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.

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.

Peptide correction of disorders in rat mesenteric microcirculatory system during inflammation.

PGP peptide had a protective effect in contractile dysfunction of the rat mesenteric lymph vessels under conditions of inflammation, irrespective of the time of its injection (before or after inflammatory agent). The preventive effect of this peptide is largely determined by its capacity to prevent mast cells activation. PGP injected 2 h after induction of inflammation did not inhibit secretory activity of mast cells, which suggests other mechanisms of its therapeutic action.

The role of protective effects of proline-containing peptides (PGP, PG, and GP) in contractile dysfunction of mesenteric lymphatic vessels in rats with experimental acute peritonitis.

The development of acute peritonitis in rats induced by intraperitoneal injection of thioglycollate was accompanied by a decrease in contractile function of mesenteric lymphatic vessels and impaired response to norepinephrine. Administration of proline-containing peptides after induction of inflammation significantly decreased the severity of these disorders. Our results attest to the possibility of using peptides for the correction of mesenteric microcirculatory disturbances during inflammation.

[Effectiveness of ultrasmall doses of endogenous bioregulators and immunoactive compounds].

The data and hypotheses on the mechanisms of action of ultrasmall doses (USD) and ultralow concentrations (ULC) of endogenous bioregulators and immunoactive compounds (regulatory peptides, cytokines, etc.) are presented. The reliability of the published data on the effectiveness of USD and ULC within the concentration limits 10(-13) - 10(-24) M and lower is considered.

[Effect of new synthetic anxiolytic selank on gastric wall blood flow and mesenteryc lymphatic vessels contractility in anesthetized rats].

The influence of a new heptapeptide Selank on microcirculation in anesthetized white rats was investigated. Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) is a new synthetic anxiolytic which exerts obvious antiulcerogenic action and promotes healing of experimental ulcers. Action of the peptide on gastric blood flow in the stomach by using the method ofhydrogenic clearance and Selank action on mesenteric lymphatic contractility by microscopical observation in situ, were studied. Selank fail to influence basal gastric blood flow but it can normalize blood flow reduced by indomethacin. The study of dose-depended of Selank effect on lymphatic vessels contractility showed that its low concentration (10(-12)--10(-14) M) enhanced amplitude and increase frequency of lymphatic vessel contractions which indicates an enhancement of lymphatic flow. The high doses of peptide (10(-6)--10(-10) M) also augmented the contraction amplitude but decreased its frequency. The maintenance of adequate blood flow and lymphatic vessel contractility can be one of the mechanisms of the Selank antiulcerogenic properties.

Effect of acute hypoxia in pregnant females on contractile activity of lymphatic vessels in the offspring.

Delayed consequences of acute hypoxia were studied in 60-day-old rat pups. The animals were exposed to acute hypobaric hypoxia on day 10 of embryogenesis. The offspring of intact females served as the control. Reactivity of mesenteric lymphatic vessels to norepinephrine was studied by vital microscopy. The frequency and duration of lymphatic vessel contractions in males significantly increased compared to the control. In females the duration of norepinephrine-induced lymphatic vessel contractions increased, while the frequency and amplitude of contractions and basal vascular tone did not differ from the control.

[Role of adrenoreceptors in the effect of thyroliberin on lymphatic vessels]. / Rol' adrenoretseptorov v mekhanizme deistviia tiroliberina na limfaticheskie sosudy.

Formerly we showed that TRH had simulative effect on mesenteric bovine and rat lymphatic vessels (LV) in very low concentration--10(-12)-10(-18) M. In present paper, participation of LV alpha- and beta-receptors in realization of TRH activity on rat mesenteric lymphatic vessels was studied in situ. Propranolol increased the stimulative effect of TRH, isoproterenol exerted an opposite effect. Phentolamine, prazosin eliminated the simulative effect of TRH, yohimbine resulted in additional gain of effect, which seems to testify 1) presynaptic action of TRH or 2) increase of the output of norepinephrine, which is potentiated by alpha 2-adrenoceptor antagonists. Also the participation of adrenergic receptors in positive chronotropic effects of mesenteric rat LV was studied using the method of selective destruction of dopamine-containing neurons after 6-OHDA infusion. As it occurred, desympathization hindered development of stimulating action of TRH. Thus, the efficiency of TRH as a stimulator of LV is connected with activation of adrenergic mechanisms.

[The effect of ultra small doses of thyroliberin on the structural changes in endoplasmic reticulum membranes in vitro]. / Strukturnye izmeneniia v membranakh éndoplazmaticheskogo retikuluma pri deistvii sverkhmalykh doz tiroliberina in vitro.

Peptides are known to have the ability of modulating the activity of important regulatory cellular systems. One of them--thyroliberin, i.e. thyreotropin-releasing hormone (TRH), causes changes in the membrane structure and morphology of rat erythrocytes, as well as activates retractive activity of lymphatic vessels in ultra low concentrations (10(-10) to 10(-16) mol/l). In this study we used an electron spin resonance (ESR) method to explore the effect of TRH in a wide range of concentrations (10(-4) to 10(-18) mol/l) on thermo-induced structural transitions and microviscosity of lipid bilayer of the endoplasmic reticulum membrane of mice (C57 bI) liver cells. Two stable free radicals were used as paramagnetic probes: 2,2,6,6-tetramethil-4-capryolyl-1-oxyl and 16-doxyl-stearic acid, that are localized in superficial and deep layers of the membrane respectively. TRH caused a statistically significant change (p < 0.001) in microviscosity of the membrane surface layer. The largest effect (up to 30% decrease) was observed at TRH concentrations of 10(-10) and 10(-16) mol/l. It was also demonstrated that an addition of 10(-4), 10(-10) and 10(-16) mol/l of TRH decreases effective activation energy and temperature (by several degrees) of the thermo-induced structural transitions. The observed changes in the parameters of the membrane surface layer induced by TRH may be essential for its physiological activity, because of the obtained negative correlation (r = 0.99; p < 0.001) between the membrane microviscosity and frequency of lymphatic vessels' contraction. Complex changes in the structure of deep hydrophobic layer of the membrane caused by TRH were observed in this study as well. Higher concentrations of TRH (10(-4) and 10(-10) mol/l) produced results that were similar to the effect of TRH on the superficial lipid layer of the membrane, whereas the effect of ultra low TRH concentration (10(-16) mol/l) was reversed for microviscosity, number and activation energy of structural transitions in contrast with the case of surface layer. The results of this study suggest presence of a nonspecific factor in the effect of TRH on structural characteristics of the lipid component of biological membranes. It is possible, that the change of structural properties of biological membranes may be a part of the mechanism of TRH action at ultra low concentrations.

[Direct and prolonged effect of thyroliberin in ultra small doses on contractility of the white rat mesentery lymphatic vessels]. / Priamoe i otsrochennoe deistvie sverkhmalykh doz tiroliberina na sokratitel'nuiu aktivnost' limfaticheskikh sosudov bryzheiki beloi krysy.

The prolonged effect of thyroliberin in ULD after single intramuscular injection on contractility of lymphatic vessels directly was investigated. The controlled group of animals received injection of 0.2 ml of physiological solution. The experimental group was injected by 0.2 ml of thyroliberin in concentrations of 10(-10) or 10(-16) mol/l (1 x 10(-4) and 1 x 10(-10) micrograms/kg of the body weight respectively). During the experiment the animals were grouped in the following way: 1) directly after the injection; 2) 3 hours later; 3) on the 1st day and then every day during 2 weeks. Lymphatic vessels reactivity of the experimental animals as well as controlled was studied by application of thyroliberin and noradrenalin (in concentrations of 1 x 10(-16) and 1 x 10(-6) mol/l respectively) directly on mesentery lymphatic vessels. The lymphatic vessels reaction in control group of animals on the noradrenalin and thyroliberin was the same during the period of observation. Thyroliberin stimulated contractility at concentration of 1 x 10(-16) mol/l. The reaction of experimental group was dramatically decreased to 10(-4) mol/l on the 1st and the 3rd day (in the case i.m. injected concentration 1 x 10(-10) mol/l) and to 10(-10) mol/l (in the case of i.m. injected concentration 10(-16) mol/l). The lymphatic vessels reactivity to exogenous thyroliberin gradually established at the 6-7th days till 12th day from the moment of thyroliberin injection. The mechanisms of the action of thyroliberin in ULD are discussed.

Glyprolines and semax prevent stress-induced microcirculatory disturbances in the mesentery.

One-hour immobilization stress considerably disturbed microcirculation in the mesentery: blood flow in small mesenteric vessels decreased or stopped and numerous hemorrhages appeared. Lymphatic vessels lost spontaneous activity and did not respond to norepinephrine. Administration of Semax and glyprolines 1 h before stress decreased the severity of stress-induced microcirculatory disturbances. PGP and GP were most effective in this respect.

[Effect of thyroliberin on contractility and electrical activity of isolated bovine lymphangions]. / Deistvie tiroliberina na sokratitel'nuiu i élektricheskuiu aktivnost' izolirovannykh limfangionov byka.

The role of regulatory peptides is the least explored part in the field of humoral regulation of lymphatics. In this paper we continue a systematic investigation of their effects on the lymphatic vessels of various animals. The effect of thyroliberin was studied on bovine mesenteric lymphatics. The isolated lymphatics contractility and smooth muscle cell electrical activity were investigated. Thyroliberin in ultra low concentrations (1 x 10(-13)-1 x 10(-18) M) exerts a considerable stimulating effect. The mechanism of the theroliberin ultra-low concentrations action and a possibility of the medical usage of the obtained results, are discussed.

[Role of peptides in regulation of the contractile activity of lymphatic vessels]. / Uchastie peptidov v reguliatsii sokratitel'noi deiatel'nosti limphaticheskikh sosudov.

The review sums up our own and literature data on effects of regulatory peptides upon contractility of lymphatic vessels and lymph flow. Some specific features of the peptides activity: the efficiency in ultra-low concentrations and the biphasic effects, are analyzed.

[The effect of thyroliberin on the structural characteristics of rat erythrocytes]. / Vliianie tiroliberina na strukturnye osobennosti éritrotsitov krys.

The effect of regulatory peptide thyrotropin-releasing hormone (TRH) on the structure of the plasma membrane and morphology of rat erythrocytes was studied using a spin probe and scanning electron microscopy. EPR spectra of the spin probe introduced in the intramembrane space demonstrate that TRH at 10(-7) and 10(-3) M induces structural changes in the erythrocyte membrane. Scanning electron microscopy showed that introduction of TRH at 10(-11), 10(-7), and 10(-3) M in the erythrocyte suspension increased the proportion of discocytes as compared to the control. This effect is due to TRH-induced cell transformation in discocytes. The obtained data suggest that TRH affects the membrane structure and the morphology of erythrocytes, changes the functional activity of these cells and, thus, indirectly influences the rate of the oxygen supply to tissue.

[The effectiveness of ultralow doses and concentrations of biologically active compounds]. / Ob éffektivnosti ul'tramalykh doz i kontsentratsii biologicheski aktivnykh soedinenii.

Numerous data of literature are analysed on the biological activity of ultra-low (10(-12)-10(-19) M) concentrations and corresponding doses of same bioregulators. Our own data are presented on the modulation of lymphatic vessel contractility by peptides (thyroliberin, defensin, and tuftsin) in concentrations ranging from 10(-13) to 10(-16) M. Hypothetic mechanisms of these phenomena are discussed.

[The use of thyrotropin-releasing hormone in clinical practice as a lymphatic stimulator in the treatment of acute pancreatitis]. / Primenenie v klinicheskoi praktike tiroliberina kak limfostimuliatora pri lechenii ostrogo pancreatitia.

Experiments were conducted to study the modulating effect of thyrotropin-releasing hormone, (TRH) on the contractility of lymphatic vessels of the rat mesenterium. Later, TRH was applied in the clinic in the treatment of edematous and destructive forms of acute pancreatitis in 15 patients. as a result, echoscopy showed diminished edema of the pancreas, amylasemia decreased, the concentration of middle mass molecules in the blood reduced and their transport in the urine intensified. The agent was infused into the veins and into the lymphatic vessels, which allowed its dose to be reduced by half.

[Thyroliberin: new physiological effects and prospects of clinical use]. / Tiroliberin, novye fiziologicheskie éffekty i perspektivy klinicheskogo primeneniia.

In addition to the well-known activities of TRH (stimulation of respiration, antidepressant action, increase of motility, antishock action, therapeutic effects against ataxia, and so forth), some new properties were established. TRH was found (1) to stimulate the contractility of lymph vessels in ultra-low doses and to be useful in the treatment of acute pancreatitis; (2) to normalize cerebral circulation in rats and neonates after asphyxia; (3) to improve the electrophysiological parameters of the retina and pigmented epithelium in rats and man, to exert a long-term positive influence on the health status of patients suffering from senile retinal macular dystrophy; (4) to potentiate the analgesic effect of low doses of morphine in a definite range of doses (analog PR-546). It is of paramount importance that most of the indicated activities of TRH may hold promise for clinical application.