ABSTRACT

Dopamine and morphine modulate GH and LH release, probably at a hypothalamic locus. To investigate this in more detail, we studied the influence of these substances on somatostatin and LH-releasing hormone (LHRH) release from rat hypothalamic fragments in vitro. Hypothalamic fragments were incubated in Earle's medium. After 60 min of preincubation, medium from two 20-min incubations was collected and somatostatin and LHRH levels measured by radioimmunoassay. Dopamine (10 nmol/l–0·1 mmol/l) induced a progressive increase (r = 0·41; P <0·01) in basal somatostatin levels. K ⁺ (30 mmol/l)-induced somatostatin release was also increased (r = 0·54; P <0·01) by increasing doses of dopamine. Metoclopramide (10 μmol/l) blocked the dopamine (1 μmol/l)-induced increase in somatostatin release. No significant relationship between dopamine and LHRH was found either basally or after K ⁺ (30 mmol/l) stimulation. Basal somatostatin was negatively correlated (r = −0·63; P <0·01) with morphine concentrations. No significant correlation was found after K⁺ (30 mmol/l) depolarization. Basal LHRH release was not influenced by morphine, while K ⁺(30 mmol/l)-induced release was significantly lower than controls only at a concentration of 10 nmol/l. These results suggest that dopamine and morphine act at a hypothalamic level to modulate GH release through alterations in somatostatin secretion. Dopamine and morphine have no consistent effect on hypothalamic LHRH release.

J. Endocr. (1985) 106, 317–322

Levels of endogenous somatostatin, gastric inhibitory polypeptide (GIP), glucagon and insulin were measured during gastric (abomasal) emptying in the conscious calf. Isotonic NaHCO₃ infused into the duodenum increased rates of emptying of a saline test meal and of gastric acid secretion, but had no effect on basal levels of blood glucose, somatostatin, GIP, insulin or glucagon. By contrast, intraduodenal infusion of 60 mm-HCl caused complete inhibition of gastric emptying, reduction of acid secretion, and an immediate increase in plasma somatostatin from 121·3 ± 9·4 (s.e.m.) to 286·3 ± 16·3 pg/ml (P <0·01) but levels of GIP, insulin, glucagon and glucose were unaltered. Intravenous injection of somatostatin (0·5 μg/kg) suppressed the antral electromyographic recording and gastric efflux so long as plasma somatostatin levels remained above approx. 200 pg/ml. This suggests that somatostatin can be released by intraduodenal acidification and that it inhibits gastric function by an endocrine effect. Since somatostatin retards gastric emptying it may therefore have an indirect role in nutrient homeostasis by limiting discharge of gastric chyme to the duodenum.

Abstract

Somatostatins are a diverse family of peptides that influence various aspects of animal growth, development, and metabolism. Recent work in our laboratory has shown that somatostatins stimulate hepatic lipolysis in rainbow trout. In this study we characterized somatostatin-binding sites in trout hepatic membrane preparations. We also examined changes in binding characteristics brought about by food deprivation. Binding of [Tyr¹¹]-somatostatin-14 (SS-14) was saturable, reversible, and time- and temperature-dependent. Under optimal conditions, [Tyr¹¹]-SS-14 specific binding averaged 5·7 ± 0·3%. While SS-14 and SS-28 (an N-terminally extended form of SS-14 and derived from the same gene as SS-14) displaced [Tyr¹¹]-SS-14 specific binding (ED₅₀ values of approximately 50 nm and 100 nm respectively), salmon SS-25 (containing [Tyr⁷,Gly¹⁰]-SS-14 at its C terminus and presumably derived from a gene different from that giving rise to SS-14/SS-28), except at pharmacological concentrations, did not. Significant specific binding was also detected in brain, esophagus, stomach, upper and lower intestine, pancreas, and adipose tissue. Scatchard analysis suggested the existence of two classes of hepatic somatostatin-binding sites: a high-affinity site with a K _d of 23 nm and B_max of 1·4 pmol/mg protein and a low-affinity site with a K _d of 379 nm and B_max of 4·9 pmol/mg protein. Fasting resulted in reduced growth and elevated plasma levels of SS-14 compared with fed animals. SS-14 binding capacity of the high-affinity class in liver membranes isolated from fasted fish increased by 120% over that from fed counter-parts. No difference in K _d for the high-affinity binding class or in either K _d or B_max of the low-affinity class was noted between fasted and fed animals. These data support the role of the liver as a target of somatostatin and suggest that fasting enhances hepatic sensitivity to SS-14 binding.

Journal of Endocrinology (1996) 150, 179–186

ABSTRACT

Pancreatic somatostatin-like immunoreactivity (SLI), immunoreactive insulin (IRI) and glucagon-like immunoreactivity (GLI) were measured during growth in ducks. The content of each hormone increased progressively but at different rates in the dorsal, ventral and splenic lobes of the pancreas. In the almost fully grown duck, the splenic lobe contained 80 and 63% of the total content of GLI and SLI respectively but low levels of IRI (23%), which were highest in the dorsal lobe (53%). In contrast to the hormonal content, only total GLI concentrations increased during development, the SLI concentrations remaining stable and IRI concentrations declining during growth. Gel filtration of pancreatic extracts indicated that most of the SLI in the pancreas of young and adult birds was somatostatin-14, although somatostatin-28 was present in the ventral lobe of young birds and larger molecular forms were present in the ventral and dorsal lobes. These changes in pancreatic hormonal content and concentration are dissimilar to age-related changes in SLI, GLI and IRI previously observed in the plasma of ducks. Plasma levels of pancreatic hormones may thus be controlled by hormonal and/or neural factors during post-hatch growth.

J. Endocr. (1987) 113, 65–70

ABSTRACT

To examine the characteristics of GH secretion following the termination of the infusion of somatostatin, unrestrained adult female Wistar rats were subjected to repeated infusions of somatostatin separated by 30-min control periods. When somatostatin was infused for 150 min at a dose of 3, 30 or 300 μg/kg body wt per h, the magnitude of the rebound GH secretion increased in a dose-dependent manner. The infusion of somatostatin at a dose of 300 μg/kg body wt per h for 60, 150 or 240 min progressively augmented the size of the rebound GH secretion. When an antiserum to rat GH-releasing factor (GRF) was injected i.v. 10 min before the end of the infusion, the peak amplitude of the rebound GH secretion (300 μg/kg body wt, 150 min) was reduced to less than 20% of that of control rats. The rebound GH secretion (300 μg/kg body wt per h, 150 min) was augmented by a bolus injection of human GRF (1 μg/kg body wt). The combined effect of the end of infusion of somatostatin and a bolus injection of GRF on the amount of GH secreted was additive. The plasma GH response to GRF was completely inhibited when human GRF (3 μg/kg body wt per h) and somatostatin (300 μg/kg body wt per h) were infused simultaneously for 150 min. The magnitude of the rebound GH secretion following the termination of the co-administration was larger than that following the somatostatin infusion alone, but this rebound was not enhanced by a bolus injection of human GRF. Moreover, the amount of GH secreted was significantly less than that after the termination of somatostatin infusion plus a bolus injection of human GRF in the absence of preceding GRF administration.

These results suggest that at least part of the influence of somatostatin on GH secretion is exerted at the level of the hypothalamus through modulating the release of GRF. In addition, it is inferred that the simultaneous infusion of GRF and somatostatin induces the attenuation of the GH response to GRF through a receptor effect.

Journal of Endocrinology (1989) 122, 583–591

ABSTRACT

Patterns of prolactin release were examined using stimulating and inhibiting agents. Primary cultured pituitary cells primed with oestrogens were used for perifusion experiments. TRH (100 nmol/l) increased the peak prolactin concentration to 360% of the basal concentration, while TRH, under inhibition by 1 nmol somatostatin/l, raised the peak prolactin concentration to 185% of the basal levels. When the somatostatin concentration was increased to 10, 100 and 1000 nmol/l, TRH still stimulated prolactin release to 128%, 121% and 140% respectively, indicating that concentrations of somatostatin of 10 nmol/l or higher did not further suppress the stimulatory effect of TRH. TRH (1 μmol/l) stimulated prolactin release under the influence of 0 (control), 1, 10, 100 and 1000 nmol dopamine/l (plus 0·1 mmol ascorbic acid/l) to 394, 394, 241, 73 and 68% of the basal concentration respectively, showing that the dopamine concentrations and peak prolactin concentrations induced by TRH have an inverse linear relationship in the range 1–100 nmol dopamine/l. The stimulatory effect of dibutyryl cyclic AMP (dbcAMP) on prolactin release was also tested. The relationship between dbcAMP and somatostatin was similar to that between TRH and somatostatin. When adenohypophyses of male rats were used for perifusion experiments, somatostatin (100 nmol/l) did not inhibit basal prolactin release from the fresh male pituitary in contrast with the primary cultured pituitary cells, but dopamine (1 μmol/l) effectively inhibited prolactin release.

In conclusion, (1) oestrogen converts the somatostatin-insensitive route into a somatostatin-sensitive route for basal prolactin release, (2) TRH-induced prolactin release passes through both somatostatin-sensitive and -insensitive routes, (3) dopamine blocks both somatostatin-sensitive and -insensitive routes and (4) cAMP activates both somatostatin-sensitive and -insensitive routes.

Journal of Endocrinology (1991) 130, 79–86

The effects of two [d-Cys¹⁴]-analogues of somatostatin on basal plasma levels of glucagon, insulin and glucose were determined in unanaesthetized rats to re-examine a glucagon-selective action of these peptides which has been claimed by others. Somatostatin, [d-Cys¹⁴]-somatostatin and [d-Trp⁸, d-Cys¹⁴]-somatostatin caused a short-lasting, dose-dependent decrease of plasma glucagon and insulin but they had no significant influence on plasma glucose. Glucagon and insulin reached the nadir 2 min after intravenous injection of the peptides (dose range 1–10 μg/kg) or 5 min after subcutaneous administration (30 and 300 μg/kg). At the nadir, insulin was decreased to a greater extent than glucagon and the effects of all three peptides were equipotent. However, in the period after the nadir and at high doses, the time-course of some effects of the analogues on either glucagon or insulin differed from that of somatostatin. Thus, these [d-Cys¹⁴]-analogues may show partial kinetic dissociation of effects on glucagon and insulin but they are not truly selective inhibitors of glucagon release.

ABSTRACT

Immunoreactive somatostatin and substance P were determined in extracts of alimentary tract (stomach to colon) from the following groups of adult female mice: intact control, ovariectomized, ovariectomized and treated with oestradiol (50 μg/kg per day) and/or progesterone (2 mg/kg per day) for 30 days, 19-day-pregnant, and 10-day-postpartum lactating. Ovariectomy increased the somatostatin concentration of the stomach (by 52%, P < 0·05), jejunum (by 116%, P < 0·01) and caecum (by 114%, P < 0·01). These effects were partially or totally prevented by the oestradiol and progesterone treatments, especially the oestradiol-progesterone combination, except for an increase (by 126%, P < 0·01) in gastric somatostatin after treatment with oestradiol alone. Lactation also increased gastric somatostatin (by 108%, P < 0·001), but the somatostatin concentration of other regions of the alimentary tract (jejunum to colon) was reduced (by 21–55%, P < 0·05) in pregnant and lactating mice. The concentration of substance P was increased by ovariectomy in stomach (by 69%, P < 0·01), duodenum (by 84%, P < 0·05), ileum (by 163%, P < 0·001) and caecum (by 57%, P < 0·01). This effect was partially or totally prevented by treatment with progesterone alone and by the oestradiol-progesterone combination, but not by oestradiol alone. Pregnancy and lactation increased gastric substance P by 46% (P < 0·01) and 61% (P < 0·001) respectively, but substance P concentrations in other regions of the alimentary tract were not significantly altered. The results suggest that ovarian oestrogens and progestogens are important in the maintenance of normal concentrations of somatostatin and substance P in the gastrointestinal tract of female mice.

Journal of Endocrinology (1989) 122, 645–650

ABSTRACT

The present study investigated the effect of administration of somatostatin (SRIF) on the release of prolactin in men. No effect was observed when SRIF was administered to eugonadal men. Release of prolactin was inhibited, however, when SRIF was administered to oestrogen-treated agonadal subjects (male-to-female trans-sexuals) and to an even greater degree when subjects had been pretreated with a combination of oestrogen and cyproterone acetate. This is consistent with findings in the rat. Thus in man, as in the rat, SRIF can inhibit prolactin secretion, but only after treatment with oestrogen.

J. Endocr. (1984) 103, 333–335

Somatostatin is a neuropeptide that is widely distributed throughout the body. It acts as a neurohormone and a neurotransmitter and may also have an immunomodulatory role. The genes for five subtypes of somatostatin receptors (sst) have been cloned, suggesting that the diverse effects of the peptide might be mediated by different receptors. We are interested in studying the role of sst ininflammation, using an animal model. Because of the up-regulation of sst expression in inflamed joints in human rheumatoid arthritis, we chose rat adjuvant arthritis as an experimental model. In order to determine which of the sst subtypes might be important in immune modulation, subtype expression in leukocytes isolated from different lymphoid tissues of the rat was studied. Also, the expression levels of the most abundantly expressed sst mRNAs in leukocytes from spleen and blood were compared in rats with adjuvantarthritis and controls, using a semi-quantitative approach. Furthermore, the effect of systemic administration of a long-acting somatostatin analogue, octreotide, which binds selectively to sst subtypes 2 and 5 (sst2 and sst5), on the incidence and the severity of rat adjuvant arthritis, was studied. The main sst expressed in cells of the rat immune system, both resting and activated, were found to be sst3 and sst4. This contrasts with the human and murine situations, in which sst2 appears to be the main subtype expressed in the immune system. No quantitative differences in sst subtype mRNA levels in leukocytes from spleen and blood were found between rats with adjuvant arthritis and controls. Finally, no effect of systemic administration of octreotide on either the incidence or severity of adjuvant arthritis in Lewis rats was found. As octreotide binds selectively to sst2 and sst5, the absence of an immunomodulatory effect of this analogue in rat adjuvant arthritis corroborates our finding that these sst subtypes are not expressed in cells of the rat immune system. In conclusion, cells of the rat immune system appear to express a spectrum of sst (sst3 and sst4) different from that found in human granulomatous and autoimmune disease (mainly sst2). Therefore, the rat adjuvant arthritis model appears to be suitable only for studying the immunomodulatory effects of somatostatin analogues which have a high affinity for sst3 and sst4, but not for studying the immunomodulatory effects of octreotide, which has a high affinity only for sst2 and sst5.