RESUMO
We studied the action of a new indolinone derivative GRS, acetylsalicylic acid (ASA), and their combination on platelet aggregation, vasodilatory endothelial function, neurological status, and cerebral infarction area in experimental focal cerebral ischemia/reperfusion in rats. GRS compound (10 mg/kg), ASA (10 mg/kg), and their combination in the same doses were administered orally once a day as a suspension in 1% starch solution over 5 days after pathology modeling. Sham-operated and control animals were administered 1% starch solution. On day 5 after pathology modeling, platelet aggregation and brain damage area were studied in a half of rats in each group, and the vasodilatory function of the endothelium was studied in the other half. Neurological deficit was assessed 4 h and 1, 3, and 5 days after pathology modeling. GRS compound and ASA equally effectively prevent platelet aggregation and the development of neurological deficit in rats. GRS compound restores the vasodilatory effects of the endothelium, but only ASA contributes to reduction of the cerebral infarction area. In case of combined administration, GRS and ASA do not exhibit synergy in their antiaggregant effect.
Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Ratos , Animais , Inibidores da Agregação Plaquetária/farmacologia , Guanilil Ciclase Solúvel , Aspirina/farmacologia , Agregação Plaquetária , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Vasodilatadores/farmacologia , Infarto Cerebral , Amido , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
The specific JNK inhibitor and NO donor 11H-indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) demonstrated pronounced neuroprotective properties in an in vivo model of ischemic stroke in rats. The pharmacokinetic behavior of IQ-1 was studied in two animal species (rats, rabbits) after intravenous administration in a dose of 1 mg/kg. IQ-1 concentrations in venous blood plasma were measured by the liquid chromatography-tandem mass spectrometry method. The pharmacokinetics of IQ-1 was adequately described by the two-compartmental model. The calculated C0 for IQ-1 in rabbit and rat plasma were 2239.83±1229.55 and 1552.50±182.23 ng/ml, respectively. Two animal species are characterized by extensive tissue distribution of IQ-1 (Vss exceeded the total body water in rabbits and rats by 3.6 and 5.6 times, respectively) and high clearance values (88-94% of hepatic blood flow).
Assuntos
Fígado , Ratos , Coelhos , Animais , Infusões Intravenosas , Distribuição Tecidual , Cinética , Injeções Intravenosas , Administração IntravenosaRESUMO
The effect of p-tyrosol on the main hemodynamic parameters and contractile function of the heart was studied and a morphometric assessment of left-ventricular remodeling was performed in Wistar rats 2 months after acute 1-h myocardial ischemia followed by reperfusion. p-Tyrosol in a dose of 20 mg/kg was injected intraperitoneally 5 times: 20 min before the start of reperfusion, 4 h after the start of reperfusion, and then once a day over the next 3 days. Administration of p-tyrosol to animals in the acute period of myocardial infarction slowed down the formation of systolic and diastolic myocardial dysfunction, improved the pumping function of the heart, maintained the hemodynamic parameters at a significantly higher level, and reduced left-ventricular remodeling in the late period of myocardial infarction. In 2 months after acute myocardial ischemia modeling, the dimensions of the left-ventricular cavity, the area of the postinfarction focus, and the area of connective tissue in rats treated with p-tyrosol were significantly lower than in the control group. In the group treated with p-tyrosol, no anterior left-ventricular wall aneurysms were found.
Assuntos
Infarto do Miocárdio , Remodelação Ventricular , Animais , Infarto do Miocárdio/tratamento farmacológico , Álcool Feniletílico/análogos & derivados , Ratos , Ratos Wistar , Função Ventricular EsquerdaRESUMO
New antithrombotic drug GRS, a soluble guanylate cyclase stimulator, after repeated administration in a dose of 10 mg/kg alleviates the symptoms of endothelial dysfunction in rats with myocardial infarction; it restores antiplatelet activity of the blood vessel wall and vasodilatory function of the endothelium without producing significant effect on endothelium-independent vasodilation. GRS also has direct antiaggregant and antihypertensive effects in therapeutic doses. The obtained data suggest that GRS can be therapeutically useful in patients with cardiovascular diseases accompanied by endothelial dysfunction.
Assuntos
Guanilato Ciclase , Infarto do Miocárdio , Animais , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Humanos , Infarto do Miocárdio/tratamento farmacológico , Óxido Nítrico , Ratos , Guanilil Ciclase Solúvel , Vasodilatadores/farmacologiaRESUMO
2,6-Diisobornyl-4-methylphenol (Dibornol, 10 mg/kg intragastrically daily for 5 days after myocardial ischemia/reperfusion) 1.5-fold increased rat survival during the acute post-infarction period in comparison with the control group. In survivors, Dibornol reliably prevented post-ischemic progression of heart failure in the delayed post-infarction period (30 days after ischemia/reperfusion), which was seen from an increase in the left-ventricular developed pressure by 22%, left-ventricular contractility index by 19%, and +dP/dt by 34%. Left-ventricular end-diastolic pressure was by 39% lower than in control animals. Morphological study of heart sections from control group animals showed that Dibornol reduced the area of post-ischemic myocardial damage in the delayed period after ischemia/reperfusion to 3±1% (vs 18±2% in the control group).
Assuntos
Cresóis/uso terapêutico , Ventrículos do Coração/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Pressão Sanguínea/efeitos dos fármacos , Cresóis/química , Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Masculino , Reperfusão Miocárdica , Traumatismo por Reperfusão Miocárdica/metabolismo , RatosRESUMO
Cytochrome p450-mediated metabolism of GRS (indolinone antiaggregant) and its effects on activities of cytochrome p450 isoenzymes were studied. Inhibition of 6 isomers of cytochrome p450 in human liver microsomes was studied with the use of specific substrates. It was found that human liver cytochrome p450 enzymes could not induce degradation of GRS and that GRS was not an inductor or inhibitor of cytochrome p450 family members 1A2, 2C9, 2C19, 2D6, 2C8, and 3A4. Hence, clinical use of the prospective antiaggregant would not involve the risk of uncontrolled fluctuations in GRS concentrations in the organism because of interactions between the drugs.
Assuntos
Microssomos Hepáticos/efeitos dos fármacos , Oxindóis/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Animais , Biotransformação/efeitos dos fármacos , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Ensaios Enzimáticos , Expressão Gênica , Humanos , Cinética , Fígado/efeitos dos fármacos , Fígado/enzimologia , Microssomos Hepáticos/enzimologia , NADP/metabolismo , Ratos , Verapamil/farmacologiaRESUMO
This study aimed at assessing the regenerative effect of p-tyrosol in transient global cerebral ischemia modeled in adult male Wistar rats by reversible occlusion of the three major vessels originating from the aortic arch and supplying the blood to the brain. p-Tyrosol was administered intraperitoneally in a dose of 20 mg/kg over 10 days after surgery. The death of NeuN+ mature neurons and the number of newly formed DCX+ neurons were assessed in the CA1 field of the hippocampus that is highly susceptible to damage in this model. We found that ischemia induced death of more than 50% mature neurons in the hippocampal CA1 field (p<0.001). p-Tyrosol stimulated the formation and growth of new neurons in the normally non-proliferative CA1 region of the hippocampus (p<0.05) and produced a neuroprotective effect on mature neurons (p<0.01).
Assuntos
Região CA1 Hipocampal/fisiologia , Ataque Isquêmico Transitório/patologia , Neurogênese/efeitos dos fármacos , Neurônios/fisiologia , Fármacos Neuroprotetores/farmacologia , Álcool Feniletílico/análogos & derivados , Animais , Região CA1 Hipocampal/citologia , Modelos Animais de Doenças , Proteína Duplacortina , Masculino , Regeneração Nervosa/efeitos dos fármacos , Álcool Feniletílico/farmacologia , Ratos , Ratos WistarRESUMO
We studied anti-ischemic activity of n-tyrozol under conditions of repeated transient myocardial ischemia in rats caused by repeated (5×3 min) occlusion of the left coronary artery. n-Tyrozol administered intraperitoneally in a dose of 20 mg/kg daily over 4 days before the ischemia modeling (the last injection 15 min prior to the start of the experiment) produced a clear-cut anti-ischemic effect: it reduced ST elevation and promoted more complete recovery of ECG during reperfusion. During reperfusion periods, n-tyrozol significantly decreased the risk of ventricular fibrillation and shortened the duration of tachyarrhythmia episodes (ventricular tachycardia and fibrillation).
Assuntos
Arritmias Cardíacas/tratamento farmacológico , Cardiotônicos/farmacologia , Oclusão Coronária/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Álcool Feniletílico/análogos & derivados , Fibrilação Ventricular/tratamento farmacológico , Animais , Arritmias Cardíacas/fisiopatologia , Oclusão Coronária/fisiopatologia , Vasos Coronários/cirurgia , Esquema de Medicação , Injeções Intraperitoneais , Isquemia Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Álcool Feniletílico/farmacologia , Ratos , Ratos Wistar , Resultado do Tratamento , Fibrilação Ventricular/fisiopatologiaRESUMO
The effects of dihydroquercetin (50 mg/kg intragastrically daily for 6 weeks) on the density of capillary network (mean number of capillaries per mm2), mean capillary diameter, structure of capillary network, capillary diameter distribution (<3, 3-5, 5-7, and 7-9 µ), and local cerebral blood flow (by laser Doppler) in the visual cortex were studied in SHR rats during the development of arterial hypertension (from the 6th to the 12th week of life). Normally, the systolic and diastolic BP progressively increased in SHR rats during this period. Dihydroquercetin did not affect the development of arterial hypertension. At the same time, the drug significantly increased the mean diameter of capillaries (by 11%), capillary network density (by 23%), and in the percentage of capillaries with a diameter of 3-9 µ (passable for erythrocytes; by 42%). Positive effects of dihydroquercetin on the structure of microcirculatory bed improved microcirculation: local cerebral blood flow in the visual cortex of SHR rats was significantly higher (by 36%) than in rats receiving no flavonoid and close to the value in Wistar-Kyoto rats. Dihydroquercetin improved microvascularization and microcirculation in the cerebral cortex of SHR rats during the formation of arterial hypertension.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Microcirculação/efeitos dos fármacos , Quercetina/análogos & derivados , Animais , Encéfalo/irrigação sanguínea , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Circulação Cerebrovascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Quercetina/uso terapêutico , Ratos , Ratos Endogâmicos WKYRESUMO
Changes in cerebral neurogenesis provoked by ischemia and the effect of fluoxetine on this process were studied using a three-vessel occlusion model of global transient cerebral ischemia. The global transient cerebral ischemia was modeled on male Wistar rats by transient occlusion of three major vessels originating from the aortic arch and supplying the brain (brachiocephalic trunk, left subclavian artery, and left common carotid artery). The cells expressing doublecortin (DCX, a marker of young neurons) were counted in the hippocampal dentate gyrus on day 31 after ischemia modeling. It was found that ischemia inhibited neurogenesis in the dentate gyrus in comparison with sham-operated controls (p<0.05), while fluoxetine (20 mg/kg/day) injected over 10 days after surgery restored neurogenesis to the control level (p<0.001).
Assuntos
Giro Denteado/citologia , Giro Denteado/efeitos dos fármacos , Fluoxetina/uso terapêutico , Ataque Isquêmico Transitório/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Animais , Proteína Duplacortina , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
We propose a modification to rat model of transient global cerebral ischemia with four-vessel occlusion avoiding pneumothorax and minimizing the consequences of surgery. Survival and neurological deficit in rats in this model was studied over 5 days.
Assuntos
Modelos Animais de Doenças , Ataque Isquêmico Transitório/fisiopatologia , Doenças do Sistema Nervoso/patologia , Animais , Ataque Isquêmico Transitório/etiologia , Ataque Isquêmico Transitório/cirurgia , Masculino , Doenças do Sistema Nervoso/diagnóstico , Ratos , Ratos Wistar , Análise de SobrevidaRESUMO
We studied the effects of novel sterically hindered phenol, 4-methyl-2,6-diisobornyl phenol (dibornol) on the rheological properties of the blood in the model of myocardial ischemia/reperfusion. Dibornol (100 mg/kg intraperitoneally for 3 days before and 5 days after ischemia/reperfusion) decreased blood viscosity by 9-25% in comparison with that in sham-operatedanimals by modulating cellular (erythrocyte deformability and aggregation) and plasma (plasma viscosity) rheological parameters. Normalization of blood rheology under the influence of dibornol increased the availability of oxygen to tissues at high shear rates by 9-18% after acute ischemia/reperfusion in rats.
Assuntos
Canfanos/farmacologia , Canfanos/uso terapêutico , Cresóis/farmacologia , Cresóis/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Animais , Viscosidade Sanguínea/efeitos dos fármacos , Deformação Eritrocítica/efeitos dos fármacos , Masculino , Ratos , Ratos WistarRESUMO
We studied the antithrombotic and thrombolytic effects of Trombovazim, a highly-purified proteolytic enzyme preparation obtained by immobilization of bacterial proteinases (Bacillus) on polyethylene oxide with a molecular weight of 1.5 kDa. Blood absorption of the preparation was evaluated after intragastric administration. In vitro experiments showed that Trombovazim produces anticoagulant and thrombolytic effects, which manifested in inhibition of fibrin clot formation and acceleration of its lysis. Drug concentration in the blood was elevated from the 4th to the 7th hour after intragastric administration of Trombovazim in a dose of 2250 U/kg, being maximum by the 5th hour (0.044+/-0.011 U/ml). Course treatment with Trombovazim (1000 U intragastrically, twice daily for 3 days) had a thrombolytic effect on rats with experimental intravascular thrombosis. This effect was manifested in a decrease in thrombus weight and increase in the percent of rats with recanalization of the occluded carotid artery.
Assuntos
Anticoagulantes/farmacologia , Proteínas de Bactérias/farmacologia , Trombose das Artérias Carótidas/tratamento farmacológico , Peptídeo Hidrolases/farmacologia , Animais , Anticoagulantes/sangue , Anticoagulantes/farmacocinética , Proteínas de Bactérias/sangue , Proteínas de Bactérias/farmacocinética , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiopatologia , Trombose das Artérias Carótidas/induzido quimicamente , Circulação Cerebrovascular/efeitos dos fármacos , Compostos Ferrosos , Fibrina/metabolismo , Masculino , Peptídeo Hidrolases/sangue , Peptídeo Hidrolases/farmacocinética , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Experiments on rats showed that n-tyrosol limited the increase in blood viscosity during thermal exposure at a shear rate of 5-300 sec(-1) and inhibited ADP-induced platelet aggregation. The effects of n-tyrosol are comparable to that of pentoxyphylline.
Assuntos
Viscosidade Sanguínea/efeitos dos fármacos , Álcool Feniletílico/análogos & derivados , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Animais , Hemorreologia , Técnicas In Vitro , Masculino , Álcool Feniletílico/farmacologia , Ratos , Ratos WistarRESUMO
Antiarrhythmic activity of n-tyrosol was demonstrated on the model of early occlusion and reperfusion arrhythmia. The preparation reduces the incidence of ventricular tachycardia and fibrillation, increases the percent of animals without ventricular arrhythmia, and moderates the severity of developing ventricular arrhythmias.
Assuntos
Antiarrítmicos/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Álcool Feniletílico/análogos & derivados , Animais , Álcool Feniletílico/uso terapêutico , Ratos , Ratos Wistar , Taquicardia Ventricular/prevenção & controle , Fibrilação Ventricular/prevenção & controleRESUMO
Experiments on narcotized rats with crush syndrome showed that low resistant animals developed pronounced hypovolemia, hemoconcentration, blood hyperviscosity, impairment of oxygen metabolism, and central and peripheral hemodynamic disturbances, whereas in highly resistant rats the hemodynamics and oxygen supply to tissues were maintained at a sufficient level, while hemoconcentration and the increase in blood viscosity were less pronounced.
Assuntos
Síndrome de Esmagamento , Choque , Animais , Relação Dose-Resposta a Droga , Hemodinâmica , Hipovolemia , Masculino , Oxigênio/metabolismo , RatosRESUMO
Narcotized rats with crush syndrome develop severe syndrome of increased blood viscosity. A strict correlation was found between changes in blood viscosity at different shear rates and total peripheral vascular resistance. The severity of central hemodynamic and hemorheological disturbances was different in rats with different reaction of total peripheral vascular resistance to injury accompanied by shock.