Rise In Plasma Growth Hormone Research Articles

Kisspeptin Stimulates Growth Hormone Release by Utilizing Neuropeptide Y Pathways and Is Dependent on the Presence of Ghrelin in the Ewe.

Although kisspeptin is the primary stimulator of gonadotropin-releasing hormone secretion and therefore the hypothalamic-pituitary-gonadal axis, recent findings suggest kisspeptin can also regulate additional neuroendocrine processes including release of growth hormone (GH). Here we show that central delivery of kisspeptin causes a robust rise in plasma GH in fasted but not fed sheep. Kisspeptin-induced GH secretion was similar in animals fasted for 24 hours and those fasted for 72 hours, suggesting that the factors involved in kisspeptin-induced GH secretion are responsive to loss of food availability and not the result of severe negative energy balance. Pretreatment with the neuropeptide Y (NPY) Y1 receptor antagonist, BIBO 3304, blocked the effects of kisspeptin-induced GH release, implicating NPY as an intermediary. Kisspeptin treatment induced c-Fos in NPY and GH-releasing hormone (GHRH) cells of the arcuate nucleus. The same kisspeptin treatment resulted in a reduction in c-Fos in somatostatin (SS) cells in the periventricular nucleus. Finally, blockade of systemic ghrelin release or antagonism of the ghrelin receptor eliminated or reduced the ability of kisspeptin to induce GH release, suggesting the presence of ghrelin is required for kisspeptin-induced GH release in fasted animals. Our findings support the hypothesis that during short-term fasting, systemic ghrelin concentrations and NPY expression in the arcuate nucleus rise. This permits kisspeptin activation of NPY cells. In turn, NPY stimulates GHRH cells and inhibits SS cells, resulting in GH release. We propose a mechanism by which kisspeptin conveys reproductive and hormone status onto the somatotropic axis, resulting in alterations in GH release.

Gene expression of growth hormone family and glucocorticoid receptors, osmosensors, and ion transporters in the gill during seawater acclimation of Mozambique tilapia, Oreochromis mossambicus

This study characterized endocrine and ionoregulatory responses accompanying seawater (SW) acclimation in Mozambique tilapia (Oreochromis mossambicus). Changes in plasma hormones and gene expression of hormone receptors, putative osmosensors, and ion transporters in the gill were measured. Transfer of freshwater (FW)-acclimated tilapia to SW resulted in a marked elevation in plasma osmolality and a significant rise in plasma growth hormone (GH) levels at 12 hr and 14 days after transfer. Significant reductions in plasma prolactin (PRL(177) and PRL(188)) levels also occurred in SW-transferred fish; no effect of transfer upon plasma cortisol or insulin-like growth factor I was observed. Gene expression of GH receptor increased strongly 6 hr after transfer, whereas PRL receptor was lower than controls at 12 hr. By contrast, mRNA levels of somatolactin and glucocorticoid receptors were unaffected by SW transfer. Osmotic stress transcription factor 1 mRNA levels rose significantly between 3 and 12 hr, whereas the calcium-sensing receptor was unaffected. Aquaporin-3 gene expression was strongly down-regulated during SW acclimation from 12 hr until the conclusion of the experiment. Na(+)/K(+)/2Cl(-) cotransporter gene expression increased significantly 3 hr after transfer, whereas expression of Na(+)/Cl(-) cotransporter, specific to FW-type chloride cells, declined by 6 hr into SW acclimation. The response of Na(+)/H(+) exchanger was less pronounced, but showed a similar pattern to that of the Na(+)/Cl(-) cotransporter. These results suggest that acquisition of hyposmoregulatory mechanisms in Mozambique tilapia entails the coordinated interaction of systemic hormones with local factors in the gill, including hormone receptors, ion transporters, and osmosensors.

GH secretory responses to ghrelin and GHRH in growing and lactating dairy cattle

Release of growth hormone (GH) is known to be regulated mainly by GH-releasing hormone (GHRH) and somatostatin (SRIF) secreted from the hypothalamus. A novel peripheral release-regulating hormone, ghrelin, was recently identified. In this study, differences of the GH secretory response to ghrelin and GHRH in growing and lactating dairy cattle were investigated and an alteration of plasma ghrelin levels was observed. The same amounts of ghrelin and GHRH (0.3 nmol/kg) were intravenously injected to suckling and weanling calves, early and mid-lactating cows and non-lactating cows. Plasma ghrelin levels were also determined in dairy cattle in various physiological conditions. The peak values of ghrelin-induced GH secretion were increased in early lactating cows compared to those in non-lactating cows. The relative responsiveness of GH secretion to ghrelin was also increased compared with that to GHRH in early lactating cows. GH secretory responses to GHRH were blunted in mature cows with and without lactation. Conversely, GHRH-induced GH secretory response was greater than that to ghrelin in calves, and also greater in calves than in mature cows. Plasma ghrelin concentrations were elevated in early lactating cows compared to those in non-lactating cows. Plasma GH concentrations were higher in suckling calves and early lactating cows compared with those in non-lactating cows. These results suggest that GHRH is an effective inducer of GH release in growing calves, and that the relative importance of ghrelin in contributing to the rise in plasma GH increases in early lactating cows.

Growth hormone (GH) rebound rise following somatostatin infusion withdrawal: studies in dogs with the use of GH-releasing hormone and a GH-releasing peptide.

Evidence has been presented that in both animals and humans the rebound secretion of growth hormone (GH) following withdrawal of an infusion of somatostatin (SS) is due to the functional activation of the hypothalamic GH-releasing hormone (GHRH) neurons of the recipient organism. Based on this premise, this study has sought to assess the existence of functional interactions between endogenous GHRH released by a SS infusion withdrawal (SSIW) and growth hormone-releasing peptides (GHRPs), a class of compounds allegedly acting via GHRH. Five young dogs (3 to 4 years old, 2 male and 3 female) were administered, on different occasions, three consecutive intravenous boli of physiological saline (0.1 ml/kg), or GHRH (2 microg/kg), or EP92632 (125 microg/kg), a GHRP compound, or GHRH plus EP92632 at the end of three cycles of 1-h SS infusions (8 microg/(kg x h)) or during a 6-h infusion of saline. Under saline infusion (SALI), plasma GH levels were unaltered, whereas each SSIW cycle was followed by similar GH secretory episodes. Administration of the first GHRH bolus under SALI induced a rise in plasma GH concentrations slightly higher than that induced by the first cycle of SSIW, but the GH response to the second and third GHRH boli was similar to that after SSIW. Following SSIW, the response to the first bolus of GHRH was higher than that during SALI, but the second and third cycles of SSIW induced GH responses similar to those evoked by the GHRH bolus. During SALI, administration of the first bolus of EP92632 induced a rise in plasma GH which was higher than that induced by the first GHRH bolus, the second bolus elicited a GH peak of lesser amplitude and there was a partial restoration of the GH response to the third peptide bolus. SSIW strikingly enhanced the GH release to the first EP92632 bolus, a pattern also present, although to a lesser extent, with the second and third cycles of SSIW. Under SALI, combined administration of GHRH and EP92632 had a synergistic effect on GH release, but a progressive reduction was present in the GH response to the second and third GHRH plus EP92632 boli. SSIW increased only weakly the GH response to the first co-administration of the peptides over that present after administration of EP92632 alone, and did not induce a GH response higher than that present during SALI when the second bolus of the peptides was administered; after the third SSIW a GH rise higher than that present during SALI was elicited by the combined administration of the peptides. (i) the uniformity of the GH rebound responses to multiple cycles of SSIW may indicate that the latter activate a physiological mechanism which mimics that normally controlling GH pulse generation; (ii) EP92632 elicits, under our experimental conditions, a plasma GH rise higher than that induced by GHRH; (iii) SSIW enhances the GH response to EP92639 alone, to an extent reminiscent of that following combined administration of GHRH and EP92632. This pattern reinforces the view that SSIW elicits release of endogenous GHRH, and infers that the GHRP challenge after SSIW may be exploited in humans to distinguish between healthy and GH-deficient adults.

Hypothalamic α2A-adrenoceptors stimulate growth hormone release in the rat

Oxymetazoline, the relatively selective α 2A-adrenoceptor agonist (with more than 60-fold selectivity over the α 2B-adrenoceptor subtype), was administered into the lateral ventricle (i.c.v.) of rats and plasma growth hormone (GH) levels were measured. Oxymetazoline was more potent to release GH after i.c.v. administration than was clonidine; 0.01 μg i.c.v. oxymetazoline already caused a significant release of GH, while at least 0.1 μg clonidine had to be administered to cause a similar response. The dose-response curve was of an inverted U shape since with 10 μg of oxymetazoline the plasma GH did not rise. When oxymetazoline was injected i.c.v. to rats with somatostatin fibres to the median eminence transected by an anterolateral cut in the hypothalamus there was a significant rise in plasma GH, suggesting that oxymetazoline stimulated GHRH rather than inhibited somatostatin release. Pretreatment with CH-38083 (7,8-(methylenedioxy)-14-α-hydroxy-alloberban HCl, selective for α 2-adrenoceptors but not differentiating between α 2A and α 2B subtypes), prevented the plasma GH rise normally elicited by 1 μg i.c.v. oxymetazoline. The α 2A- and α 1-selective adrenoceptor antagonist, WB-4101 (2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4-benzodioxane hydrochloride), prevented the GH rise normally induced by oxymetazoline while prazosin, the α 2B- and α 1-selective adrenoceptor antagonist, prolonged the elevation occurring in the control rats between 30 and 60 min after oxymetazoline injection. Since both prazosin and WB-4101 are α 1-adrenoceptor antagonists but differ in their action on α 2A and α 2B subtypes as well as in their action on oxymetazoline-induced GH secretion, the antagonist studies suggest that oxymetazoline stimulates GH release through activation of α 2A-adrenoceptors stimulatory to GHRH release, and not by an action through α 2B- or α 2C- or α 1-adrenoceptors. Since WB-4101 also antagonized clonidine action on GH release we also suggest that the major component may be the stimulation of the α 2A-adrenoceptors in the clonidine action on GH release.

Selective responses of hormones involved in carbohydrate and lipid metabolism and properties of erythrocyte membranes during the menstrual cycle in premenopausal women consuming moderate amounts of alcohol

The effects of chronic consumption of moderate amounts of alcohol on hormones associated with lipid and carbohydrate metabolism, plasma concentrations of triacylglycerol and cholesterol, insulin receptors on erythrocyte membranes, and erythrocyte membrane fluidity were studied during three phases of the menstrual cycle in 37 premenopausal women. Subjects were given either 30 g ethanol or an equienergetic fruit juice for three menstrual cycles in a crossover design. Blood samples were analyzed during the luteal, midcycle, and follicular phases. Administration of alcohol induced a significant rise in plasma glucagon and cortisol uniformly across the entire menstrual cycle. A similar rise in plasma growth hormone was observed at midcycle during the period when subjects consumed alcohol. A marginal effect was observed on cholesterol and somatomedin C concentrations. Insulin binding to erythrocyte ghosts was not affected by either alcohol or menstrual-cycle phase. Erythrocyte membranes were more fluid during the follicular phase than during the luteal phase of the menstrual cycle when the women were consuming the alcohol. There were no perceptible interactions between alcohol and phases of the menstrual cycle for the indexes studied, except membrane fluidity.

Vitamin B6 and exercise.

This paper presents an overview of vitamin B6 and exercise, including the role that vitamin B6 plays in gluconeogenesis and glycogenolysis and changes in vitamin B6 metabolism during exercise. The dietary vitamin B6 intakes of athletes are also reviewed. Most studies report that male athletes have adequate dietary intakes of vitamin B6, whereas some females, especially those with low energy intakes, appear to have low vitamin B6 intakes. Few studies have assessed the vitamin B6 status of nonsupplementing athletes using the recommended status criteria. The role that vitamin B6 may play in attenuating the rise in plasma growth hormone observed during exercise is also reviewed. Finally, recommendations are given for further research in the area of vitamin B6 and exercise.

Osmoregulatory actions of growth hormone and its mode of action in salmonids: A review

Osmoregulatory actions of growth hormone (GH) and its mode of action in salmonids are reviewed. We present evidence suggesting that insulin-like growth factor I (IGF-I) mediates some of the actions of GH on seawater acclimation. Plasma concentration and turnover of GH rise following exposure to seawater. Exogenous GH (in vivo) increases gill Na(+),K(+)-ATPase activity and the number of gill chloride cells, and inhibits an increase in plasma osmolarity and ions following transfer of fish to seawater. A single class of high affinity GH receptors is present in the liver, gill, intestine, and kidney. The levels of IGF-I mRNA in the liver, gill and kidney increased after GH-injection. After transfer to seawater, IGF-I mRNA increased in the gill and kidney following the rise in plasma GH, although no significant change was seen in the liver. Injection of IGF-I improved the ability of the fish to maintain plasma sodium levels after transfer to seawater. GH treatment also sensitizes the interrenal to adrenocorticotropin (ACTH), increasing cortisol secretion. Both cortisol and IGF-I may be involved in mediating the action of GH in seawater adaptation, although studies on the effect of GH on osmoregulatory physiology of non-salmonid species are limited. An integrated model of the osmoregulatory actions of GH is presented, and areas in need of research are outlined.

Diagnostic value of growth hormone-releasing hormone test in children and adolescents with idiopathic growth hormone deficiency.

Average growth hormone (GH) peaks following an i.v. growth hormone releasing hormone (GHRH) 1-29 stimulation test were significantly lower in 48 children and adolescents with GH deficiency (GHD) than in 20 age-matched controls (15.2 + 12.7 vs 37.5 + 28.1 ng/ml, 2 P less than 0.001). Twelve patients exhibited a low GH peak (less than 5 ng/ml), 27 demonstrated a normal response (greater than 10 ng/ml) and 9 showed an intermediate rise in plasma GH (5-10 ng/ml). Six of the 12 patients with low GH response to the first GHRH stimulation failed to respond to two other tests immediately before and after a 1 week priming with s.c. GHRH. These subjects with subnormal GH increase at repeat testing had total GHD (TGHD) and multiple pituitary hormone deficiency (MPHD) and had suffered from perinatal distress. On the contrary, 26 of 27 patients with normal GH response to the first test had isolated GHD and only a minority (8/27) had signs of perinatal distress. It is concluded that perinatal injuries primarily damage pituitary structures and that a pituitary defect more probably underlies more severe forms (TGHD and MPHD) of GHD.

Pathophysiology and gene abnormalities of endocrine tumors

Various functioning and non-functioning tumors arise from endocrine glands in both the sporadic and familial forms and pathophysiology of the tumors is variable due to differences in the sort of tumor-bearing endocrine organs and in the amount of hormones released. In this paper, gene abnormalities in growth hormone (GH)-secreting pituitary adenoma, ectopic GHRH-producing tumor, multiple endocrine neoplasia (MEN) and ectopic parathyroid hormone (PTH)-producing tumor are documented in relation to etiology and pathophysiology. GH-secreting pituitary adenoma is heterogeneous in clinical features, pathological findings and GH responses to various secretagogues. A point mutation of codon 201 of Gs alpha gene was observed in 2 out of 45 GH-secreting pituitary adenomas (4.4%), but no point mutation of Gi2 alpha gene was found. Pituitary tumors may occur at any stage of differentiation from the totipotent cells to mature anterior pituitary cells, and the mutations of Gs alpha and H-ras genes as well as loss of heterozygosity (LOH) found on chromosome 11 in some adenomas must be involved in their tumorigeneses. Since 1959, 34 patients with ectopic GHRH-producing tumor associated with acromegaly have been reported. In our case of MEN type 1, the paradoxical rise of plasma GH after TRH or glucose administration disappeared after resection of the tumor. The tumor cells showed neither rearrangement nor amplification of GHRH gene and 20 oncogenes including ras, myc, and erb. Only LOHs of HRAS1 and D11S151 were detected in this tumor, but no point mutation was found in HRAS1 gene. Therefore, a kind of tumor suppressor gene may be involved in the tumorigenesis of the tumor in addition to inactivation of MEN-1 locus. In MEN-1 patients, we reported LOH on chromosomes 1, 9, 11 and 16, while we reported point mutation as being present only in Gs alpha gene on chromosome 20. This point mutation was found specifically in GH-secreting pituitary adenoma but not in hyperplastic parathyroid and pancreas adenoma. These data suggest that in MEN-1 patients tumorigenesis occurs and advances from hyperplasia and adenoma to cancer during multistep changes of genes such as inactivation of MEN-1 gene and other tumor suppressor genes and activation of oncogenes. Ectopic PTH-producing tumor was first reported by us in 1989, and this was followed by 2 papers. These patients showed a disturbance of consciousness and high levels of serum calcium and plasma PTH.(ABSTRACT TRUNCATED AT 400 WORDS)

Manipulation of protein and fat accretion in growing cattle

ß-adrenergic agonists are powerful repartitioning agents, increasing muscle protein accretion and reducing fat deposition in a variety of species. Their exact mode of action is not fully understood but some of their effects are similar to those elicited by exogenous growth hormone administration. Whilst there are few reports of plasma growth hormone (GH) concentrations being elevated in animals treated with ß-agonists, several in vitro studies have clearly demonstrated a direct stimulation of GH release from perifused or cultured pituitary or adenohypophyseal cells on administration of these agents. More recently, a brief, rapid rise in plasma GH has been demonstrated in rats infused intra-atrially with isoproterenol and this was sustained when the animals were pre-treated with somatotropin release inhibitory factor (somatostatin; SRIF) antiserum. This raises the possibility that ß-adrenergic agonists do stimulate GH release in vivo but that this response is rapidly counteracted by SRIF release.The aim of this work was to attempt to enhance the repartitioning effect of ß-adrenergic agonists by immunizing young cattle against SRIF whilst administering cimaterol.

Down-regulation of α2-adrenoceptors involved in growth hormone control in the hypothalamus of infant rats receiving short-term clonidine administration

In infant rats short-term administration of the α 2-adrenoceptor agonist, clonidine (CLO), induces refractoriness to the growth hormone (GH)-releasing effect of an acute CLO challenge. CLO reportedly stimulates GH release via increased release of GH-releasing hormone (GHRH) from the hypothalamus. Based on these premises, in this study we investigated the possibility that repeated CLO administration may induce down-regulation of hypothalamic α 2-adrenoceptors, involved in GH control, thus prohibiting the GH-releasing effect of the drug. α 2-Adrenoceptor binding was determined in different brain regions of 10-day-old rats pretreated for 5 days with CLO (150 μg/kg, b.i.d.) and killed 14 h after last CLO administration. [ 3 H]p- Aminoclonidine ( [ 3 H] PAC ) was used as the specific ligand of α 2-adrenoceptors. Treatment with CLO decreased by about 30% the maximum number of binding sites ( B max) in areas of the mediobasal hypothalamus (MBH) involved in the stimulatory control of GH secretion, i.e. nucleus periventricularis arcuatus, nucleus ventromedialis hypothalami and nucleus lateralis hypothalami. Reduction of B max for [ 3H]PAC binding was observed also in the nucleus periventricularis hypothalami, an area involved in the inhibitory control of GH secretion and, among extrahypothalamic areas, only in the cortex piriformis. In no brain areas was the affinity constant ( K d) for [ 3 H] PAC binding significantly changed after CLO pretreatment. Binding studies performed with a specific ligand of α 1-adrenoceptors, [ 3 H] prazosin , showed that the effect of CLO was specific since no changes in the B max or K d were present in either hypothalamic or extrahypothalamic regions. In these rats, which are refractory to the GH-releasing effect of CLO, an opioid peptide analogue, FK 33-824, which like CLO acts via release of GHRH from the hypothalamus, was still capable of eliciting a rise in plasma GH. In all, these data indicate that: (1) CLO-induced α 2-adrenoceptor down-regulation in some hypothalamic nuclei may explain the refractoriness to the GH-releasing effect of an acute CLO challenge present in short-term CLO pretreated infant rats; (2) there is, likely, an opioidergic interneuron between α 2-adrenergic and GHRH-secreting neurons.

Growth Hormone Response Induced by Synthetic Human Growth Hormone‐Releasing Factor (1–44) in Healthy Dogs

The growth hormone (GH) secretory response to varying doses (1, 5 and 25 micrograms/kg) of intravenous (i.v.) human GH releasing factor (GRF) (1-44) was measured in four, 16-month-old female dogs and compared to the GH response to placebo (vehicle solubilizing GRF) and standard clonidine test (10 micrograms/kg i.v.). The three doses of GRF had no apparent clinical side effects and were capable of eliciting a rapid increase in the mean plasma GH level. The rise in plasma GH occurred within 5 minutes with a peak response at 15-30 minutes. However inter-subject variability of the GH response was large in terms of magnitude and time course. By analysis of the areas under the response curves it was shown that GRF 1-44 was as effective in stimulating GH release as clonidine and that a dose of 1 microgram/kg GRF 1-44 could be a good choice for use as a standard test dose in the dog.

Time course of changes in plasma concentrations of the growth related hormones during protein restriction in the domestic fowl (Gallus domesticus).

Experiments were conducted to evaluate the possible role of circulating growth hormones triiodothyronine (T3), thyroxine (T4), and insulin-like growth factor I (somatomedin-C; IGF-I) in the elevation of plasma growth hormone (GH) which occurs in protein-restricted chickens. Plasma hormone changes were determined over a 2-week period of protein depletion by feeding a 5% protein diet as well as a similar period of protein repletion with a 20% protein diet. The rise in plasma GH was observed in two separate studies. Plasma concentrations of T4, T3, and IGF-I were all depressed in protein-restricted chicks prior to or concurrent with the GH elevation. In the protein repletion time course study, T4 and T3 concentrations were normalized prior to or concurrent with plasma GH normalization. However, IGF-I concentrations in repleted chicks did not return to control levels until after normal levels of GH were observed. These data suggest that thyroid hormones may play a greater role in the regulation of GH secretion during periods of malnourishment than IGF-I; the latter being currently thought to be a peripherally circulating inhibitor of GH release in animals.

Changes in plasma growth hormone in diabetic and nondiabetic subjects during the glucose clamp

A group of 22 newly diagnosed noninsulin-dependent diabetic subjects and seven nondiabetic subjects underwent a glucose clamp at plasma glucose 100 mg/dL with insulin infusion rates of 1.0 and 10 mU/kg/min. During both insulin infusion rates, there was a sustained rise in plasma growth hormone (GH) above basal in 18 of the 22 diabetic subjects. Basal GH values were 2.37 ± 0.67 ng/mL, rising above basal during the lower insulin infusion (6.1 ± 3.3 ng/mL, P = 0.05) with a further rise at the higher insulin level (8.58 ± 2.0 ng/mL, P < 0.001). There was no rise in GH in any of the nondiabetic subjects. In neither group was there any rise above basal in cortisol, prolactin, glucagon, or somatostatin (SRIH). In a group of three nondiabetic subjects, a rise in GH similar to that seen in the diabetic group was induced by elevating the plasma glucose to 200 mg/dL for 60 minutes prior to the euglycemic clamp procedure. However, it is unlikely that changes in plasma glucose account totally for the changes in plasma GH described in the diabetic subjects since a rise in plasma GH was also seen in four diabetic subjects clamped at their fasting plasma glucose. We conclude that in newly diagnosed noninsulin-dependent diabetic subjects there is a rise in plasma GH during the euglycemic clamp procedure, which may be due to both the prior lowering of plasma glucose and the high plasma insulin levels.

Growth hormone response to hpGRF-40 in different forms of growth retardation and endocrine-metabolic diseases

The effect of one of the new human pancreatic growth hormone releasing factors (hpGRFs) was assessed in children or young adults with different forms of growth retardation or endocrine-metabolic diseases. Intravenously administered synthetic hpGRF-40 (1 microgram/kg) induced a clear-cut and prompt rise in plasma growth hormone (GH) levels in 8 normal prepubertal children and a definite GH rise in 11 out of 14 children with isolated GH deficiency (IGHD) and one child with the Silver-Russel syndrome. In two out of three subjects with craniopharyngioma hpGRF-40 did not induce any plasma GH increase. In seven out of ten children with constitutional growth delay (CGD), hpGRF-40 induced a biphasic GH response, with a prompt small GH increment followed by a second, more consistent rise. Both in children with IGHD and with CGD the rise in plasma GH following hpGRF-40 was markedly lower than in controls. In children with CGD the GH response to hpGRF-40 was defective, despite the fact that in most of them the GH response to standard pharmacological stimuli was normal according to generally accepted criteria. hpGRF induced a small but sustained plasma GH rise in four hypothyroid subjects, while in three out of four children with idiopathic obesity the GH response to hpGRF was strikingly reduced. These data demonstrate that hpGRF is a potent stimulus of GH release in normal prepubertal children and a physiological means of investigating GH function in diseases associated with growth impairment.

Peripheral α2 Adrenoceptor Stimulation Contributes to the Sympatholytic Effect of Guanfacine in Humans

Guanfacine 3 mg was infused into six volunteers over 1 h on two occasions to investigate whether its sympatholytic effect is centrally or peripherally mediated. On one occasion, the central effects of guanfacine were blocked by prior administration of idazoxan 0.2 mg/kg i.v. (45 min preguanfacine); central alpha 2-blockade was confirmed by inhibition of the guanfacine-induced rise in plasma growth hormone. Rapid disappearance of idazoxan from the circulation prevented antagonism of peripheral alpha 2 receptor effects of guanfacine (confirmed by suppression of plasma insulin by guanfacine on both occasions). Idazoxan elevated plasma noradrenaline concentration by 0.26 +/- 0.018 ng/ml; however, guanfacine caused a similar (approximately 30%) reduction in plasma noradrenaline after both idazoxan and vehicle. Idazoxan elevated systolic and diastolic blood pressure, but no change was observed after guanfacine on either occasion. Thus, the reduction in plasma noradrenaline caused by guanfacine appears to be peripherally mediated but is not due to baroreceptor activation. This is consistent with stimulation of presynaptic alpha 2 receptors.

Growth hormone releasing effect of hpGRF-40 in rats at different time intervals following ablation of the mediobasal hypothalamus

We have investigated the effect of hypothalamo-pituitary disconnection in the rat on the growth hormone (GH) responsiveness to human pancreatic GH-releasing factor (hpGRF). Adult female rats, sham-operated (sham-op) or bearing a complete mechanical ablation of the mediobasal hypothalamus (MBH-A) were challenged, while under urethane anesthesia, with hpGRF-40 (20,100,500 ng/rat i.v.) at different time intervals after surgery. In sham-op rats only 500 ng/rat of hpGRF-40 stimulated GH release, while in 1-and 7-day MBH-A rats the stimulation also occurred with the lower hpGRF doses and the rise in plasma GH was greater than in sham-op controls. Twenty-one and 42 days after the placing of the lesions the GH response to hpGRF-40 was still present at the 500 ng/rat dose, though it was smaller than in sham-op controls. Evaluation of pituitary GH content demonstrated a progressive and rapid decline starting the first day after the placing of the lesions. These data indicate that GH responsiveness to hpGRF is: 1) enhanced in the anterior pituitary shortly after hypothalamo-pituitary disconnection and, 2) despite a striking reduction of the pituitary GH stores, it is maintained after these lesions. The physiologic growth hormone (GH) releaser in the rat is GH-releasing factor and, recently, a group of peptides has been characterized from human pancreatic tumors (hpGRFs) (1,2) which are potent and specific GH-releasers in both animals (3) and man (4). The availability of these peptides, which show a high degree of homology with the physiologic rat hypothalamic GRF (5), offers the unique opportunity to assess somatotrope responsiveness to GRF molecules in rats with hypothalamo-pituitary disconnection. In this study we have first evaluated the GH pituitary responsiveness to increasing doses of hpGRF-40 in rats following mechanical ablation of the mediobasal hypothalamus (6). These rats, by definition, lack the effect of both central nervous system (CNS) inhibitory (e.g. somatostatin) and stimulatory (e.g. GRF) influences to GH release. With the aim to ascertain how the lack of these two opposing inputs reflects on the secretory capacity of the somatotropes, we also investigated the GH response to hpGRF-40 at different time intervals after the lesioning. In a study in rats with electrolytic lesions of the ventromedial-arcuate region of the hypothalamus Tannenbaum et al (7) had shown persistence of the GH response to huge doses of a hpGRF analog.

Blockade of hp-GRF-40-induced GH release in normal men by a cholinergic muscarinic antagonist.

In five healthy young men, pretreatment with the cholinergic muscarinic antagonist pirenzepine (0.6 mg/kg iv) almost completely abolished the rise in plasma growth hormone (GH) elicited by an iv bolus injection of 1 microgram/kg human pancreatic GH-releasing factor 1-40 (hp-GRF-40). These data demonstrate that cholinergic receptor sites involved in GH-releasing mechanisms do not interact with GRF-secreting structures in the central nervous system. A mechanism mediated via hypothalamic release of somatostatin or, alternatively, a direct pituitary site of action, can be postulated for the blocking effect of pirenzepine.

Changes in plasma GH levels and clinical activity during bromocriptine therapy in acromegaly. The value of predictive tests.

Twenty-seven patients with active acromegaly despite previous treatment by surgery and/or radiotherapy received bromocriptine in a dose of 10-20 mg daily for a period of 6-9 months. The results of chronic bromocriptine treatment were evaluated by measurement of plasma growth hormone (GH) levels during the day and by subjective and objective criteria of clinical activity. The results of chronic bromocriptine treatment were also compared with four biochemical criteria obtained before treatment e.g. basal plasma prolactin (Prl) levels and the plasma GH response to oral administration of 2.5 mg bromocriptine respectively iv administration of 200 micrograms TRH and 500 micrograms somatostatin. The main observations may be summarized as follows: 1) The mean pre-treatment GH levels during the day ranged from 6-207 mU/1. Hyperprolactinaemia was present in 6 patients. 2) During bromocriptine treatment mean plasma GH levels decreased to less than 50% in 11 patients (GH responders) whereas in 19 patients changes of mean plasma GH and of subjective criteria of clinical activity were concordant. 3) Glucose tolerance improved significantly (P less than 0.01) in 10 GH-responders and the urinary hydroxyproline/creatinine ratio decreased significantly (P less than 0.05) in 8 GH-responders. 4) Five out of 6 patients with hyperprolactinaemia belonged to the group of GH-responders. 5) A single dose of 2.5 mg bromocriptine induced a more than 50% decrease of plasma GH in 8 of 11 GH-responders and in 5 of 16 GH non-responders.(ABSTRACT TRUNCATED AT 250 WORDS)