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PubMed1984

Somatostatin-20: a novel NH2-terminally extended form of somatostatin isolated from porcine duodenum together with somatostatin-28 and somatostatin-25.

Liquid chromatography of porcine duodenal extracts, in conjugation with bioassay on guinea-pig ileum myenteric plexus longitudinal muscle preparation, yielded substances which inhibited electrically-evoked twitches of the preparations, but whose actions could not be reversed by naloxone, an opioid antagonist. The substances were determined to be NH2-terminally extended forms of somatostatin, i.e. somatostatin-28, somatostatin-25 and somatostatin-20. This is the first time that somatostatin-20 has been isolated from animal tissues.

Amino Acid Sequence↗

PubMed1983

A high molecular weight form of somatostatin-28 (1-12)-like immunoreactive substance without somatostatin-14 immunoreactivity in the rat pancreas. Evidence that somatostatin-14 synthesis can occur independently of somatostatin-28.

Synthesis of somatostatin-14 (S-14) could occur through direct enzymatic processing of precursor somatostatin (prosomatostatin) or via sequential breakdown of prosomatostatin leads to somatostatin-28 (S-28) leads to S-14. If direct processing is important, it should theoretically generate S-14 and a molecule equivalent to prosomatostatin without the S-14 sequence. In an attempt to identify such a molecule, I characterized the molecular forms of S-28(1-12)-like immunoreactivity (S-28(1-12) LI) in the rat pancreas and compared the relative amounts of these forms with those of S-14-like immunoreactivity (S-14 LI). Pancreatic extracts were chromatographed on Sephadex G-50 and Sephadex G-75 columns (Pharmacia Fine Chemicals Inc., Piscataway, NJ) under denaturing conditions and immunoreactivity in the eluting fractions was analyzed by region-specific radioimmunoassays (RIAs). For RIA of S-28(1-12) LI we used a newly developed rabbit antibody R 21 B, 125I-Tyr12 S-28(1-14), and S-28(1-12) standards. This system detects S-28, S-28(1-12), high molecular weight forms of S-28(1-12), but not S-14. S-14 LI was measured using antibody R149, which detects S-14, S-28, and higher molecular weight S-14-like substances, but not S-28(1-12). Three forms of S-28(1-12) LI were identified: Mr 9,000-11,000, Mr 1,200 (corresponding to S-28(1-12), and Mr less than 1,000, comprising, respectively, 35, 53, and 12% of total immunoreactivity. The relative abundance of the 9,000-11,000 mol wt S-28(1-12) LI material was unchanged following removal of S-14 LI from pancreatic extracts by affinity chromatography before gel filtration. Serial dilutions of fractions containing 9-11,000 and 1,200 mol wt materials exhibited parallelism with synthetic S-28(1-12). The total pancreatic concentration of S-28(1-12) LI was 1.56 pmol/mg protein, of which S-28(1-12) accounted for 0.83 pmol/mg protein and 9-11,000 S-28(1-12) LI comprised 0.55 pmol/mg protein. Pancreatic S-14 LI concentration was 2.07 pmol/mg protein, of which 98% corresponded to S-14. S-28-related peaks accounted for <1% of immunoreactivity in both RIAs. I concluded that (a) S-14 is the main form of pancreatic S-14 LI; (b) S-28 is present in very small quantities, in the pancreas; (c) S-28(1-12) LI consist mainly of S-28(1-12) and 9-11,000 mol wt S-28(1-12) LI; (d) 9-11,000 l wt S-28(1-12) LI could represent prosomatostatin without the S-14 sequence; (e) the finding of high concentrations of 9-11,000 mol wt S-28(1-12) LI suggests that S-14 synthesis can occur independently of S-28 and that direct processing of prosomatostatin is an important pathway for S-14 synthesis in the pancreas.

Animals↗

PubMed1995

Effects of insulin, glucagon, and somatostatin on the release of somatostatin-25 and somatostatin-14 from rainbow trout, Oncorhynchus mykiss, pancreatic islets in vitro.

Somatostatins are a diverse family of peptides known to modulate insulin and glucagon secretion as well as to stimulate glycogenolysis and lipolysis in salmonid fish. In this study, Brockmann bodies (bisected to yield hemi-islets) isolated from rainbow trout, Oncorhynchus mykiss, were used to study the effects of insulin, glucagon, and somatostatin at various concentrations of glucose (1, 5, and 10 mM) on pancreatic somatostatin release. The release of somatostatin-25, the most predominate form of somatostatin in salmonid pancreas, was stimulated by insulin in the presence of 1 and 5 mM glucose but not in the presence of 10 mM glucose, whereas glucagon stimulated somatostatin-25 release only in the presence of high (10 mM) glucose. Somatostatin-25 release also was stimulated by somatostatin-14. The secretion of somatostatin-14 was suppressed by insulin in the presence of 5 and 10 mM glucose and was stimulated by glucagon in the presence of high (10 mM) glucose. These results indicate that insulin, glucagon, and somatostatin-14 are regulators of somatostatin-14 and somatostatin-25 pancreatic release in rainbow trout and that these effects are modulated by glucose.

Animals↗

PubMed1999

Effects of somatostatin, somatostatin analogs, and endothelial cell somatostatin gene transfer on smooth muscle cell proliferation in vitro.

OBJECTIVE: Somatostatin analogs inhibit neointimal hyperplasia and smooth muscle cell (SMC) proliferation in vivo. The gene transfer of somatostatin to endothelial cells (ECs) represents a potential means of local delivery of somatostatin to areas of arterial injury. This study tested the hypothesis that the retroviral gene transfer of somatostatin to ECs would inhibit SMC proliferation in vitro and evaluated the effects of somatostatin analogs on DNA synthesis and the growth of SMCs. METHODS: Media transfer and coculture were used to determine the effects of somatostatin-producing ECs on SMC proliferation in vitro. The effects of a variety of somatostatin isoforms and analogs on the proliferation of SMCs, mitogenesis of serum-restimulated quiescent SMCs, and arterial explants were measured. RESULTS: Despite the production of biologically relevant concentrations of somatostatin by ECs, no inhibition of SMC proliferation was noted. Somatostatin analogs inhibited DNA synthesis in arterial explants but did not inhibit either DNA synthesis or growth of cultured SMCs, which showed a likely effect of somatostatin on the initial transition in SMC phenotype. CONCLUSION: Somatostatin exerts inhibitory effects on SMC proliferation only during the early transition to a proliferative phenotype. There are significant differences between this in vivo transition and the standard serum-restimulated model of cultured SMCs. These differences may account for the failure of somatostatin to inhibit SMC proliferation in the standard in vitro models.

Animals↗

PubMed1988

Somatostatin receptors on rat cerebrocortical membranes. Structural characterization of somatostatin-14 and somatostatin-28 receptors and comparison with pancreatic type receptors.

Somatostatin binding and cross-linking to its receptors on rat cerebrocortical membranes were characterized with [125I-Tyr1]somatostatin-14 and [125I-Leu8, D-Trp22, Tyr25]somatostatin-28. When [125I-Tyr1]somatostatin-14 was cross-linked to its receptors with the photoreactive cross-linker, N-(5-azido-2-nitrobenzoyloxy)succinimide, the hormone was specifically associated with a Mr = 72,000 protein band in the presence or absence of reducing agents. Affinity labeling of the Mr = 72,000 protein band was decreased with increasing concentrations of unlabeled somatostatin-14 and nonhydrolyzable guanine nucleotide analog, guanyl-5'-yl imidodiphosphate (Gpp(NH)p). Pretreatment of cerebrocortical membranes with islet-activating protein resulted in a decrease in subsequent labeled somatostatin-14 binding and affinity-labeling of the protein and abolished an inhibitory effect of somatostatin-14 on vasoactive intestinal peptide-stimulated increase in adenylate cyclase activity. When the affinity-labeled protein was solubilized with Zwittergent 3-12 and adsorbed to wheat germ agglutinin-agarose, it was eluted by N-acetylglucosamine. [125I-Leu8, D-Trp22, Tyr25]somatostatin-28 cross-linking to cerebrocortical and pancreatic membranes with the same photoreactive agent revealed specifically labeled protein bands of a Mr = 74,000 in cerebrocortical membranes and a Mr = 94,000 in pancreatic membranes, respectively. These results suggest that: 1) somatostatin receptor on cerebrocortical membranes is a monomeric glycoprotein with a Mr = 70,000 binding subunit, coupled to guanine nucleotide regulatory protein, and 2) the Mr = 70,000 protein may be a common receptor for somatostatin-28 and somatostatin-14 and is distinct from a common pancreatic type receptor.

Adenylyl Cyclases↗

PubMed1981

Somatostatin-28, somatostatin-14 and somatostatin analogs: effects on thermoregulation.

Somatostatins, somatostatin-14, somatostatin-28, and desAA [D-Trp8]-somatostatin, with differential potencies, act in the brain to reverse chemical-induced hypothermia and to produce hyperthermia. Somatostatins are more potent and loger acting than prostaglandin E2 in producing hyperthermia. Hyperthermia, induced by somatostatins, is not prevented by previous treatment with the prostaglandin synthesis inhibitor indomethacin. Somtostatins given to obese ob/ob mice prevent development of lethal hypothermia and result in maintenance of euthermia. Continuous infusion of somatostatins results in desensitization to the hyperthermic effects of these peptides. Endogenous somatostatins may be involved in regulation of body temperature.

Animals↗

PubMed1985

Localization and characterization of brain somatostatin receptors as studied with somatostatin-14 and somatostatin-28 receptor radioautography.

The localization and characterization of receptors for somatostatin-14 (S-14) and somatostatin-28 (S-28) were studied in the rat brain using the iodinated agonists [Tyr0,D-Trp8]S-14 and [Leu8,D-Trp22,Tyr25]S-28 as tracers. Slide-mounted frozen sections were used for the radioautographic localization and biochemical characterization of somatostatin receptors. In the latter case counting was performed on scraped off serial sections from rostral regions of the brain. Specificity studies demonstrated that either tracer could be displaced with S-28, S-14 or their agonists. The N-terminus fragment (1-12) of S-28 as well as a number of unrelated peptides were unable to compete with either tracer, indicating that the binding capacity for ligand-receptor recognition is located in the C-terminal portion of S-28. Scatchard analysis of saturation curves gave a one-site interaction with Kd values of 0.42 +/- 0.09 nM and 0.32 +/- 0.04 nM for the S-14 and S-28 iodinated agonists, respectively. By radioautography, the distribution of receptors for both S-14 and S-28 appeared very similar with high levels of binding in the deep layers of the cortex, the cingulate cortex, the claustrum, the locus coeruleus and most structures of the limbic system. Treatment with cysteamine, which caused a somatostatin depletion in the brain, was required to observe labeling in the hypothalamus. In some caudal areas of the brain, especially in the cerebellar nuclei, the solitary tract nucleus and the nucleus of the vagus nerve, only labeling with the S-28 agonist could be detected. This S-28 binding could be displaced by native S-14 (10(-6) M). Generally, there was a correlation between the localization of somatostatin receptors and that of immunoreactive somatostatin, as evaluated by immunocytochemistry. However, in some areas, an inverse correlation between receptor and peptide concentrations was observed. These results are in agreement with previous data suggesting that somatostatin could act as a neurotransmitter or neuromodulator in several brain areas.

Animals↗

PubMed1998

Effects of the two somatostatin variants somatostatin-14 and [Pro2, Met13]somatostatin-14 on receptor binding, adenylyl cyclase activity and growth hormone release from the frog pituitary.

Two isoforms of somatostatin from frog brain have been recently characterized, namely somatostatin-14 (SS1) and [Pro2, Met13]somatostatin-14 (SS2). The genes encoding for the precursors of these two somatostatin variants are expressed in hypothalamic nuclei involved in the control of the frog pituitary. The aim of the present study was to investigate the effect of SS1 and SS2 on adenohypophysial cells. Autoradiographic studies using [125I-Tyr, D-Trp8] SS1 as a radioligand revealed that somatostatin binding sites are evenly distributed in the frog pars distalis. The SS2 variant was significantly (P < 0.01) more potent than SS1 in competing with the radioligand (IC50= 1.2 +/- 0.2 and 5.6 +/- 0.6 nM, respectively). Both SS1 and SS2 induced a modest but significant reduction in cAMP formation in dispersed distal lobe cells but did not affect spontaneous growth hormone (GH) release. Synthetic human GRF (hGRF) induced a significant increase in cAMP accumulation and GH release in this system. Both SS1 and SS2 inhibited the stimulatory effects of hGRF on cAMP formation and GH secretion. These data show that the SS1 and SS2 variants can regulate adenohypophysial functions. The fact that GH cells are exclusively located in the dorsal area of the frog adenohypophysis, while somatostatin receptors are present throughout the pars distalis, indicates that the two somatostatin isoforms may control the secretion of pituitary hormones additional to GH in amphibians.

Adenylyl Cyclases↗

PubMed1984

Enzymes processing somatostatin precursors: an Arg-Lys esteropeptidase from the rat brain cortex converting somatostatin-28 into somatostatin-14.

The post-translational proteolytic conversion of somatostatin-14 precursors was studied to characterize the enzyme system responsible for the production of the tetradecapeptide either from its 15-kDa precursor protein or from its COOH-terminal fragment, somatostatin-28. A synthetic undecapeptide Pro-Arg-Glu-Arg-Lys-Ala-Gly-Ala-Lys-Asn-Tyr(NH2), homologous to the amino acid sequence of the octacosapeptide at the putative Arg-Lys cleavage locus, was used as substrate, after 125I labeling on the COOH-terminal tyrosine residue. A 90-kDa proteolytic activity was detected in rat brain cortex extracts after molecular sieve fractionation followed by ion exchange chromatography. The protease released the peptide 125I-Ala-Gly-Ala-Lys-Asn-Tyr(NH2) from the synthetic undecapeptide substrate and converted somatostatin-28 into somatostatin-14 under similar conditions (pH 7.0). Under these experimental conditions, the product tetradecapeptide was not further degraded by the enzyme. In contrast, the purified 15-kDa hypothalamic precursor remained unaffected when exposed to the proteolytic enzyme under identical conditions. It is concluded that this Arg-Lys esteropeptidase from the brain cortex may be involved in the in vivo processing of the somatostatin-28 fragment of prosomatostatin into somatostatin-14, the former species being an obligatory intermediate in a two-step proteolytic mechanism leading to somatostatin-14.

Animals↗

PubMed1998

Interrelationships between somatostatin sst2A receptors and somatostatin-containing axons in rat brain: evidence for regulation of cell surface receptors by endogenous somatostatin.

Using an antipeptide antibody, we reported previously on the distribution of the somatostatin sst2A receptor subtype in rat brain. Depending on the region, immunolabeled receptors were either confined to neuronal perikarya and dendrites or distributed diffusely in tissue. To investigate the functional significance of these distribution patterns, we examined the regional and cellular relationships between somatostatin axons and sst2A receptors in the rat CNS, using double-labeling immunocytochemistry. Light and confocal microscopy revealed a significant correlation (p < 0.02) between the distribution of somatodendritic sst2A receptor immunoreactivity and that of somatostatin terminal fields, both quantitatively and qualitatively. Furthermore, in regions of somatodendritic labeling, a subpopulation of sst2A-immunoreactive cells was also immunopositive for somatostatin, suggesting that a subset of sst2A receptors consists of autoreceptors. By contrast, in regions displaying diffuse sst2A labeling only moderate to low densities of somatostatin terminals were observed, and no significant relationship was found between terminal density and receptor immunoreactivity. At the electron microscopic level, areas expressing somatodendritic sst2A labeling were found by immunogold cytochemistry to display low proportions of membrane-associated, as compared with intracellular, receptors. Conversely, in regions displaying diffuse sst2A receptor labeling, receptors were predominantly associated with neuronal plasma membranes, a finding consistent with the high density of sst2 binding sites previously visualized in these areas by autoradiography. Double-labeling studies demonstrated that in the former but not in the latter regions, sst2A-immunoreactive somata and dendrites were heavily contacted by somatostatin axon terminals. Taken together, these results suggest that the low incidence of membrane-associated receptors observed in regions of somatodendritic sst2A labeling may be caused by downregulation of cell surface receptors by endogenous somatostatin, possibly through ligand-induced receptor internalization.

Animals↗

PubMed1986

Evidence of somatostatin as a humoral modulator of motilin release in man. A study of plasma motilin and somatostatin during intravenous infusion of somatostatin, secretin, cholecystokinin, and gastric inhibitory polypeptide.

In six healthy persons receiving graded intravenous infusions of synthetic somatostatin the plasma motilin concentrations decreased significantly (p less than 0.05) already with doses giving physiological plasma somatostatin levels, and a rebound of plasma motilin was observed after cessation of infusion of pharmacological somatostatin doses. After an intravenous secretin infusion (280 pmol/kg-h) producing pharmacological plasma secretin concentrations, a comparable plasma somatostatin increase was observed together with a substantial decrease in plasma motilin (p less than 0.05). Infusion of cholecystokinin in a pharmacological dose and of gastric inhibitory polypeptide (GIP) in doses giving plasma GIP levels in the physiological range had no effect on plasma somatostatin or motilin. Circulating plasma somatostatin may be a physiological modulator of the motilin release, and the plasma motilin fall seen during infusion of pharmacological doses of secretin may possibly be explained by the secretin-induced somatostatin release occurring simultaneously.

Adult↗

PubMed1985

The somatostatin-28 convertase of rat brain cortex generates both somatostatin-14 and somatostatin-28.

The products generated after addition of the ARG-LYS esteropeptidase activity purified from rat brain to synthetic somatostatin-28 were analyzed using radioimmunoassay, HPLC and amino acid analysis. In addition to somatostatin-14, both free arginine and free Lysine were identified together with somatostatin-28. The dipeptide ARG-LYS was not present, which indicates that three peptide bonds were hydrolyzed in order to achieve excision of the doublet. Since it is likely that the octacosapeptide is a precursor for both somatostatin-14 and somatostatin-28, these observations add further support to the hypothesis that the convertase is also involved in the in vivo processing of endogenous somatostatin-28.

Animals↗

PubMed1992

Isolation of [Pro2,Met13]somatostatin-14 and somatostatin-14 from the frog brain reveals the existence of a somatostatin gene family in a tetrapod.

Two somatostatin-related peptides were isolated in pure form from an extract of the brain of the European green frog, Rana ridibunda. The primary structure of the most abundant component was identical to that of mammalian somatostatin-14. The primary structure of the second component, present in approximately 5% of the abundance of somatostatin-14, was established as Ala-Pro-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Met-Cys. This sequence shows two substitutions (Pro for Gly2 and Met for Ser13) compared with mammalian somatostatin-14. The data provide evidence for a somatostatin gene family in tetrapods as well as in teleost fish.

Amino Acid Sequence↗

PubMed1984

Subcellular distribution of somatostatin-14, somatostatin-28 and somatostatin-28 (1-12) in rat brain cortex and comparisons of their respective binding sites in brain and pituitary.

Subcellular distribution and binding characteristics of the three endogenous peptides somatostatin-14 (SRIF-14), somatostatin-28 (SRIF-28) and somatostatin-28(1-12) (SRIF-28(1-12] derived from preprosomatostatin were investigated in the rat brain cortex. The three peptides are predominantly recovered from a crude mitochondrial pellet (P2), containing the pinched off nerve endings. Specific high affinity binding sites for 125I-N-Tyr-SRIF-14 and 125I-N-Tyr-SRIF-28 are present on pituitary and brain membranes. Under the same conditions, 125I-N-Tyr-SRIF-28(1-12) binding is undetectable. Moreover, SRIF-28(1-12) does not displace 125I-N-Tyr-SRIF-14 or 125I-N-Tyr-SRIF-28 binding. SRIF-28 is more potent than SRIF-14 to displace 125I-N-Tyr-SRIF-28 binding to brain and pituitary membranes, while both peptides are equipotent to displace 125I-N-Tyr-SRIF-14 binding. Finally, the regional distribution of 125I-N-Tyr-SRIF-14 and 125I-N-Tyr-SRIF-28 binding sites in the brain is identical. In conclusion, the present results are consistent with a neurotransmitter and neurohormonal role for SRIF-14 and SRIF-28. The function of SRIF-28(1-12) in brain remains to be elucidated. Additionally, a differential role for SRIF-14 and SRIF-28 both in adenohypophysis and brain cannot be ascertained at the present time.

Animals↗

PubMed1985

Somatostatin-14 and somatostatin-28 pretreatment down-regulate somatostatin-14 receptors and have biphasic effects on forskolin-stimulated cyclic adenosine, 3',5'-monophosphate synthesis and adrenocorticotropin secretion in mouse anterior pituitary tumor cells.

Activation of somatostatin-14 (S-14) receptors on mouse AtT-20 pituitary tumor cells by S-14 or somatostatin-28 (S-28) inhibits forskolin-stimulated cAMP synthesis and ACTH secretion. In this study, the effects of prolonged exposure of cells to S-14 or S-28 was found to reduce, in a time- and concentration-dependent fashion, the density of S-14 receptors without affecting the affinity of these sites for [125I]Tyr11-S-14. This response was rapidly reversible after removal of peptide from incubation media. Additionally, S-14 and S-28 pretreatment also resulted in a time-dependent sensitizing effect on forskolin-stimulated cAMP formation and ACTH secretion which preceded S-14 receptor down-regulation. Enhancement of the forskolin response was concentration dependent, with maximal effects observed at 10(-8) M with either peptide. Higher pretreatment concentrations of S-14 resulted in an abolition of the enhanced biological response to forskolin; pretreatment with S-28 (10(-6) M) depressed forskolin- and (-)isoproterenol-induced cAMP formation below levels observed in nonpretreated cells. The enhancing effect of S-14 and S-28 required new protein synthesis, since it was partially blocked by cycloheximide; the depressor effect was independent of new protein synthesis. Both the enhanced and depressed forskolin responses after peptide pretreatment were reversible after withdrawal of S-14 or S-28; normalization of the forskolin response (cAMP formation and ACTH secretion) followed the return to control levels of S-14 receptor density. Pretreatment of cells with 10(-8) M or 10(-6) M S-28 increased and decreased, respectively, the ACTH secretory response to agonists which act in the absence of prior cAMP synthesis such as 8-bromo-cAMP, A-23187, and phorbol ester. The data suggest that S-14 receptor down-regulation is not causally associated with the sensitizing effects of S-14 and S-28 on adenylate cyclase and that the S-14 receptor may be also coupled to other effector systems which are involved in regulating the secretory function of AtT-20 cells.

Adenylyl Cyclases↗

PubMed1983

Regional distribution of the Mr 15,000 somatostatin precursor, somatostatin-28 and somatostatin-14 in the rat brain suggests a differential intracellular processing of the high molecular weight species.

Three different forms of immunoreactive somatostatin (Mr 15,000, 3,000 and 1,600) were immunologically detected in extracts made from six neural structures of the rat brain. The largest represents the proform, while the smaller were identified by high pressure liquid chromatography with bovine somatostatin-28 (S-28) and -14 (S-14) respectively. In each of the brain structures studied highly variable proportions of precursor, S-28 and S-14 were found. These observations provide suggestive evidence that the intracellular processing of the 15,000 Mr proform may occur differently in the various somatostatinergic pathways of the brain. They argue in favor of a biological role for the precursor in providing distinct relative proportions of S-14 and S-28 in specific rat brain regions.

Animals↗

PubMed2006

Somatostatin and dopamine-somatostatin multiple ligands directed towards somatostatin and dopamine receptors in pituitary adenomas.

AIM: We report the comparative efficacy of octreotide, cabergoline and multiple ligands directed towards the different somatostatin subtypes (ssts), such as BIM-23A779 and SOM-230, and of chimeric analogs which bind both somatostatin and the dopamine D2 receptors (D2R), such as BIM-23A760 and BIM-23A781, in cell cultures from human growth hormone (GH)-secreting pituitary adenomas. PROCEDURES: RT-PCR analysis of the quantitative expression of the different ssts and D2R mRNAs was performed on tumor fragments of 22 GH-secreting adenomas collected after surgery. Pharmacological studies, using the different ligands, were performed on cell cultures of such tumors. RESULTS: sst2, sst5 and D2R were constantly coexpressed in all tumors, in variable amounts. The levels of expression of sst2 and D2R mRNAs were significantly correlated with the maximal GH suppression by either octreotide or cabergoline (p < 0.001). In each tumor tested, 3 patterns of response, in terms of GH suppression, were observed. GH secretion was preferentially inhibited by the sst2 preferential compound octreotide in 61% of the tumors. In 19% of the tumors, the maximal inhibition of GH release was achieved with the sst5 preferential compound BIM-23268. The dopamine analog cabergoline was the most effective inhibitor of GH secretion in 21% of cases. Among the compounds tested, the most potent inhibitors of GH secretion were the sst2, sst5, D2R chimeric compound BIM-23A760, followed by the sst universal ligand SOM-230. CONCLUSIONS: The variable patterns of response to sst2, sst5 and dopamine D2 analogs may explain the greater efficacy of drugs which bind to the 3 receptors in suppressing GH secretion. The biological potency (EC50) and efficacy of the chimeric compound BIM-23A760 on GH secretion can be partly explained by its high affinity for sst2. The effect of multiple receptor activation on the functions of other pituitary tumor types, such as prolactinomas and corticotropinomas, is not presently analyzed, and the efficacy of multireceptor ligands remains to be elucidated.

Adenoma↗

PubMed1985

Cysteamine induces a loss of tissue somatostatin-28 when measured as somatostatin-28(15-28)-like immunoreactivity but not when assessed as somatostatin-28(1-14)-like immunoreactivity: evidence for the importance of the disulfide bond for cysteamine action.

The reported loss of somatostatin-14 (S-14)-like immunoreactivity (LI) by cysteamine (CSH) could be mediated through an action on the S-14 disulfide bond. If so, then in the case of somatostatin-28 (S-28) (a linear 14 amino acid N-terminally extended form of S-14), it should be possible to demonstrate with region-specific antisera, a selective effect of CSH on the disulfide bond containing C-terminal half of the molecule. To obtain evidence for this, we have determined by RIAs, the effect of CSH on S-28 concentration measured separately as S-28(15-28) LI and S-28(1-14) LI in the jejunal mucosa, a tissue rich in S-28. Four hours after a single sc injection of CSH to rats, mucosal S-28(15-28) LI was reduced from 16.4 +/- 0.6 to 4.6 +/- 0.51 pmol/mg protein (P less than 0.01). By contrast, S-28(1-14) LI sustained no loss and in fact increased from 27.6 +/- 1.9 to 41.6 +/- 2.2 pmol/mg protein (P less than 0.01). On Sephadex G-50 columns (in 6 M urea) approximately 70% of S-28(15-28) LI and S-28(1-14) LI coeluted with synthetic S-28 marker. These data suggest that CSH acts on the 15-28 segment of the S-28 molecule and renders it nonimmunoreactive probably through interaction with the disulfide bond. This mechanism probably also accounts for CSH-induced S-14 loss.

Animals↗