Effect of somatostatin on the secretin-induced gastric secretions of pepsin and mucus in cats

The effect of somatostatin 14 on gastric stimulation produced by secretin was determined in 6 conscious cats equipped with a gastric fistula and a denervated fundic pouch. Somatostatin strongly inhibited the basal and secretin-induced pepsin secretion. It did not, however, inhibit the secretin-induced mucus secretion, even though it decreased the basal mucus secretion. During somatostatin administration, the secretagogue effect of secretin on mucus secretion might be dissociated from its stimulatory action on pepsin secretion.     

Plasma and tissue levels of digestive regulatory peptides during postnatal development and weaning in the calf.

Changes in the concentrations of cholecystokinin, gastric inhibitory peptide, gastrin, motilin, pancreatic polypeptide, secretin, somatostatin, and vasoactive intestinal peptide in calf plasma and antral, duodenal and/or pancreatic tissues were assessed by radioimmunoassay during postnatal development and after weaning in 50 male Holstein-Friesian calves (randomly distributed into 10 groups of 5 animals each). The calves in the first group were killed at birth while those in 6 other groups were colostrum-fed for 2 days and then milk-fed until 7, 28, 56, 70 or 119 days of age. Those in the remaining 3 groups were given the same diets until day 28, were then weaned between day 29-56, and slaughtered on days 56, 70 or 119. In milk-fed animals, changes in plasma and tissue concentrations of almost all digestive regulatory peptides were observed during the 1st month of postnatal life, especially at day 2. Weaning was accompanied by variations in the plasma concentrations of somatostatin, secretin, gastrin, pancreatic polypeptide and gastric inhibitory peptide but not by any apparent change in peptide tissue concentrations (except VIP in the duodenum). Thus, the variations in tissue concentrations are primarily age-related, while plasma concentrations were modified by age and weaning.     

Agonism,Antagonism, and Inverse Agonism Bias at the Ghrelin Receptor Signaling

The G protein-coupled receptor GHS-R1a mediates ghrelin-induced growth hormone secretion, food intake, and reward-seeking behaviors. GHS-R1a signals through G_q, G_i/o, G₁₃, and arrestin. Biasing GHS-R1a signaling with specific ligands may lead to the development of more selective drugs to treat obesity or addiction with minimal side effects. To delineate ligand selectivity at GHS-R1a signaling, we analyzed in detail the efficacy of a panel of synthetic ligands activating the different pathways associated with GHS-R1a in HEK293T cells. Besides β-arrestin2 recruitment and ERK1/2 phosphorylation, we monitored activation of a large panel of G protein subtypes using a bioluminescence resonance energy transfer-based assay with G protein-activation biosensors. We first found that unlike full agonists, G_q partial agonists were unable to trigger β-arrestin2 recruitment and ERK1/2 phosphorylation. Using G protein-activation biosensors, we then demonstrated that ghrelin promoted activation of G_q, G_i1, G_i2, G_i3, G_oa, G_ob, and G₁₃ but not G_s and G₁₂. Besides, we identified some GHS-R1a ligands that preferentially activated G_q and antagonized ghrelin-mediated G_i/G_o activation. Finally, we unambiguously demonstrated that in addition to G_q, GHS-R1a also promoted constitutive activation of G₁₃. Importantly, we identified some ligands that were selective inverse agonists toward G_q but not of G₁₃. This demonstrates that bias at GHS-R1a signaling can occur not only with regard to agonism but also to inverse agonism. Our data, combined with other in vivo studies, may facilitate the design of drugs selectively targeting individual signaling pathways to treat only the therapeutically relevant function.     

Nanomolar Levels of Dimethylsulfoniopropionate, Dimethylsulfonioacetate, and Glycine Betaine Are Sufficient To Confer Osmoprotection to Escherichia coli

We combined the use of low inoculation titers (300 ± 100 CFU/ml) and enumeration of culturable cells to measure the osmoprotective potentialities of dimethylsulfoniopropionate (DMSP), dimethylsulfonioacetate (DMSA), and glycine betaine (GB) for salt-stressed cultures of Escherichia coli. Dilute bacterial cultures were grown with osmoprotectant concentrations that encompassed the nanomolar levels of GB and DMSP found in nature and the millimolar levels of osmoprotectants used in standard laboratory osmoprotection bioassays. Nanomolar concentrations of DMSA, DMSP, and GB were sufficient to enhance the salinity tolerance of E. coli cells expressing only the ProU high-affinity general osmoporter. In contrast, nanomolar levels of osmoprotectants were ineffective with a mutant strain (GM50) that expressed only the low-affinity ProP osmoporter. Transport studies showed that DMSA and DMSP, like GB, were taken up via both ProU and ProP. Moreover, ProU displayed higher affinities for the three osmoprotectants than ProP displayed, and ProP, like ProU, displayed much higher affinities for GB and DMSA than for DMSP. Interestingly, ProP did not operate at substrate concentrations of 200 nM or less, whereas ProU operated at concentrations ranging from 1 nM to millimolar levels. Consequently, proU⁺ strains of E. coli, but not the proP⁺ strain GM50, could also scavenge nanomolar levels of GB, DMSA, and DMSP from oligotrophic seawater. The physiological and ecological implications of these observations are discussed.     

Blockade of bombesin receptors with [Leu14-psi(CH2NH)-Leu13]bombesin fails to suppress nutrient-induced CCK release from rat duodenojejunum

The present study was undertaken in order to delineate the contribution of enteric bombesin (BBS)-containing nerves in the food-induced release of intestinal cholecystokinin (CCK). For this purpose, the isolated vascularly perfused rat duodenojejunum model was used and the new compound [Leu14-psi(CH2NH)-Leu13]BBS was infused intraarterially at a concentration of 10(-6) M to block the BBS receptors. Vascular infusion of BBS alone (10(-8) M or 10(-9) M) provoked a dose-dependent release of CCK-like immunoreactivity (CCK-LI). The secretion pattern of CCK was biphasic and consisted of a transient peak (300-400% above basal) followed by a sustained response (200-300% above basal). Vascular coinfusion of the BBS analogue with BBS 10(-9) M completely abolished both phases of CCK release while only the second phase of CCK secretion was profoundly reduced upon coadministration of BBS 10(-8) M with the BBS receptor antagonist. Luminal administration of mixed nutrients induced a prompt and well-sustained release of CCK-LI which was unaffected upon arterial infusion of the BBS analogue. These data suggest that the intestinal supply in BBS-producing nerves is not involved in the food-induced release of intestinal CCK in the rat.     

Ghrelin Stimulation of Growth Hormone-Releasing Hormone Neurons Is Direct in the Arcuate Nucleus

Background

Ghrelin targets the arcuate nucleus, from where growth hormone releasing hormone (GHRH) neurones trigger GH secretion. This hypothalamic nucleus also contains neuropeptide Y (NPY) neurons which play a master role in the effect of ghrelin on feeding. Interestingly, connections between NPY and GHRH neurons have been reported, leading to the hypothesis that the GH axis and the feeding circuits might be co-regulated by ghrelin.

Principal Findings

Here, we show that ghrelin stimulates the firing rate of identified GHRH neurons, in transgenic GHRH-GFP mice. This stimulation is prevented by growth hormone secretagogue receptor-1 antagonism as well as by U-73122, a phospholipase C inhibitor and by calcium channels blockers. The effect of ghrelin does not require synaptic transmission, as it is not antagonized by γ-aminobutyric acid, glutamate and NPY receptor antagonists. In addition, this hypothalamic effect of ghrelin is independent of somatostatin, the inhibitor of the GH axis, since it is also found in somatostatin knockout mice. Indeed, ghrelin does not modify synaptic currents of GHRH neurons. However, ghrelin exerts a strong and direct depolarizing effect on GHRH neurons, which supports their increased firing rate.

Conclusion

Thus, GHRH neurons are a specific target for ghrelin within the brain, and not activated secondary to altered activity in feeding circuits. These results support the view that ghrelin related therapeutic approaches could be directed separately towards GH deficiency or feeding disorders.     

Relationship between intravenous ethanol, alcohol-induced inhibition of pancreatic secretion and plasma concentration of immunoreactive pancreatic polypeptide, vasoactive intestinal peptide, and somatostatin in man

We have studied in seven men, consuming less than 50 g alcohol daily, the effect of intravenous (i.v.) ethanol on (a) hormonally (secretin + CCK PZ) submaximally stimulated pancreatic secretion and (b) blood levels of pancreatic polypeptide (PP), vasoactive intestinal peptide (VIP) and somatostatin. After intravenous ethanol (600 mg/kg), pancreatic secretion decreased in all subjects and plasma levels of PP and VIP increased significantly. Moreover, there was a significant correlation between the mean inhibition of chymotrypsin output and the mean increase in PP plasma levels during the first 45 min following ethanol infusion. Therefore i.v. infusion of alcohol elicits release of PP and VIP and PP release could explain in part at least the alcohol-induced pancreatic inhibition observed in non-alcoholic men.