Effects of Prolyl-Glycyl-Proline (PGP) peptide on disorders in rat mesenteric lymphatic vessel function induced by injection of substance 48/80.

Injection of substance 48/80 to rats led to dysfunction of mesenteric lymphatic microvessels, in particular inhibition of their contractility and modification of their reaction to norepinephrine. Injection of PGP peptide before and after substance 48/80 alleviated these disorders. The results indicated the possibility of peptide correction of lymphatic vessel dysfunction.

Tripeptide Pro-Gly-Pro prevents disturbances in osmotic resistance of rat erythrocytes under conditions of inflammation.

The development of inflammation (experimental model of peritonitis induced by administration of sodium thioglycolate) was accompanied by a decrease in osmotic resistance of erythrocytes. Changes in osmotic resistance of erythrocytes associated with preliminary (15 min before induction of inflammation) administration of peptide Pro-Gly-Pro were significantly weaker, and the percentage of hemolyzed cells was reduced. The peptide injected against the background of developed inflammation (1 h 45 min after induction) had no corrective effect on osmotic resistance. During in vitro experiments, Pro-Gly-Pro did not affect hemolysis of intact erythrocytes. These results support the assumption that prophylactic administration of the peptide protects erythrocyte membranes and increases their osmotic resistance.

Effect of acute and moderate repeated stress on disturbances in reactivity of mesenteric lymphatic vessels during inflammation in rats.

We studied the effect of acute (single immobilization for 1 h) and repeated (daily immobilization for 1 min, 5 days) moderate stress on disturbances in contractility of mesenteric lymphatic vessels in rats with experimental peritonitis. Acute stress was shown to potentiate, while moderate repeated stress attenuate the effect of inflammatory stimulus. It can be hypothesized that moderate repeated stress improves adaptive capacities of the organism, which manifests in reduction or prevention of dysfunction in contractile activity of lymphatic vessels.

[A comparative analysis of distribution of glyprolines administered by various routes].

The distribution of the glyprolines Pro-Gly-Pro and Thr-Lys-Pro-Arg-Pro-Gly-Pro (Selanc) was analyzed and compared in tissues of rat organs after different ways of their administration using the peptides uniformly labeled with tritium. Comparative data on changes in concentrations of the peptides in the rat organs after their intraperitoneal, intranasal, intragastric, and intravenous administration are given. The intranasal administration of both peptides was shown to be optimal for the delivery of glyproline molecules in the CNS. A high affinity of the studied glyprolines for gastric tissues was found for all the ways of their administration. We suggest that a high efficiency of action of glyprolines on homeostasis of the gastric mucous tunic was partially provided by accumulation of these peptides (to high concentrations) in gastric tissues.

Effects of glyprolines on stress-induced behavioral disorders in rats.

We report here studies on the antistress protective actions of three peptides of the glyproline family: Pro-Gly-Pro, Pro-Gly, and Gly-Pro. Stress (10 min forced swimming) evoked typical changes in the behavioral activity of rats in the elevated cross maze and hole board tests, providing evidence of a significant increase in anxiety and a decrease in the level of orientational-investigative activity. Prior (15 min before stress) i.p. administration of Pro-Gly-Pro and Gly-Pro at a dose of 3.7 microM/kg significantly decreased the stress-induced behavioral abnormalities. This demonstrates the possibility that peptides Pro-Gly-Pro and Gly-Pro may affect CNS structures involved in forming the body's responses to stress-inducing factors. Peptide Pro-Gly, at an equimolar dose, had no marked protective effect and only slightly decreased the stress-induced abnormalities in the behavior of rats.

[Short peptide fragments with antiulcer activity from a collagen hydrolysate].

A peptide acidic hydrolysate of collagen (PHC) was obtained under conditions (4 N HCl) ensuring the predominant formation of short peptides, glyprolines. They were separated and their antiulcer activity was studied. Thirty individual peptides with molecular masses of 174-420 amu were isolated from the PHC by HPLC. The PHC was shown to predominantly contain 2- to 4-aa peptides, including PG, GP, and PGP. Experiments on rats demonstrated that, on intragastric administration at a dose of 1 mg/kg, PHC enhances the stability of the gastric mucosa to the action of ulcerogenic factors, such as ethanol and stress, and exhibits a protecting antiulcer effect. Even a lesser dose (0.1 mg/kg), which reduced ulcer area twofold, was effective in the stress model of ulcer formation. The intraperitoneal and intragastric administration of PHC at a dose of 1 mg/kg was found to exhibit a therapeutic effect in the acetate model of ulcer formation.

[Evenly tritium-labeled peptides and their in vivo and in vitro biodegradation].

Biologically active peptides evenly labeled with tritium were used for studying the in vitro and in vivo biodegradation of the peptides. Tritium-labeled peptides with a specific radioactivity of 50-150 Ci/mmol were obtained by high temperature solid phase catalytic isotope exchange (HSCIE) with spillover tritium. The distribution of the isotope label among all amino acid residues of these peptides allows the simultaneous determination of practically all possible products of their enzymatic hydrolysis. The developed analytical method includes extraction of tritium-labeled peptides from organism tissues and chromatographic isolation of individual labeled peptides from the mixture of degradation products. The concentrations of a peptide under study and the products of its biodegradation were calculated from the results of liquid scintillation counting. This approach was used for studying the pathways of biodegradation of the heptapeptide TKPRPGP (Selank) and the tripeptide PGP in blood plasma. The pharmacokinetics of Selank, an anxiolytic peptide, was also studied in brain tissues using the intranasal in vivo administration of this peptide. The concentrations of labeled peptides were determined, and the pentapeptide TKPRP, tripeptide TKP, and dipeptides RP and GP were shown to be the major products of Selank biodegradation. The study of the biodegradation of the heptapeptide MEHFPGP (Semax) in the presence of nerve cells showed that the major products of its biodegradation are the pentapeptide HFPGP and tripeptide PGP. The enkephalinase activity of blood plasma was studied with the use of evenly tritium-labeled [Leu]enkephalin. A high inhibitory effect of Semax on blood plasma enkephalinases was shown to arise from its action on aminopeptidases. The method, based on the use of evenly tritium-labeled peptides, allows the determination of peptide concentrations and the activity of enzymes involved in their degradation on a tg scale of biological samples both in vitro and in vivo.

Antiulcer effects of amylin: a review.

Amylin belongs to the calcitonin peptide family. Amylin is a peptide synthesized not only in the beta cells of pancreatic islets, but in small quantities also in other organs like in the intestinal and gastric mucosa, lungs and central nervous system. It is located in the same secretory granules as insulin. Amylin participates in the maintenance of glucose and calcium homeostasis. It also inhibits food intake and decreases body weight. Furthermore, amylin inhibits gastric acid secretion. It protects the gastric mucosa in ulcer models like stress, vagal stimulation, ethanol, acetic acid, reserpine and serotonine administration and pylorus ligation. This protective antiulcer is seen not only at pharmacological but also at near-physiological doses-0.5mkg/kg. Moreover amylin also exerts curative properties in the acetic acid and indomethacin ulcer models. Amylin decreases the aggressive factors like acid-pepsin secretion, increases mast cell stability and increases protective mechanisms like bicarbonate gastric secretion, dilates blood vessels, and it increases lymphatic mesenteric activity. Amylin seems to be a powerful protector of gastric mucosa in animals by increasing the stability of gastric mucosa. Further research remains, however, to be done.

[Effects of pancreatic polypeptide amylin on ulceration and acid gastric secretion]. / Vozdeistvie pankreaticheskogo polipeptida amilina na iazvoobrazovanie i kisluiu zheludochnuiu sekretsiiu.

The effects of the pancreatic polypeptide amyline on ulceration and acid gastric secretion were studied in rat experiments. Pyloric ligation was used as a model of ulceration. Amyline administration caused significantly less gastric mucosal damage in response to pyloric ligation. The severity of gastric mucosal damage averaged 47 +/- 13 mm2 in the control group and 25 +/- 11 mm2 (p < 0.005). The rate of acid gastric secretion in the animals whose pylorus had been ligated as judged by the pH of gastric content was significantly higher than that in the controls (2.87 +/- 0.22 and 2.34 +/- 0.17 (p = 0.05). It is concluded that amyline has a noticeable effect on the gastric mucosa. It is suggested that suppressed acid gastric secretion, i.e. reduced influence of aggressive agents on the gastric mucosa, is a mechanism of antiulcerative action of the peptide.

[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.

[Atrioventricular conductive disorders as a consequence of activation of the intracardiac reflex apparatus]. / Narusheniia atrioventrikuliarnogo provedeniia vsledstvie aktivatsii vnutriserdechnogo reflektornogo apparata.

Experiments were conducted on isolated and vagotomized frog hearts (Rana temporaria). It is suggested that certain forms of disturbances of the atrioventricular node, the Wolff--Parkinson--White syndrome and parasystole, result from activation of the atrioventricular reflex mechanisms.

[Parasympathetic regulation of the heart in teleosts and factors determining the regulatory direction of the chronotropic effect]. / Parasimpaticheskaia reguliatsiia serdtsa kostistykh ryb i faktory, opredeliaiushchie reguliatornuiu napravlennost' khronotropnogo éffekta.

Changes in the sinus rhythm of the cod heart in response to single brief bursts of stimuli (50-200 msec) delivered to the vagus with different intervals after P-wave, were investigated. The moment of vagal stimulation in respect to cardiac cycle, the duration of free running cardiac period and intensity of nerve activity were found to be the factors determining the regulatory direction of chronotropic effects (acceleration or inhibition of the heart). Possible mechanisms of parasympathetic acceleration of the cardiac rhythm are discussed.

[The relationship between changes in the temporal and frequency characteristics of parasympathetic nerve activity and effects on the heart]. / Zavisimost' éffektov na serdtse v zavisimosti ot izmenenii vremennykh i chastotnykh kharakteristik parasimpaticheskogo nervnogo vozdeistviia

Changes of chronotropic effect on the frog heart on stimulation of part of extracardiac pathways, were studied. On the 10/sec stimulation during 1.5 sec, cardioinhibitory effect occurred. On 0.2 sec duration of the stimulation the positive chronotropic effect was observed. The heart rate increased on the 3/sec stimulation of the undegenerating extracardiac fibers by the 21st day after bilateral vagotomy; of the frequency of the stimulation was increased to 10/sec, the negative chronotropic effect occurred, and sympathectomy and the reserpine injection had no influence on the positive chrontropic effects. Both the negative and positive chronotropic effects could be prevented by atropine. The different chrontropic effects on the heart are, probably, due to activity of but a single functional type of fibers: the parasympathetic nervous fibers.

[Changes in the activity of the intracardiac postganglionic apparatus during the interaction of the regulatory sympathetic and parasympathetic effects on the pacemaker rhythm]. / Izmenenie aktivnosti vnutriserdechnogo gangliozno-sinapticheskogo apparata pri vzaimodeistvii simpaticheskikh i parasimpaticheskikh vliianii na ritm peismekera.

Chronotropic effect on the isolated sinus node of the frog heart and postganglionic impulse activity of the intracardiac pathways were studied during separate and joint stimulation of extracardiac sympathetic and parasympathetic nerves. The joint stimulation attenuated or augmented the impulse activity. This effect depended on the "energy" of initial parasympathetic and/or sympathetic activity. beta-Adrenoblocking inderal abolished the parasympathetic impulse activity augmentation. A possible role of intracardiac ganglionic system in the sympathetic-parasympathetic interaction is discussed.

[Chronotropic effects on the heart during the interaction of parasympathetic and sympathetic regulatory influences]. / Khronotropnye éffekty na serdtse pri vzaimodeistvii parasimpaticheskikh i simpaticheskikh reguliatornykh vliianii.

In the frog heart isolated sinus node with intact extracardiac sympathetic and parasympathetic pathways or intracardiac nerves, the intracellular pacemaker APs and extracellular nervous activity of the parasympathetic postganglionic intracardiac pathways were recorded. Two major sympathetic-parasympathetic interaction patterns were revealed: the antagonistic and the augmentative ones. In initial deep bradycardia, sympathetic stimulation diminished the parasympathetic inhibition, whereas in initial parasympathetic tachycardia, sympathetic stimulation augmented these parasympathetic effects. The recording of the intracellular pacemaker AP showed the effect of a complicated interaction between the sympathetic and parasympathetic transmitters on the heart pacemaker. Parasympathetic postganglionic nervous activity changed in two ways: there was either an attenuation during intense sympathetic stimulation or an augmentation during a weak sympathetic stimulation. Relative significance of the sympathetic and parasympathetic systems in the heart rate control and possible mechanisms of the two patterns of sympathetic-parasympathetic interactions, are discussed.

[Relation between intracardiac reflex effects on the rate of atrioventricular conduction and parameters of neural pathway stimulation]. / Zavisimost' vnutriserdechnykh reflektornykh vliianii na skorost' atrioventrikuliarnogo provedeniia ot parametrov stimuliatsii nervnykh putei.

Intracardiac nerves of the frog isolated heart were cut and the central or the peripheral end was stimulated. The atrioventricular (a-v) conduction was measured. The data showed that the intracardiac parasympathetic nervous system could induce both acceleration and deceleration of the a-v conduction, depending on the parameters of stimulation. Atropine blocked both the positive and the negative dromotropic effects whereas beta-adrenoblocking agent inderal was ineffective. The possible mechanism of the dromotropic effects observed are discussed.

[Influence of atropine on the chronotropic effects of stimulating the parasympathetic innervation of the heart]. / Vliianie atropina na khronotropnye éffekty pri stimuliatsii parasimpaticheskoi innervatsii serdtsa

Changes of the positive chronotropic effect in the frog atrium during stimulation of the extracardiac pathways or of the central end of intracardiac innervation after application of atropin (10(-4)--10(-5) on the sinus node, were studied. The positive chronotropic effects were abolished by the atropin application. The postganglionic impulse activity of the intracardiac nervous pathways did not change. Atropin had no influence on the sympathetic acceleration of the heart rate due to stimulation of sympathetic pathways. Positive chronotropic effects induced by stimulation of the parasympathetic extra or intracardiac pathways, are of cholinergic nature.

[Characteristics of the phase-dependent vagus effects in the heart of the frog Rana temporaria and of the cod Gadus morhua]. / Osobennosti fazozavisimykh vagusnykh éffektov v serdtse liagushki Rana temporaria i treski Gadus morhua.

In experiments on the heart of the cod Gadus morhua and frog Rana temporaria in situ, studies have been made of changes in the heart rate induced by stimulation of the vagal nerve by single brief bursts delivered at various intervals after P wave of the ECG. Certain differences were found in changes of the heart rate between these animals. In the cod, maximum chronotropic effect was equal to 65% of the duration of initial cardiac cycle, the latency of this effect being equal to 290 ms; in the frog, corresponding figures were 12-13% and approximately 940 ms. The duration of negative chronotropic effect in the heart of the cod was equal to 700 ms, that of the frog--to 2.700 ms. Functional role of these differences is discussed in relation to the problem of the development of parasympathetic regulation of the heart rate in phylogenesis of vertebrates.