RESUMEN
This study was aimed at investigating the effect of prolyl-glycyl-proline (PGP) tripeptide on vascular permeability in rats with an inflammation. It was found that the peptide reduces the rat paw edema induced by a subcutaneous administration of histamine to the same extent as the conventional anti-inflammatory agent diclofenac. However, an assessment of the relative expression level of the cox-2 gene at the inflammation focus using real-time PCR showed that, in contrast to diclofenac, PGP does not affect the cox-2 gene expression. This is indicative of the fact that they have different mechanisms of action. We used the model of acute peritonitis induced by an intraperitoneal injection of thioglycolate to demonstrate that the inflammatory response of an organism is accompanied by increased vascular permeability in the tissues of the stomach and small intestine. Pre-administration (30 minutes before the induction of the inflammation) of PGP prevented this increase, whereby the level of vascular permeability, exudate volume in the peritoneal cavity, and the amount of the Evans Blue dye in this exudate remained at the control level. Therefore, these results suggest that the anti-inflammatory action of PGP is based on its ability to prevent an increase in vascular permeability.
RESUMEN
Tripeptide glycyl-prolyl-proline (PGP), a regulatory peptide of the glyproline family, possesses a pronounced anti-inflammatory effect primarily due to its ability to prevent secretion of the proinflammatory mediator histamine by rat peritoneal mast cells. Activation of mast cell with synacthen (ACTH1-24) and substance 48/80 leads to an increase in intracellular calcium concentration. Pretreatment of mast cells with PGP prevented calcium entry into the cytoplasm from both intercellular space and intracellular stores. Acetylated peptide (N-AcPGP) produced a similar effect on histamine release and intracellular calcium content in mast cells activated with synacthen. These findings indicate that both forms of the peptide can stabilize mast cells and prevent intracellular calcium increase.
Asunto(s)
Calcio/metabolismo , Citoplasma/efectos de los fármacos , Mastocitos/efectos de los fármacos , Oligopéptidos/farmacología , Prolina/análogos & derivados , Animales , Células Cultivadas , Citoplasma/metabolismo , Masculino , Mastocitos/metabolismo , Oligopéptidos/química , Cavidad Peritoneal/citología , Prolina/química , Prolina/farmacología , RatasRESUMEN
This study is dedicated to the research of the regulatory peptide PGP and its acetylated form (N-AcPGP) effect on the paw edema formation and vascular permeability in rat skin. Edema was induced by subcutaneous administration of histamine. Vascular permeability was determined by intradermal injection of mast cells activators corticotropin-releasing hormone (CRH), lipopoly-saccharide (LPS), Synacthen (corticotropin analogue), histamine and compound 48/80. We established that PGP reduced the size of the paw edema, but N-AcPGP had an opposite effect increasing paw edema. Skin vascular permeability didn't increase in rats under the administration of PGP or N-AcPGP with additional injections of CRH, LPS and Synacthen, but with additional injections of histamine and substance 48/80. We demonstrated in vitro that pretreatment with both PGP and N-AcPGP reduced histamine secretion by rat's peritoneal mast cells under activation by Synacthen. These results provide evidence that the effect of the peptides on vascular permeability is mainly mediated by the influence on the secretory activity of mast cells.
Asunto(s)
Permeabilidad Capilar/efectos de los fármacos , Oligopéptidos , Prolina/análogos & derivados , Piel , Acetilación , Animales , Edema/tratamiento farmacológico , Edema/metabolismo , Histamina/metabolismo , Masculino , Mastocitos/citología , Mastocitos/metabolismo , Oligopéptidos/farmacocinética , Oligopéptidos/farmacología , Prolina/farmacocinética , Prolina/farmacología , Ratas , Piel/irrigación sanguínea , Piel/metabolismoRESUMEN
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.
Asunto(s)
Eritrocitos/efectos de los fármacos , Inflamación/tratamiento farmacológico , Oligopéptidos/farmacología , Presión Osmótica/efectos de los fármacos , Prolina/análogos & derivados , Animales , Células Cultivadas , Oligopéptidos/uso terapéutico , Prolina/farmacología , Prolina/uso terapéutico , RatasRESUMEN
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.
Asunto(s)
Vasos Linfáticos/efectos de los fármacos , Norepinefrina/administración & dosificación , Oligopéptidos/uso terapéutico , Prolina/análogos & derivados , p-Metoxi-N-metilfenetilamina/análogos & derivados , p-Metoxi-N-metilfenetilamina/administración & dosificación , Animales , Inyecciones Intramusculares , Vasos Linfáticos/fisiopatología , Masculino , Mesenterio/efectos de los fármacos , Prolina/uso terapéutico , RatasRESUMEN
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.
Asunto(s)
Inflamación/fisiopatología , Vasos Linfáticos/fisiología , Mesenterio/irrigación sanguínea , Restricción Física/fisiología , Estrés Fisiológico/fisiología , Animales , Inflamación/inducido químicamente , Masculino , Ratas , Tioglicolatos/toxicidadRESUMEN
Experiments on outbred albino male rats showed that psychoemotional stress induced by intraperitoneal injection of cholecystokinin-4 (100 microg/kg) increased anxiety, impaired orientation and exploration activities in the elevated plus-maze and hole-board tests, and increased the level of depression of Porsolt test. Preliminary intranasal administration of glyprolines (15 min before cholecystokinin) in a dose of 3.7 micromol/kg prevented the development of stress-induced behavioral disturbances. Administration of peptides 30 min after cholecystokinin-4, i.e., to rats with developed behavioral disturbances, almost completely abolished these disturbances.
Asunto(s)
Dipéptidos/uso terapéutico , Oligopéptidos/uso terapéutico , Prolina/análogos & derivados , Estrés Psicológico/tratamiento farmacológico , Animales , Ansiedad/inducido químicamente , Ansiedad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Depresión/inducido químicamente , Conducta Exploratoria/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Prolina/uso terapéutico , Ratas , Estrés Psicológico/inducido químicamente , TetragastrinaRESUMEN
Experiments on male outbred albino rats showed that stress (10-min swimming) increased anxiety and inhibited orientation and exploratory activities. Poststress (15 min after the end of swimming) intranasal administration of peptides Pro-Gly-Pro and Gly-Pro in a dose of 3.7 micromol/kg prevented stress-induced behavioral disorders. This effect persisted for 3 h.
Asunto(s)
Dipéptidos/uso terapéutico , Oligopéptidos/uso terapéutico , Trastornos de Estrés Traumático/tratamiento farmacológico , Estrés Psicológico/complicaciones , Animales , Animales no Consanguíneos , Conducta Animal/efectos de los fármacos , Dipéptidos/administración & dosificación , Conducta Exploratoria/efectos de los fármacos , Inyecciones Intraperitoneales , Masculino , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/uso terapéutico , Oligopéptidos/administración & dosificación , Ratas , Reflejo de Sobresalto/efectos de los fármacos , Trastornos de Estrés Traumático/etiología , Trastornos de Estrés Traumático/fisiopatología , NataciónRESUMEN
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.
Asunto(s)
Mesenterio/irrigación sanguínea , Oligopéptidos/farmacología , Peritonitis/fisiopatología , Prolina/análogos & derivados , Animales , Vasos Linfáticos/efectos de los fármacos , Vasos Linfáticos/fisiología , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/fisiología , Microcirculación/efectos de los fármacos , Norepinefrina/farmacología , Peritonitis/inducido químicamente , Prolina/farmacología , Ratas , TioglicolatosRESUMEN
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.
Asunto(s)
Conducta Animal/efectos de los fármacos , Síntomas Conductuales/tratamiento farmacológico , Síntomas Conductuales/etiología , Dipéptidos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Estrés Fisiológico/complicaciones , Animales , Dipéptidos/química , Conducta Exploratoria/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , RatasRESUMEN
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.
Asunto(s)
Vasos Linfáticos/fisiopatología , Mesenterio/irrigación sanguínea , Péptidos/uso terapéutico , Peritonitis/tratamiento farmacológico , Prolina/uso terapéutico , Sustancias Protectoras/uso terapéutico , Enfermedad Aguda , Animales , Inyecciones Intraperitoneales , Cinética , Mesenterio/fisiopatología , Péptidos/administración & dosificación , Peritonitis/inducido químicamente , Peritonitis/patología , Prolina/administración & dosificación , Prolina/química , Sustancias Protectoras/administración & dosificación , Ratas , Tioglicolatos/toxicidadRESUMEN
Generation of thrombin and activated protein C in the inflammatory focus was demonstrated in rats with experimental acute peritonitis. The contents of thrombin and activated protein C peaked by the 30th and 120th minute of inflammation, respectively. In vitro study showed a decrease in spontaneous and compound 48/80-induced secretion of beta-hexosaminidase by peritoneal mast cells under the influence of activated protein C in low concentrations. The antiinflammatory effect of protein C in the focus of acute peritonitis is probably realized through NO release from peritoneal mast cells. This conclusion is derived from the data that L-NAME abolishes the protective effect of activated protein C.
Asunto(s)
Mastocitos/metabolismo , Proteína C/farmacología , Amidohidrolasas/metabolismo , Animales , Inflamación/fisiopatología , Masculino , Mastocitos/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Cavidad Peritoneal , Ratas , Ratas Wistar , Trombina/metabolismoRESUMEN
Protective and antistress effects of three glyprolines--PGP, PG and GP, were studied. Stress influences produced typical changes of behavioural activity of rats in the elevated pluz-maze and the hole-board tests. These changes suggest a significant enhancement of anxiety and a drop of the level of orientation-investigative activity. A preliminary (15 minutes before stress agent) intraperitoneal administration of PGP or GP in doses of 3.7 microm/kg significantly decreased stress disturbances of behaviour. Analysis of these data shows to the possibility of PGP and GP influences on the CNS structures, which take part in the organism reciprocal reactions to stress factor. The peptide GP at equimolar dose didn't possess pronounced protective properties and just slightly decreased stress disturbance of behavioural activity of rats.
Asunto(s)
Conducta Animal/efectos de los fármacos , Dipéptidos/administración & dosificación , Aprendizaje por Laberinto/efectos de los fármacos , Estrés Fisiológico/fisiopatología , Animales , Inyecciones Intraperitoneales , Masculino , RatasRESUMEN
Tripeptide PGP in a dose of 1 mg/kg had a correcting effect on behavioral disorders in rats induced by stress exposure (forced swimming). PGP prevented the increase in anxiety and decrease in orientation and exploratory activity. Our results suggest that the effect of this peptide is realized via central nervous structures involved in organism's response to stress factors.
Asunto(s)
Conducta Animal/efectos de los fármacos , Oligopéptidos/farmacología , Prolina/análogos & derivados , Prolina/farmacología , Estrés Psicológico , Animales , Animales no Consanguíneos , Ansiedad/prevención & control , Conducta Exploratoria/efectos de los fármacos , Inyecciones Intraperitoneales , Masculino , Orientación/efectos de los fármacos , Ratas , Natación , Factores de TiempoRESUMEN
Intraperitoneal injection of cholecystokinin-4 in a dose of 100 mg/kg markedly increased secretory activity of mast cells in the mesentery and subcutaneous fat. These changes developed 5 min after treatment and progressed in time. Over the first 15 min we observed primarily merocrine secretion (granulolysis), while 60 min after cholecystokinin-4 administration apocrine secretion (degranulation) prevailed. In vitro cholecystokinin-4 had no effect on secretory activity of mast cells. Our findings suggest that stimulation of secretory activity of mast cells is determined by psychoemotional stress associated with activation of the sympathoadrenal and hypothalamic-pituitary-adrenal systems.
Asunto(s)
Mastocitos/metabolismo , Estrés Psicológico/fisiopatología , Tetragastrina/farmacología , Animales , Masculino , Ratas , Estrés Psicológico/inducido químicamenteRESUMEN
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.
Asunto(s)
Hormona Adrenocorticotrópica/análogos & derivados , Hormona Adrenocorticotrópica/farmacología , Mastocitos/metabolismo , Oligopéptidos/farmacología , Fragmentos de Péptidos/farmacología , Prolina/análogos & derivados , Prolina/farmacología , Estrés Psicológico/inducido químicamente , Acetilcolina/metabolismo , Hormona Adrenocorticotrópica/administración & dosificación , Animales , Animales no Consanguíneos , Modelos Animales de Enfermedad , Inyecciones Intraperitoneales , Masculino , Mastocitos/citología , Mastocitos/efectos de los fármacos , Mesenterio/citología , Mesenterio/efectos de los fármacos , Mesenterio/fisiopatología , Oligopéptidos/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Prolina/administración & dosificación , Ratas , Estrés Psicológico/fisiopatologíaRESUMEN
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.
Asunto(s)
Hormona Adrenocorticotrópica/análogos & derivados , Hormona Adrenocorticotrópica/farmacología , Mesenterio/irrigación sanguínea , Microcirculación/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Prolina/farmacología , Animales , Hemorragia/tratamiento farmacológico , Hemorragia/fisiopatología , Inmovilización , Masculino , Mesenterio/fisiopatología , Microcirculación/fisiología , Microcirculación/fisiopatología , Norepinefrina/farmacología , Oligopéptidos/química , Oligopéptidos/farmacología , Prolina/análogos & derivados , Ratas , Flujo Sanguíneo Regional/efectos de los fármacos , Flujo Sanguíneo Regional/fisiología , Estrés Fisiológico/tratamiento farmacológico , Estrés Fisiológico/etiología , Estrés Fisiológico/fisiopatologíaRESUMEN
Blood coagulation plays a key role among numerous mediating systems that are activated in inflammation. Receptors of the PAR family serve as sensors of serine proteinases of the blood clotting system in the target cells involved in inflammation. Activation of PAR-1 by thrombin and of PAR-2 by factor Xa leads to a rapid expression and exposure on the membrane of endothelial cells of both adhesive proteins that mediate an acute inflammatory reaction and of the tissue factor that initiates the blood coagulation cascade. Certain other receptors (EPR-1, thrombomodulin, etc.), which can modulate responses of the cells activated by proteinases through PAR receptors, are also involved in the association of coagulation and inflammation together with the receptors of the PAR family. The presence of PAR receptors on mast cells is responsible for their reactivity to thrombin and factor Xa and defines their contribution to the association of inflammation and blood clotting processes.
Asunto(s)
Coagulación Sanguínea , Inflamación , Receptores de Trombina/metabolismo , Animales , Humanos , Modelos Biológicos , Glicoproteínas de Membrana Plaquetaria/metabolismo , Unión Proteica , Receptor PAR-1 , Receptor PAR-2 , Receptores de Superficie Celular/metabolismo , Trombina/metabolismoRESUMEN
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.
Asunto(s)
Amiloide/farmacología , Mucosa Gástrica/efectos de los fármacos , Mastocitos/metabolismo , Acetilcolina/metabolismo , Animales , Bradiquinina/metabolismo , Inyecciones Intraperitoneales , Polipéptido Amiloide de los Islotes Pancreáticos , Masculino , Ratas , Ratas Wistar , Úlcera/patología , Agua/metabolismoRESUMEN
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.