[Antiulcer effects of the tripeptide PGP and its possible metabolites (PG, GP, glycine, and proline) in different models of ulcer induction in rats]. / Protivoiazvennye éffekty tripeptida PGP i ego vozmozhnykh metabolitov( PG, GP, glitsina i prolina) na raznykh modeliakh vyzova iazv u krys.

The study of the effect of equimolar concentrations (3.7 micromol/kg) of the tripeptide PGP and its possible metabolites--PG, GP, proline, and glycine--on ethanol-, stress-, and indomethacin-induced ulcer development in rats showed that only PGP exhibited consistent antiulcer effects on all three ulceration models. Glycine and proline tended to increase the area of indomethacin-induced lesions in the stomach. PG reduced the ethanol- and indomethacin-induced lesions approximately twofold but was considerably less effective in stress-induced ulcer. GP decreased the stress- and indometacin-induced ulcer but tended to stimulate the ethanol-induced lesions. The results of this study indicate that the antiulcer activity of PGP may be related to the effect of this tripeptide itself and to proteolysis of PGP to dipeptides and amino acids as well.

[Highly stable regulatory oligopeptides: experience and applications]. / Vysokostabil'nye reguliatornye oligopeptidy: opyt i perspektivy primeneniia.

The most stable regulatory peptides (RP) including the new family of RP (glyprolines) and derivatives of hybrid peptide MEHFPGP are characterized. High ability of glyprolines to penetrate into the blood-stream through the gastrointestinal tract is demonstrated. Antiulcer, antithrombotic and antidiabetic activities of glyprolines were discovered in experiments on white rats. The activity of oligopeptides PGP, PG and GP is compared. Mechanisms of glycoprolines activities and feasibility of their administration with connective tissue food proteins are discussed. Thus, glyprolines are perspective drugs for treatment of gastric ulcer, correction of hemostasis and thrombosis suppression prepared for preclinical trial.

[Semax and some glyproline peptides accelerate the healing of acetic ulcers in rats]. / Semaks i nekotorye gliprolinovye peptidy uskoriaiut zazhivlenie atsetatnykh iazv u krys.

Previously we showed that peptides PGP, PG, GP and semax have protective anti-ulcer properties using different models of ulcerogenesis. Semax (MEHFPGP) is a nootropic analogue of adrenocorticotropin 4-7 stabilized by PGP in the C-terminal region. In this study we examined the impact of these peptides on the development and healing of acetic ulcers in rats. The histomorphological and dynamical characteristics of acetic ulcers are most similar to human chronic ulcers. All the peptides were shown to accelerate the process of ulcer cicatrisation in a varying degree (GP semax PG PGP). The dynamics of structural changes in the place of ulcer formation investigated with the use of cytohistological control demonstrated that their anti-ulcer effects can be related to their ability to accelerate ulcer clarification from necrotic tissues and to activate the process of cicatrisation and epithelization. PGP and GP were also shown to reduce the inflammation in the ulcer zone on the fifth day after acetic acid application.

Metabolism of PGP peptide after administration via different routes.

Main pathways of degradation of PGP peptide possessing antiulcer and antithrombotic activities were studied after its intraperitoneal, intragastric, and intraintestinal administration. In experiments on rabbits we showed by HPLC that unmodified PGP is released into the blood after administration by all three routes and is detected in the plasma over 3-5 h. PG dipeptide is a more stable PGP metabolite presumably determining (together with tripeptide) its pharmacological properties.

Secretory activity of mast cell during stress: effect of prolyl-glycyl-proline and Semax.

Stress increased secretory activity of mast cells in the mesentery and subcutaneous fat of rats. Intraperitoneal injection of Semax and prolyl-glycyl-proline in doses of 0.05 and 1 mg/kg, respectively, 1 h before stress abolished this effect. The test preparations did not modulate secretory activity of mast cells in unstressed animals. Semax and prolyl-glycyl-proline in vitro prevented activation of mast cells with synacten and acetylcholine. The stabilizing effect of peptides on mast cells probably determines their antiulcer activity.

Possible mechanism underlying the effect of Semax on the formation of indomethacin-induced ulcers in rats.

Intraperitoneal injection of Semax (synthetic analogue of ACTH4-7, MEHFPGP) in a dose of 50 mg/kg produced a protective effect on rats with experimental indomethacin-induced ulcers. Experiments on narcotized rats showed that Semax in the studied dose had no effect on basal blood flow in the stomach, but prevented reduction of blood flow induced by indomethacin. The antiulcer effect of Semax is probably related to improvement of blood flow in the gastric wall disturbed by indomethacin.

[Homeostasis of the gastric mucosa and blood circulation. 2. Role of ischemia in disruption of the gastric mucosa]. / Gomeostaz slizistoi obolochki zheludka i krovotoka. Soobshchenie 2. Rol' ishemii v narushenii gomeostaza slizistoi obolochki zheludka.

To date there is a lot of data of literature indicating that microcirculatory disorders play the main role in the development of gastric mucosal damages induced by stress, ethanol, nonsteroidal antiinflammatory drugs and tobacco smoke. Under stress gastric mucosal blood flow disorders may be caused by the actication of sympathetic nervous system. Ulcer healing is accompanied by the angiogenesis and by the increase of blood flow in the ulcer border and tissues surrounding the ulcer. Therefore now the main studies are concentrated on the search of defence-enhancing agent rather than drugs for antisecretory therapy. Therapeutic strategy suggests the use of some potential vasodilators such as NO donors, prostaglandin analogues, oxygen radical scavengers, endothelin, leukotrienes, platelet-activating factor antagonists and/or their synthesis inhibitors. At present, the therapeutic possibilities seem to be restricted and nothing indicates that stimulation of the defensive factor only, is more effective in the treatment of peptic ulcer than inhibition of aggressive factors. However we suggest that blood flow correction may be very important for the treatment of refractory ulcers or for prophylaxis of stress ulceration and peptic ulcer recurrence.

[Correction of the stomach blood flow as a mechanism of anti-ulcer effects of short proline-containing peptides]. / Korrektsiia krovotoka zheludka kak odin iz vozmozhnykh mekhanizmov protivoiazvennykh éffektov korotkikh prolinsoderzhashchikh peptidov.

Intraperitoneal administration of the PGP did not change basal mucosal blood flow, whereas the PG and GP significantly decreased it. Ethanol and Indomethacin caused a rapid and stable decrease in the blood flow. Administration of the PGP prior to ethanol abolished this effect. Injections of the PGP and PG following Indomethacin administration prevented reduction of the mucosal blood flow. Administration of the GP did not change the blood flow decrease induced with Indomethacin. The mucosal blood flow correction seems to be one of the possible mechanisms of the PGP and PG antiulcer effect. The effect seems to be realised through a change in the CNS activity.

[Homeostasis in the gastric mucosa and blood circulation. Part 1. Mechanisms of the adequate blood flow maintenance in the gastric mucosa]. / Gomeostaz slizistoi obolochki zheludka i krovotok. Soobshchenie 1. Mekhanizmy podderzhaniia adekvatnogo krovotoka v slizistoi obolochke zheludka.

The increase of mucosal blood flow in response to food entrance into stomach or different irritant action is the component of gastric mucosal defence barrier. Sufficient blood flow ensures normal acid-bicarbonate balance in gastric mucosa, supports the healing process and prevents superficial damages from developing into deep ones. Capsaicin-sensitive afferent nerve fibers play the large role in the blood flow regulation. The influence of these nerve fibers on the gastric blood flow is mediated by the calcitonin-gene related peptide. This peptide released from peripheral afferent terminals improves microcirculation in stomach walls. Moreover nerve impulses from afferent neurons modulate parasympathetic activity that in turn induces the increase of gastric mucosal blood flow through both choilinergic and noncholinergic mechanisms. The gastric mucosal blood flow may be also regulated by humoral and paracrine metabolites. Nitric oxide and prostaglandines are the most important low molecular weight compounds. They play the main role in the maintenance of the basal gastric mucosal blood flow and in the development of hyperemic responses to harmful agents.

[Pancreatic hormone amylin and integrity of the gastric mucosa]. / Pancreakticheskii gormon amilin i tselostnost' slizistoi obolochki zheludka.

The paper presents experimental findings of some possible mechanisms of protective antiulcerous action of amyline. Amyline is the second beta-cell pancreatic hormone, which has been just recently discovered. The authors have studied the effects of amyline on gastric secretion, mast cell functions, mesenteric lymphatic microvascular contractility, i.e. on individual aggressive and protective factors of the gastric mucosa. Amyline has been found to inhibit basal acid gastric secretion and the secretion stimulated by vagal irritation. The peptide reduces the secretory activities of mast cells. Amyline given to animals increases the heparin saturation index of mast cells and decreases the degranulation index. Amyline-induced stabilization of mast cells appears to followed by the decreased release of histamine and other damaging substances. The stimulating effect of amyline on the contractile activity of mesenteric lymphatic vessels was recorded in rats. Amyline increases both the frequency and amplitude of their contractions. The increased lymph flow that is closely associated with microcirculation promotes the maintenance of tissue homeostasis. Therefore, the protective antiulcerous properties of amyline reduce the action of aggressive agents on the gastric mucosa and stimulate protective ones.

Effect of amylin on mast cell secretion as a possible mechanism increasing gastric mucosa resistance.

Water-immersion restraint stress increased secretory activity of mast cells and led to the formation of erosive lesions in the gastric mucosa. Intraperitoneal administration of amylin in a dose of 0.5 microg/kg 1 h before stress suppressed degranulation of mast cells and decreased the severity of gastric mucosa damages. In in vitro experiments amylin abolished the activating effects of acetylcholine and bradykinin on mast cell degranulation. Amylin-induced stabilization of activated mast cells probably underlies its protective effects during ulceration.

Effect of Semax on homeostasis of gastric mucosa in albino rats.

The ACTH(4-7)analogue Semax administered intraperitoneally in a dose of 50 microg/kg 1 h before exposure to ulcerogenic factors (ethanol, water immersion immobilization stress) protected gastric mucosa from damage. Postoperative treatment with Semax for 5 days after application of glacial acetic acid on the mucosa prevented acetic acid-induced ulcers and promoted their healing. The antiulcer effects of Semax in the studied dose were comparable with those of tripeptide Pro-Gly-Pro in a dose of 1 mg/kg.