Somatostatin mediates the effect of growth hormone surges on splanchnic biogenic amines

Experiments were conducted in trained, conscious dogs fitted with an indwelling portal catheter. Radioenzymatic methods were employed for the quantitative measurement of plasma-free serotonin and catecholamines. An injection of ovine growth hormone (GH, 100 micrograms/kg) or an equimolar amount of somatostatin (somatotropin release inhibitory factor, SRIF, 7.5 micrograms/kg) into a saphenous vein led, within the first 15 min, to a transient but significant increase in plasma serotonin and a decrease in the concentrations of dopamine, norepinephrine, and epinephrine. The changes were frequently in excess of 40% of baseline values, and were found only in the portal and not in the peripheral circulation. When the animals were pretreated with an antiserum specifically directed against SRIF, GH surges no longer caused alterations in the portal levels of biogenic amines. Thus, the effects of spike concentrations of GH on plasma serotonin and catecholamines are apparently mediated by SRIF, a novel and unexpected function for a hormone that is known as an inhibitor of GH secretion.     

The effect of growth hormone on biogenic amines in the hepatic portal circulation of the dog

The effects of a spike concentration of growth hormone (GH) on hepatic portal and peripheral levels of free serotonin and catecholamines were studied by improved radioenzymatic methods in trained, conscious, normal, adult dogs fitted with an indwelling portal catheter. An injection of ovine GH (6 or 100 micrograms/kg) into a cephalic vein produced in the hepatic portal circulation a transient, statistically significant rise of serotonin and a concomitant significant reduction in the concentration of dopamine, norepinephrine, and epinephrine. No change was found in the peripheral circulation, partly because the amines were conjugated to sulfates and glucuronides and these derivatives are not detectable by our assays. Thus, a pulse of GH not only stimulates the release of pancreatic hormones and glucose turnover, but also affects the portal profile of glucoregulatory bioamines. The present investigation lends further support to our view that the splanchnic area represents an endocrine system whose preferential target is the liver.     

The effect of tryptophan on biogenic amines in the hepatic portal circulation of the dog

Mongrel dogs were fitted with indwelling hepatic portal catheters. After recovery from surgery, experiments were conducted in fasting, unrestrained, fully conscious, normal dogs which were accustomed to handling and withdrawal of blood samples. L-Tryptophan, a specific serotonin precursor, was injected into a saphenous vein, 10 microM/kg body weight, dissolved in saline. Plasma serotonin, dopamine, norepinephrine, and epinephrine were determined by radioenzymatic assays in blood samples withdrawn at frequent intervals for 2 h, simultaneously from the indwelling catheter and from a catheter temporarily inserted into a saphenous vein other than the one used for the injection of tryptophan. The injection of the amino acid caused a significant elevation of the concentration of platelet-free serotonin within 60 min and this was accompanied by a reduction in the concentration of the catecholamines, dopamine, norepinephrine, and epinephrine. The changes occurred only in the portal circulation and were not detected in peripheral blood samples. The results of these experiments indicate the existence of a cause and effect related interdependence between the splanchnic serotonergic and adrenergic systems in that the tryptophan-stimulated increase in serotonergic activity resulted in a concomitant reduction in gut adrenergic activity.     

Secretory bursts of growth hormone secretion in the dog may be initiated by somatostatin withdrawal

In 28 6-h experiments on 10 conscious resting trained male dogs, plasma growth hormone (GH) was determined at 5-min intervals by radioimmunoassay. For all experiments, the basal GH concentration in plasma was 0.80 +/- 0.06 ng mL-1. In each experiment, 1-3 secretory bursts of GH occurred, raising plasma GH 2.4 to 15.3 times basal concentrations (for all 43 bursts, 6.6 +/- 0.4 times the basal value). Metabolic clearance rates (MCR) and apparent distribution volumes (V) were determined, using stepwise infusions of canine GH. The MCR (3.99 +/- 0.30 mL kg-1 min-1) and V (57.9 +/- 5.5 mL kg-1) were used to transform the GH concentration versus time data into GH secretion rates, using a single compartment approach. Basal GH secretion rates for all 28 experiments were 3.12 +/- 0.24 ng kg-1 min-1. The secretory bursts yield peak GH secretion rates of 9.4 +/- 0.8 times basal secretion and these steep-sloped bursts last 25.1 +/- 1.2 min. Six-hour infusions of 0.15 microgram kg-1 min-1 of somatostatin (SRIF) abolished all secretory bursts but did not lower basal secretion rates. In five of seven SRIF infusion experiments in which samples were taken after the infusion ceased a secretory burst was seen in the hour following cessation of infusion (in four cases within 10 min). These secretory bursts lasted 23.0 +/- 2.9 min and were similar to those seen in control experiments. Infusions of SRIF at 0.05 microgram kg-1 min-1 had no effect. These results imply that during basal GH secretion, a surfeit of SRIF impinges on the somatotrophs, as extra SRIF does not further lower basal secretion. However, during secretory bursts, very little SRIF must be present, as exogenous SRIF blocks these bursts. The bursts are similar in duration to overshoots provoked in perifused dispersed rat somatotrophs by removal of an SRIF signal. It seems likely that their cause in vivo is similar. (All values are means +/- SEM.)     

The effect ofl-deprenyl on behavior,cognitive function,and biogenic amines in the dog

Behavioral and pharmacological effects of oral administration ofl-deprenyl in the dog are described. Spontaneous behavior is unaffected at doses below 3 mg/kg while at higher doses there was stereotypical responding. There was evidence of improved cognitive function in animals chronically treated with a 1 mg/kg dose but the effectiveness varied considerably between subjects. Chronic administration produced a dose dependent inhibition in brain, kidney and liver monoamine oxidase B, and had no effect on monoamine oxidase A. There were also dose dependent increases in brain phenylethylamine and in plasma levels of amphetamine. Dog platelets did not have significant levels of MAO-B. Brain dopamine and serotonin metabolism were unaffected byl-deprenyl at doses up to 1 mg/kg. It appears that for the dog, deamination of catecholamines is controlled by MAO-A. Nevertheless, it is suggested thatl-deprenyl serves as a dopaminergic agonist, and there is also evidence that it affects adrenergic transmission. These catecholaminergic actions may account for the effects ofl-deprenyl on behavior and cognitive function.     

Effects of passive immunization of growth hormone-releasing hormone and somatostatin on growth hormone secretion under conditions of high somatostatin tone.

Pulsatile GH secretion decreases during food-deprivation in the rat. It has been hypothesized that this decrease is due to elevated hypothalamic somatostatin secretion. This is based on the observation that GH increases in food-deprived rats following removal of endogenous somatostatin using passive immunization techniques. Cognizant of the important stimulatory effects of growth hormone-releasing hormone (GHRH) on GH secretion, we sought to determine if this neuropeptide plays any role in mediating GH secretion in food-deprived rats. Male rats were prepared with indwelling venous catheters using sodium pentobarbital anesthesia seven days prior to experimentation. Animals were food-deprived for 72 h, after which control blood samples were drawn from -60 to 0 min. One group was then treated with normal rabbit serum (NRS), while a second group was treated with GHRH antiserum (GHRHab). At 55 min all animals received somatostatin antiserum (SSab). No animal exhibited any spontaneous GH peak during the one hour control period or in the subsequent one hour period following the administration of GHRHab or NRS. Absence of GH pulsatility during food-deprivation, coupled with no decrease in GH levels in food-deprived rats treated with GHRHab suggest that diminished GHRH pulsatility is likely during food-deprivation. Subsequent treatment of these animals with SSab resulted in an identical 2.5 fold increase in GH concentrations. This result suggests that GHRH is not involved in the GH rebound following somatostatin withdrawal in food-deprived rats.     

The effect of immunization against somatostatin on growth rates and growth hormone secretion in the chicken

The effect of both active passive immunization against somatostatin on growth rate and growth hormone levels was studied in chickens. Passive immunization against somatostatin by administration of antiserum had no effect on rate of growth of chickens and no persistent effect on circulating growth hormone (GH) levels. In acute experiments, administration of anti-somatostatin serum caused a marked elevation of GH levels in chickens at both 4 and 8 weeks of age, but the relative stimulation was greater in the older birds. Active immunization against somatostatin significantly stimulated growth rate in chickens, but was not shown to have a clear effect on circulating GH levels. These data suggest that somatostatin control over GH secretion may not be fully developed in the chicken at 4 weeks of age, but that immuno-neutralization of somatostatin can produce an increase rate of growth in chickens similar to that seen in mammals.     

Developmental correlation between hypothalamic somatostatin and hypophysial growth hormone

Summary The objective of the present study was to determine, by means of immunocytochemistry, the age in fetal development at which GH is first detectable in the pituitary gland and somatostatin in the median eminence, and to correlate temporally the development of these two hormones throughout the remainder of pregnancy. Mice were studied at 15–19 days of gestation with the peroxidase-antiperoxidase (PAP) technique of Sternberger. Somatotropes in the pars distalis were initially detected at 16 days of gestation and by 17 days they were a prominent component of the parenchymal cell population of the hypophysis. These cells were ovoid and distributed uniformly throughout the pars distalis; many were located adjacent to sinusoidal capillaries. Their number and staining intensity increased by 19 days. Somatostatin was not consistently observed in the median eminence until 19 days of gestation. Reaction product indicative of the presence of somatostatin in presumptive nerve endings was located on the ventral surface of the median eminence and in the external lamina of the infundibulum in proximity to the superficial portal capillaries. Results of the present investigation support the concept that the potential for neuroendocrine control of GH secretion exists in the mouse by the end of fetal development. Several hypotheses concerning the temporal relationship between the appearance of somatostatin in the hypothalamus and of GH in the anterior pituitary gland are discussed.Supported by a Biomedical Research Support Grant (NIH RR 5417). Appreciation is extended to the National Pituitary Agency, NIAMDD for the following radioiodination-grade hormones: hGH, rPRL, rTSH, rFSH and hCG     

Insulin sensitivity in adults with growth hormone deficiency and effect of growth hormone treatment

Adult growth hormone deficiency (GHD) is a multifactorial disorder in which pituitary dysfunction associated with pituitary adenomas or their treatment plays a major role. The introduction of recombinant growth hormone (GH) for the treatment of GHD has opened up new treatment avenues but has also raised concerns about possible untoward long-term metabolic effects of GH, such as the potential effect of GH on insulin sensitivity and a deterioration in glucose tolerance. Research has shown that GH induces insulin resistance by the stimulation of lipolysis and a concomitant switch from oxidation of glucose to oxidation of lipids, during both acute and chronic treatment. However, although this is a consistent effect of GH therapy, it does not mean per se that it leads to abnormal glucose tolerance and diabetes mellitus. This article discusses this and other potential long-term metabolic effects of GH, and raises a number of questions to be addressed by future research.     

Feeding reduces activity of growth hormone-releasing hormone and somatostatin neurons

Secretion of growth hormone (GH) is synchronized among castrate male cattle (steers) around feeding when access to feed is restricted to a 2-hr period each day. Typically, concentrations of GH increase before and decrease after feeding. Our objectives were to determine whether i) concentrations of GH decrease in blood after start of feeding; ii) activity of immunoreactive growth hormone-releasing hormone (GHRH-ir) neurons decreases in the arcuate nucleus (ARC) after feeding; iii) activity of immunoreactive somatostatin (SS-ir) neurons in the periventricular nucleus (PeVN) and ARC increase after feeding; and iv) GHRH stimulates release of GH to a similar magnitude at 0900 and at 1300 hr, in steers fed between 1000 and 1200 hr. Blood samples were collected at 20-min intervals from 0700 to 1300 hr. Groups of steers were euthanized at 0700, 0900, 1100, and 1300 hr (n = 5 per group). Dual-label immunohistochemistry was performed on free-floating sections of hypothalami using antibodies directed against Fos and Fos-related antigens (Fos/FRA) as a marker of neuronal activity in immunoreactive GHRH and SS neurons. Concentrations of GH were high before and decreased after feeding. The percentage of SS-ir neurons containing Fos/FRA-ir in the PeVN was 50% lower (P<0.01) at 1100 hr and 36% lower (P<0.05) at 1300 hr than at 0900 hr. There was no change in percentage of SS-ir neurons containing Fos/FRA-ir in the ARC. The percentage of GHRH-ir neurons containing Fos/FRA-ir in the ARC was 66% lower (P<0.05) at 1100 hr and 65% lower (P<0.05) at 1300 hr than at 0700 hr. In contrast, the number of GHRH-ir neurons increased from 0700 to 1300 hr. GHRH-induced release of GH was suppressed at 1300 hr compared with 0900 hr. In conclusion, reduced basal and GHRH-induced secretion of GH after feeding was associated with decreased activity of GHRH neurons in the ARC and decreased activity of SS neurons in the PeVN.     

Effect of biogenic amines and cannabinoids on bacterial chemotaxis

The chemotactic response of Pseudomonas fluorescens was significantly enhanced by the stimulants dl-amphetamine and epinephrine. Acetylcholine, a physiological antagonist of epinephrine, and the cannabinoid tetrahydrocannabinol inhibited bacterial chemotaxis. It may be possible to use bacterial chemotaxis as a bioassay in biochemical studies of drug action.     

Interaction of human pancreatic growth hormone-releasing factor, thyrotropin-releasing hormone, and somatostatin on growth hormone release in chickens

The effects of synthetic somatostatin (SRIF) on serum growth hormone (GH) concentrations stimulated by exogenous administration of synthetic thyrotropin-releasing hormone (TRH) and/or human pancreatic GH-releasing factor (hpGRF) were investigated in 4-week-old cockerels. In addition, the additive effects of TRH and hpGRF on serum GH were examined. TRH and hpGRF, when given in combination intravenously, produced an additive effect on serum GH concentration that peaked 10 min after the injection. The somatostatin did not significantly affect basal GH concentrations when given alone, but did significantly decrease the magnitude of the GH response to hpGRF. In contrast, SRIF did not significantly decrease the stimulatory effects of TRH on GH release. These results suggest that TRH and hpGRF are potent GH releasers in vivo and that their stimulating effects on GH release are additive, suggesting different mechanisms for their stimulation. The results obtained from the combination studies suggest that the main site of the stimulatory action of hpGRF is at the pituitary, and that SRIF significantly inhibited the rise in serum GH induced by a synthetic hpGRF, but not that induced by TRH.