Postinhibitory overshoot of insulin release by gastric inhibitory polypeptide

Following intravenous infusion of somatostatin $\text{in vivo}$ occasionally there is a large rebound overshoot of insulin release. An $\text{in vitro}$ model to simulate this phenomenon was made by perfusing rat pancreas with gastric inhibitory polypeptide (GIP) during simultaneous perfusion with somatostatin. Adding GIP (100 ng/ml) to the perfusate for 2 minutes beginning either 3 or 9 minutes before terminating the somatostatin perfusion produced a large overshoot in insulin release. The magnitude of overshoot was greater when medium contained 300 mg/dl glucose that when it contained 150 mg/dl glucose. Perfusion with GIP for 2 minutes beginning 9 minutes before increasing the glucose concentration of the medium from 30 to 300 mg/dl elicited a large increase in both the acute and second-phase release of insulin. These suggest that post-inhibitory overshoot of insulin release after somatostatin may be produces $\text{in vitro}$ by the suppressed action of stimulatory hormones such as GIP. Prior infusion with GIP can also potentiate glucose-stimulated insulin increase.     

Synthesis and biological activity of glycosylated analogs of somatostatin

The synthesis by solid-phase methodology of two glycosylated analogs of somatostatin [Glc-Asn⁵]-SS and [NAcGlc-Asn⁵]-SS is described. These two analogs have been biologically tested on the secretion of pituitary growth hormone, pancreatic glucagon and insulin. The results show that glycosylation of somatostatin on the Asn⁵ residue decreases by a hundred fold the inhibition activity on GH release when tested $\text{in}$$\text{vitro}$. $\text{In}$$\text{vivo}$, since the activity is similar to somatostatin the carbohydrates are probably removed by some enzymatic reaction and thus liberate the full activity of somatostatin.     

Acylated des-(Ala1-Gly2)-somatostatin analogs: prolonged inhibition of growth hormone secretion

The following eight analogs of somatostatin were synthesized by solid phase: des-[Ala¹-Gly²]-somatostatin (I); des-[Ala¹-Gly²]-H₂somatostatin (II); $\text{N}$-acetyl-Cys³-somatostatin (III); $\text{N}$-acetyl-Cys³-H₂somatostatin (IV); $\text{N}$-pyvalyl-Cys³-H₂somatostatin (V); $\text{N}$-acrylyl-Cys³-H₂somatostatin (VI); $\text{N}$-benzoyl-Cys³-H₂somatostatin (VII); $\text{N}$-hexanoyl-Cys³-H₂somatostatin (VIII). Deletion of the N-terminal dipeptide Ala¹-Gly² is compatible with high biological activity. A single s.c. injection of these analogs as a microsuspension in saline inhibits for 24–72 hours (depending on the compound) the secretion of growth hormone normally stimulated in rats by pentobarbital.     

Dopamine and norepinephrine stimulate somatostatin release by median eminence fragments invitro

The effect of catecholamines on somatostatin release by median eminence (ME) fragments was evaluated using an $\text{in}$$\text{vitro}$ incubation system. Adult male rats were used as tissue donors. Somatostatin release was readily detected during short-term incubations (10 and 30 minutes). Dopamine (DA) significantly stimulated somatostatin release during a 30 minute incubation period at the two doses tested (0.6 and 6 μM). Under similar conditions, norepinephrine (NE) stimulated somatostatin release only at the 6 μM dose. Using a shorter incubation period (10 min) and a 6 μM dose, only DA stimulated somatostatin release. The effects of DA and NE were specifically blocked by the $\text{in}$$\text{vitro}$ addition of pimozide or phentolamine, respectively, suggesting that dopaminergic and noradrenergic receptors may be present in the somatostatinergic terminals of the ME. The results indicate that both DA and NE may be involved in the regulation of somatostatin secretion.     

Somatostatin analogs which inhibit glucagon and growth hormone more than insulin release

Three analogs of somatostatin, [$\text{D}$-Cys¹⁴] -, [Ala², $\text{D}$-Cys¹⁴] - and [$\text{D}$-Trp⁸, $\text{D}$-Cys¹⁴] - somatostatin, were synthesized by the solid phase method, characterized by several means, and tested for their effects on the release of insulin, glucagon, and growth hormone. The peptides sharply suppressed the release of growth hormone $\text{in vitro}$ and glucagon $\text{in vivo}$, but had less effect on insulin secretion $\text{in vivo}$. These analogs, particularly [$\text{D}$-Trp⁸, $\text{D}$-Cys¹⁴] - somatostatin, could possibly be useful for the treatment of diabetes mellitus.     

Increased somatostatin release from pancreases of alloxan diabetic rats perfused in vitro.

Insulin, glucagon, and somatostatin release $\text{in vitro}$ from perfused pancreases of normal and alloxan-diabetic rats were compared. Insulin and glucagon responses to arginine were decreased in the diabetic group whereas both basal and arginine-stimulated somatostatin release was increased. These results suggest that alterations in pancreatic D cell $\text{function}$ as well as in D cell $\text{mass}$ may contribute to the abnormal insulin and glucagon secretion found in alloxan diabetes.     

Cyclic AMP-dependent stimulation of somatostatin secretion by isolated rat islets of Langerhans.

Immunoreactive somatostatin is released from islets of Langerhans, isolated from rat pancreas by collagenase digestion, when incubated in an $\text{in vitro}$ system. The rate of somatostatin secretion is independent of extracellular glucose concentration, but is stimulated by addition of 8-Br-cyclic AMP or theophylline.     

Intracerebroventricular somatostatin attenuates electroconvulsive shock-induced amnesia in rats

In the present study the effect of intracerebroventricularly (ICV) administered somatostatin on electroconvulsive shock- (ECS) induced retrograde amnesia was investigated in rats. The ECS significantly decreased foot shock-induced avoidance latency. Somatostatin in a dose of $\text{1}\text{μg}\text{4}\text{μl}$ (ICV) had no action on the ECS-induced retrograde amnesia, while in a dose of $\text{4}\text{μg}\text{4}\text{μl}$ it significantly increased the avoidance latency if the treatment was performed immediately, 4 hr, 20 hr or 23 hr after the ECS. The results suggest that ICV administered somatostatin has an antiamnesic effect.     

Biological potency of synthetic somatostatin in the oxidized and reduced form on the inhibition of secretion of growth hormone

The reduced and oxidized forms of synthetic somatostatin are equipotent to inhibit the secretion of immunoreactive growth hormone when tested $\text{in vitro}$ and $\text{in vivo}$ by intravenous administration. The reduced peptide has approximately half the potency and twice the duration of biological activity of the oxidized form when both are administered subcutaneously.     

Effect of bombesin-stimulated gastrin on gastric acid secretion in man

The effect of bombesin on gastrin release and gastric acid secretion was investigated in 10 healthy volunteers. Bombesin (0.6 μg · Kg^?1 · hr^?1) produced a significantly higher $\text{(}\text{p}\text{<}\text{0.001)}$ increase in plasma gastrin levels (86.7 11.1 pmo/1 than after a protein meal (39.6 ± 5.6 pmol1/1). The gastric acid secretory response to bombesin (12.1 ± 2.9 mEq · hr^?1) was however significantly lower $\text{(}\text{p}\text{<}\text{0.005)}$ than the maximal response produced by pentagostrin (20.9 ± 3.5 mEq · hr^?1) at the dose of 6 μg · Kg^?1. Atropine did not modify gastrin release induced by bombesin but significantly reduced gastric acid secretion $\text{(}\text{p}\text{<}\text{0.01)}$. From the data presented it may be hypothesized that less biologically active forms of gastrin and/or other peptides inhibiting the gastrin effect upon gastric acid secretion may be released by bombesin.     

ICI 125,211: a new gastric antisecretory agent acting on histamine H2-receptors.

$\text{In}$$\text{vitro}$, ICI 125,211 competitively antagonized the action of dimaprit on guinea pig atrium with an apparent dissociation constant of 1.5 × 10^?8M (pA₂ = 7.8). $\text{In}$$\text{vivo}$, the histamine dose-response curve in conscious gastric fistula beagles was shifted rightward in parallel without change in the maximal response by intravenous infusions of ICI 125,211 at doses of 0.01 and 0.03 umol/kg/hr (estimated pA₂ = 7.3). Our data show that this new drug is at least 10x more potent than cimetidine as an inhibitor of gastric secretion in the dog. ICI 125,211, which is an orally effective antisecretory agent in man and devoid of antiandrogenic activity, is the most potent selective H₂-blocker described to date.     

The synthesis and biological activity of Ala3,14-somatostatin

The tetradecapeptide H-Ala-Gly-Ala-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Ala-OH (Ala³, 14-somatostatin) an analog of the somatotropin release inhibiting factor (somatostatin SRIF) was synthesized by solid phase peptide methods. It shows somatotropin release inhibiting activity $\text{in vitro}$ at 5 μg/ml concentration.     

Identification and purification of factor B-GHRH from hypothalami which releases growth hormone

Exploratory purifications and assays of fractions for release of growth hormone (GH) revealed two separable entities each of which unambiguously released GH by radioimmunoassay. They are provisionally designated factor A-GHRH and factor B-GHRH until they are chemically and biologically characterized. After initial steps of isolation from porcine hypothalami, factor B-GHRH was extensively purified by stepwise chromatography using Bio-Gel P-2, Sephadex LH-20, Sephadex G-25 with a partition system of acetic acid-butanol-pyridine, DEAE-Sephadex A-25, and Bio-Gel CM-2. Assays showed that certain fractions were active, $\text{in vitro}$, at levels of $\text{ca}$. 15 μg. Factor B-GHRH is inhibited by somatostatin.     

Enteric release of vasoactive intestinal peptide after a peptone meal in the dog

Vasoactive intestinal peptide (VIP) concentrations were measured by radioimmunoassay in plasma from portal and peripheral venous blood obtained from six alert, non-anesthetized dogs before and after gastric infusion of a 10% peptone meal. Mean basal portal and cephalic vein plasma VIP concentrations were $\text{42 ± 11.7}$ and $\text{42 ± 8.0}\text{(S.E.M.) pg/ml}$, respectively. No significant changes in peripheral venous plasma VIP concentrations were noted after the peptone meal throughout the duration of the collection period. In contrast, however, the mean VIP concentration in portal plasma increased promptly after the peptone meal with a peak of $\text{79 ± 8.2}\text{pg/ml}$ ($\text{P < 0.02}$) occurring 8 min after infusion of the meal. This was followed by a gradual decline in portal plasma VIP levels, with a return to prefeeding concentrations at 60 min ($\text{44 ± 6.3}\text{pg/ml}$). Results of these studies demonstrate that following gastric infusion of a peptone meal in the dog, portal, but not peripheral, plasma VIP concentrations increase significantly. Failure to detect augmentation of peripheral vein VIP levels after the meal is probably due to hepatic clearance of VIP.     

The synthesis of 13-cis-dl-erythro-15, 16-dihydroxyprostaglandins

Both pairs of $\text{dl}$-ll-desoxy- and $\text{dl}$-13-$\text{cis}$-$\text{erythro}$-15, 16-dihydroxyprostaglandins have been synthesized via 1,4-conjugate additions of an appropriately functionalized $\text{cis}$-vinyl cuprate to the requisite cyclopentenone. These prostaglandin analogs are considerably less potent than PGE₂ as gastric secretion inhibitors or as bronchodilators.     

The effects of some pharmacologically active amines on the rate of gastric emptying in rats.

The effects of several pharmacologically active amines on gastric emptying rate in male rats has been investigated. Of the compounds tested those with anticholinergic activity; amitriptyline, nortriptyline, imipramine, desmethylimipramine, 3-methylamino-1:1-diphenyl-prop-1-ene and its primary and tertiary amine analogues, dexamphetamine and methylamphetamine, all inhibited gastric emptying of a non-absorbable marker, polyethylene {1,2?¹⁴C} glycol. The compounds with little or no anticholinergic activity did not affect gastric emptying. The activity of the compounds in inhibiting gastric emptying falls in approximately the same order as their anticholinergic activity, lending support to the hypothesis that inhibition of gastric emptying is $\text{via}$ in anti-cholinergic mechanism. The results also indicate that absorption is a prerequisite of activity in inhibiting gastric emptying and suggests that these compounds are not acting $\text{via}$ a local mechanism.     

Characterisation of gut hormones storage granules from normal human jejunum using metrizamide density gradients

Analytical subcellular fractionation techniques using metrizamide density gradients have been used to investigate the properties of the gut hormone storage granules and the principal organelles from homogenates of normal human jejunal mucoosa obtained by peroral mucosal biopsy. The individual hormones, detected by radioimmunoassay, each showed single discrete peaks in the density gradient experiments indicating localisation to single granules each with characteristic modal densities. Thus motilin showed a modal density of 1.15, gastrin 1.16, gastric inhibitory polypeptide (GIP) 1.17, enteroglucagon 1.18 and somatostatin and vasoactive intestinal peptide (VIP) 1.10 g/ml. The following organelles, characterised by their marker enzymes were located in the density gradients; plasma membrane (5′-nucleotidase) brush border (α-glucosidase, pH 6.0) mitochondria (particulate malate dehydrogenase), peroxisomes (catalase), lysosomes ($\text{N-}\text{acetyl-β-glucosaminidase}$), endoplasmic reticulum (α-glucosidase, pH 8.0), cytosol (lactate dehydrogenase). These studies provide biochemical evidence of the distinct nature of the individual gut hormone storage granules and provide a basis for studying dynamic changes in the granules in response to physiological stimuli and pathological processes.     

Inhibition of acyl coenzyme A:lysolecithin acyltransferases by local anesthetics, detergents and inhibitors of cyclic nucleotide phosphodiesterases.

Acyl coenzyme A:lysolecithin acyltransferase plays a major role in regulating the amount of lysolecithin in cell membranes. The acyltransferase activity in microsomal preparations from rat liver, rat heart and rabbit gastric mucosa is inhibited by a series of tertiary amine local anesthetics, detergents, and some inhibitors of cyclic nucleotide phosphodiesterases. Aspirin and indomethacin cause elevated lysolecithin/lecithin ratios in the stomachs of mice after oral administration. Inhibition of acyltransferase activity in microsomal preparations by local anesthetics correlates with reported anesthetic potencies at approximately $\text{1}\text{100}$ reported therapeutic dosages. In BHK-13 cells acyltransferase activity is inhibited at $\text{1}\text{3}$ to $\text{1}\text{10}$ the concentrations that have been reported to cause alterations in the mobility and topography of cell surface receptors.     

Structure of the ceramide octadekahexoside isolated from gastric mucosa

A fucose-containingceramide octadekahexoside exhibiting blood-group (A+H) activity has been isolated from hog gastric mucosa. Based on the results of partial acid hydrolysis, sequential degradation with specific glycosidases, oxidation with periodate and chromium trioxide, and permethylation analysis, we propose that the carbohydrate chain of this fucolipid contains four branches. Two of the branches are terminated by βGall→4βGlcNAc, one by $\text{αFucl→2βGall→}\text{3}\text{4}\text{βGlcNAc}$ and one by $\text{αGalNAcl→3(αFucl→2)βGall→}\text{3}\text{4}\text{βGlcNAc}$.