mammals.

In aged animals and humans the pulsatile secretion of growth hormone (GH), the mean amounts of GH released over 24 h, and the response of GH to the administration of GH-releasing hormone (GHRH) are lower than in young adults. Pituitary somatotrophic cells in old male and female rats show an impaired responsiveness to GHRH, and the reduced secretion of GH in vitro is linked with a diminished stimulation of adenylate cyclase by GHRH. Pretreatment with GHRH in vivo decreases the high basal adenylate cyclase activity in old male rats. This pretreatment does not affect the rise of adenylate cyclase concentration in these rats that is subsequently induced by GHRH administration in vitro. However, it does induce a small rise in adenylate cyclase concentration in old female rats. In young rats of either sex the same GHRH schedule does not alter adenylate cyclase activity, but it does reduce the effectiveness of subsequent acute exposure to GHRH to stimulate enzymatic activity. Short-term administration of GHRH in some aged subjects increases the response of GH to a subsequent acute challenge with GHRH. However, primary or secondary alterations in somatotrophic cells are also present in aged mammals, such as a reduction in the number of GH-immunoreactive structures or post-receptor alterations. In aged rats, major alterations in brain neurotransmitters and neuropeptides are present in hypothalamic and extrahypothalamic structures, especially in catecholaminergic and acetylcholinergic neurones. These alterations are probably due to defects in neurosecretory GHRH and somatostatin neurones. GHRH synthesis is impaired in the hypothalamus of senescent male rats, as shown by a reduction in GHRH mRNA levels and GHRH-like immunoreactivity. Although the expression of somatostatin seems to decrease with age in the rat hypothalamus, secretion and activity of this hormone is increased, resulting in an altered relationship between GHRH and somatostatin gene expression and secretion. Catecholamines induce GH release in most animal species by stimulating GHRH neurones and inhibiting somatostatin-releasing neurones. Acetylcholine stimulates GH release via muscarinic receptors, and thus inhibits the effect of somatostatin neurones. In male rats of various ages, except very young rats, systemic administration of pilocarpine, an agonist of muscarinic receptors, potentiates the GH response to GHRH during the entire lifespan.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1992

Age-related alterations in gonadotropin, adrenocorticotropin and growth hormone secretion.

This review addresses some relevant aspects of the aging of the neuroendocrine system, particularly the reproductive and the adrenocortical axis. Deterioration of the reproductive function, one of the most striking endocrine alterations occurring in aging, is related to a complex interplay of factors. They comprise alterations occurring at the level of all the three components of the reproductive axis, the gonads, the pituitary and the brain, acting synergistically to disrupt the normal pulsatile release of gonadotropins. Particular relevance is given to the neurotoxic action of estrogens during the constant estrous phase occurring in aged female rodents, at the level of hypothalamic nuclei regulating gonadotropin secretion. This effect, to be found also in women during the anovulatory period of the perimenopause, would worsen the dysregulation of the central mechanisms controlling the reproductive function. The activity of the adrenocortical (HPA) axis increases with advancing age in rodents but also, although less strikingly, in humans. The main alteration which can be evidenced in both species is a delayed post-stimulus decline in plasma corticosteroid levels, indicating a diminished sensitivity to glucocorticoids of HPA axis feedback regulation in the elderly. Increased exposure to the highly catabolic adrenal glucocorticoids appears to be associated to a loss of cerebral neurons, particularly in the hippocampus, and the emergence of cognitive deficits in the aged rats. The relevance of experimental data performed in rodents to healthy and pathological human aging is extensively discussed. Finally, this chapter considers the age-related impairment in growth hormone secretion, a common finding of all the animal species investigated so far. The etiology of the hyposomatotropism of aging is namely linked to a progressive defect in growth hormone releasing hormone-producing hypothalamic neurons, although alterations of somatostatin-producing neurons have also been described. This background knowledge makes the use of neuroactive compounds aimed at restoring the physiologic function of hypothalamic hypophysiotropic hormones a rational approach to rectify the alterations of the neuroendocrine system occurring in elderly individuals.

Adrenocorticotropic Hormone↗
PubMed1992

Interactions of galanin and arginine on growth hormone, prolactin, and insulin secretion in man.

Galanin (GAL), a 29 amino acid neuropeptide, is known to increase both basal and growth hormone-releasing hormone (GHRH)-induced growth hormone (GH) secretion while not significantly increasing prolactin (PRL) secretion in man. GAL is also endowed with an inhibiting effect on glucose-stimulated insulin release in animals, but not in man. We studied the effect of GAL (80 pmol/kg/min infused over 60 minutes) on the arginine- (ARG, 30 g infused over 30 minutes) stimulated GH, PRL, insulin, and C-peptide secretion in eight healthy volunteers (age, 20 to 30 years). GAL induced an increase of GH (GAL v saline, area under curve [AUC], mean +/- SEM: 316.5 +/- 73.9 v 93.2 +/- 20.9 micrograms/L/h, P less than .05), but failed to modify both PRL and insulin secretion. GAL enhanced the ARG-induced stimulation of both GH (1,634.1 +/- 293.1 v 566.9 +/- 144.0 micrograms/L/h, P less than .02) and PRL secretion (1,541.9 +/- 248.8 v 1,023.8 +/- 158.7 micrograms/L/h, P less than .02). On the contrary, GAL blunted the ARG-stimulated insulin (816.3 +/- 87.7 v 1,322.7 +/- 240.9 mU/L/h, P less than .05), as well as C-peptide secretion (105.1 +/- 9.8 v 132.8 +/- 17.3 micrograms/L/h, P less than .02). ARG administration induced a transient increase of glucose levels (P less than .01 v baseline) followed by a significant decrease (P less than .05 v baseline). This latter effect was prevented by the coadministration of GAL. In conclusion, these results show that in man GAL potentiates the GH response to ARG, suggesting that these drugs act at the hypothalamic level, at least in part, via different mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Growth hormone responses to cholinergically active drugs in patients with dementia of the Alzheimer type.

Patients with dementia of the Alzheimer type (DAT) reportedly have reduced concentrations and function of some brain messengers, particularly acetylcholine and somatostatin, not only in the cerebral cortex, but also in subcortical structures, e.g., the hippocampus and the hypothalamus. We wished to determine the responsive pattern of DAT patients to neurohormonal and pharmacologic probes affecting growth hormone (GH) release through an interaction with hypothalamic cholinergic and somatostatinergic (SS) neurons. In 10 DAT patients, pyridostigmine (120 mg orally, p.o.), an inhibitor of acetylcholinesterase, induced an increase in GH levels similar to that elicited by the drug in age-matched controls. In 9 DAT patients, administration of GH-releasing hormone (GHRH, 1 microgram/kg body weight, intravenously, i.v.) induced an increase in plasma GH not different from that evidenced in control subjects. In DAT patients the GHRH-induced GH increase was completely inhibited by pretreatment with atropine (1 mg intramuscularly, i.m., 15 min before administration of GHRH). These findings are considered to indicate that in DAT patients, hypothalamic cholinergic and somatostatinergic neurons involved in control of somatotropic function are preserved.

Aged↗
PubMed1992

Central mechanisms subserving the impaired growth hormone secretion induced by persistent blockade of NMDA receptors in immature male rats.

Recently, we have reported in immature female rats that short-term blockade of glutamate receptors of the N-methyl-D-aspartic acid (NMDA) subtype by the noncompetitive antagonist MK-801 induced a reduction of growth rate, basal and stimulated growth hormone (GH) release and plasma somatomedin C levels. In the present study, we investigated in immature male rats the mechanism(s) through which agonists and antagonists of glutamate receptors affect GH secretion. In 21-day-old male rats, administration of MK-801 (0.2 mg/kg i.p.b.i.d.) for 10 days induced a significant impairment of growth rate, which was unrelated to a significant reduction of food intake. GH secretion from anterior pituitary fragments of MK-801-treated rats was not significantly reduced under basal conditions but was significantly less under stimulation by 40 mM K+. Incubation of dispersed pituitary cells of 31-day-old rats with N-methyl-aspartic acid (1 and 100 microM), alone or associated with MK-801 (1 microM) did not change GH secretion. Semi quantitative densitometric analysis of hypothalami of MK-801-treated rats evidenced a clearcut decrease in the intensity of GHRH-like immuno-reactivity (LI) staining in the median eminence (ME), whereas no difference was observed in the ME-somatostatin (SS)-LI. Finally, GHRH mRNA but not SS-mRNA, evaluated by slot-blot hybridization, was reduced in the hypothalamus of MK-801-treated rats. These and our previous data would demonstrate that NMDA glutamate receptors play an important role in the neuroendocrine control of GH secretion in the rat, and suggest an action mediated by GHRH-secreting neurons.

Animals↗
PubMed1992

Effect of Thymomodulin on luteinizing hormone, prolactin and testosterone in male rats.

The effect of Thymomodulin (TMD), a calf thymus derivative, on luteinizing hormone, prolactin and testosterone was studied in male rats after acute and chronic treatment. The results showed that the stimulatory action on prolactin and testosterone secretion after acute (prolactin) or one month chronic (testosterone) treatments completely vanished during six month chronic administration. No effect was observed on luteinizing hormone after acute or chronic treatment.

Animals↗
PubMed1991

Sexually dimorphic effects of aging on rat somatotropes and lactotropes.

During the aging process modified functions of hypothalamic factors may cause sexually dimorphic changes in pituitary somatotropes and lactotropes. To test this hypothesis, pituitary tissue from young adult (4 months) and old (20-22 months) male and female rats was labeled immunocytochemically for growth hormone (GH) and prolactin (PRL). The total amount of immunoreactive material as well as the total area and number of immunoreactive structures were evaluated. With increasing age the intracellular GH content was moderately increased in male and decreased in female rats. An age-dependent PRL increase, due both to increased cell number and intracellular hormone content, was present only in female rats. The amount of GH- and PRL-immunoreactive material, distributed into classes of increasing density, differed both between sex and age groups. Our results indicate that the aging process of the somatotrope and lactotrope cell populations in rats appears to be different in the two sexes.

Aging↗
PubMed1991

Somatostatin in the hippocampus mediates dexamethasone-induced suppression of corticosterone secretion in the rat.

We evaluated the effect of different manipulations of central somatostatin (SS) neurons on dexamethasone (Dex) induced suppression of the hypophyseal-pituitary axis. The Dex suppression test was performed in male rats by evaluating the reduction of plasma levels of corticosterone occurring 4 h after administration of Dex. Administration of cysteamine, a depletor of SS stores, or passive immunization by intracerebroventricular administration of a saturating dose of anti-SS gamma-globulins completely suppressed the ability of Dex to reduce plasma corticosterone levels. Additionally, anti-SS gamma-globulins, infused under stereotaxic control into two discrete areas of the hippocampus (CA3 and DG), completely blocked Dex-induced inhibition of corticosterone secretion. These data indicate that hippocampal SS neurons play a role in the negative feedback regulation of glucocorticoid secretion.

Animals↗
PubMed1991

Age-related changes of growth hormone secretory mechanisms in the rat pituitary gland.

The mechanisms underlying the age-related decrease and increase in somatotroph responsiveness to growth hormone-releasing factor (GHRF) and somatostatin respectively were studied in rat pituitary membranes in vitro. Basal adenylate cyclase (AC) activity was similar in pituitary membranes from rats of 8 days (either sex) and male rats of 3 months, but it was almost threefold higher in membranes from male rats of 21-23 months. GHRF induced a lower percentage stimulation of AC activity in membranes from infant and old than adult rats. Somatostatin inhibited stimulation of AC induced by forskolin more effectively in membranes from adult than infant and old rats. In parallel experiments, since the tissue we used is formed by a mixed population of pituitary cells, we evaluated, for comparison, the effect on AC of neurohormones, i.e. vasoactive intestinal polypeptide (VIP) and dopamine which act primarily on lactotrophs. VIP induced a lower fold-stimulation of AC activity in membranes from infant and old than adult rats. Dopamine inhibited forskolin-induced stimulation of AC in the following rank order of magnitude: old, adult and infant rats, and was also more effective in inhibiting basal AC activity in old than in adult rats. The stimulatory and inhibitory G proteins (Gs and Gi) coupled to AC were measured indirectly by evaluating stimulatory and inhibitory effects of different concentrations of GTP on AC. GTP, at stimulatory concentrations, increased AC activity in membranes from infant and adult rats similarly whereas its effect was significantly greater in membranes from old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗