RESUMO
Bacterial lipopolysaccharide given intravenously at 30 mg/kg to anesthetized rats results in rapid systemic hypotension and hypovolemia, elaboration of cytokines, increased proteolysis and vascular endothelial dysfunction. When a monoclonal antibody SdJ5-1.17.15 (SdJ5) directed against the lipid A moiety of lipopolysaccharide was administered at (1.25 or 5.0 mg/kg) 5 min prior to the endotoxin, significant protection was afforded to rats. This protection was manifested by a significant reduction in the early hypotension, as well as attenuation of hypovolemia and proteolysis. To evaluate endothelial function, superior mesenteric artery rings were isolated from endotoxemic rats 4 h after endotoxic challenge. Lipopolysaccharide (LPS) significantly reduced superior mesenteric artery vasorelaxation to acetylcholine and A23187, two endothelium-dependent vasodilators, but not to NaNO2, an endothelium-independent vasodilator. SdJ5 significantly preserved vasorelaxation responses to both acetylcholine and A23187, indicating a marked degree of endothelial preservation by this anti-lipid A monoclonal antibody. The protection was dose-dependent since 0.3 mg/kg of SdJ5 did not provide significant protection in any variable measured. Moreover, there was no significant difference between the 1.25 mg/kg and 5.0 mg/kg dose of SdJ5. Furthermore, plasma concentrations of TNF-alpha, a cytokine involved in mediating many of the effects associated with endotoxemia, was significantly reduced in SdJ5-treated animals. Thus, SdJ5 appears to be capable of counteracting many of the in vivo sequelae of endotoxemia in rats.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Lipídeo A/toxicidade , Músculo Liso Vascular/efeitos dos fármacos , Choque Séptico/prevenção & controle , Acetilcolina/farmacologia , Análise de Variância , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Proteínas Sanguíneas/metabolismo , Calcimicina/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Humanos , Hipotensão/tratamento farmacológico , Imunoglobulina M/imunologia , Lipídeo A/administração & dosagem , Lipídeo A/imunologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Choque Séptico/tratamento farmacológico , Choque Séptico/metabolismo , Nitrito de Sódio/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The anti-shock effects of an organic nitric oxide donor, S-nitroso-N-acetylpenicillamine (SNAP), were tested in a rat model of hemorrhagic shock. Administration of SNAP at a dose of 10 mcg/kg injection followed by 10 mcg/kg/h infusion neither significantly decreased mean arterial blood pressure (MABP) nor significantly altered bleedout volumes in hemorrhagic rats, indicating that SNAP did not modify the severity of the shock protocol. However, hemorrhaged rats treated with SNAP maintained post-reinfusion MABP at significantly higher values than hemorrhaged rats receiving 0.9% NaCl (final MABP 81 +/- 3.0 mmHg vs. 54 +/- 1.1 mmHg, respectively; p < 0.001). SNAP also significantly increased survival times following hemorrhagic shock (113 +/- 4 min in SNAP treated rats compared with 70 +/- 4.5 min in vehicle treated rats, p < 0.001). The overall survival rates were 87.5% when treated with SNAP and 0% with 0.9% NaCl (p < 0.01). In hemorrhagic shock rats receiving only vehicle, a significant accumulation of neutrophils in intestinal tissue occurred as indicated by a higher MPO activity in intestinal tissue (MPO activity, 1.26 +/- 0.31 vs. 0.14 +/- 0.05U/100 mg in sham hemorrhagic shock rats, p < 0.02). Administration of SNAP significantly attenuated the neutrophil accumulation in the intestinal tissue (MPO activity, 0.42 +/- 0.09U/100 mg, p < 0.05 compared with hemorrhagic rats receiving only the vehicle). Moreover, endothelial dysfunction of superior mesenteric artery rings occurred in hemorrhagic shock rats given only 0.9% NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Penicilamina/análogos & derivados , Choque Hemorrágico/prevenção & controle , Vasodilatadores/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Íleo/efeitos dos fármacos , Técnicas In Vitro , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Penicilamina/uso terapêutico , Peroxidase/metabolismo , Ratos , Ratos Sprague-Dawley , S-Nitroso-N-Acetilpenicilamina , Choque Hemorrágico/patologiaRESUMO
To further clarify the protective mechanism(s) of defibrotide in splanchnic artery occlusion (SAO) shock, we observed the effect of defibrotide on polymorphonuclear leukocyte (PMN) accumulation in the intestinal tissue, gastric lysosomal hydrolases and endothelial function of the ischemia-reperfused superior mesenteric artery (SMA). Pentobarbital anesthetized rats were subjected to occlusion of both the celiac and superior mesenteric arteries for 90 min followed by 2 h reperfusion. The rats receiving only the vehicle for defibrotide exhibited a marked increase in intestinal myeloperoxidase (MPO) activity and a significant endothelial dysfunction manifested by the loss of endothelium-dependent vasorelaxation. Only 2 of 6 rats (33%) survived 2 h of reperfusion. In contrast, those rats treated with defibrotide exhibited significantly attenuated PMN accumulation in intestinal tissue, enhanced endothelium-dependent vasorelaxation in SMA rings, prolonged survival time and increased survival rate to 6 of 7 (i.e., 86%). However, addition of defibrotide in vitro had no direct effect on LTB4 activated PMN adherence to vascular endothelium. Moreover, defibrotide preserved gastric lysosomal membranes in vitro. These results indicate that the protective effect of intravenous administration of defibrotide on SAO shock may be related to its endothelial preserving effect reducing PMN adherence and protection of endothelial and lysosomal membrane integrity.
Assuntos
Fibrinolíticos/uso terapêutico , Oclusão Vascular Mesentérica/tratamento farmacológico , Polidesoxirribonucleotídeos/uso terapêutico , Animais , Íleo/enzimologia , Masculino , Oclusão Vascular Mesentérica/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Peroxidase/metabolismo , Ratos , Ratos Endogâmicos , Reperfusão , Choque/enzimologia , Choque/metabolismoRESUMO
Injection of sodium arachidonate (NaAr) intravenously at a dose of 2 mg/kg is uniformly lethal in rabbits within 3 min. This sudden death is characterized by a precipitous drop in mean blood pressure within 2 min after injection of NaAr, a marked decrease in the circulating platelet count, a significant increase in intratracheal pressure and in plasma thromboxane A2 (TxA2) concentration as measured by radioimmunoassay of its stable breakdown product, TxB2. Pretreatment with Bay-u-3405, a new specific thromboxane receptor antagonist, at a dose of 1 or 10 mg/kg dramatically protected rabbits against sudden death induced by injection of NaAr. All of the rabbits treated with either of these two doses of Bay-u-3405 survived, and their thrombocytopenia, elevated plasma TxB2 concentration and bronchoconstriction were significantly attenuated. However, administration of 0.1 mg/kg Bay-u-3405 exerted no protective effect in this lethal model. Bay-u-3405 was shown to be a potent and specific inhibitor of thromboxane-mimetic induced platelet aggregation in vitro. Our data clearly show that Bay-u-3405 is a very effective protective agent against NaAr-induced sudden death in rabbits, blocking all of the known deleterious effects of TxA2.
Assuntos
Ácidos Araquidônicos/antagonistas & inibidores , Carbazóis/farmacologia , Morte Súbita , Sulfonamidas/farmacologia , Tromboxanos/antagonistas & inibidores , Animais , Ácido Araquidônico , Ácidos Araquidônicos/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Eletrocardiografia , Masculino , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Coelhos , Radioimunoensaio , Tromboxano A2/toxicidadeRESUMO
We studied the effects of BN 50739, a novel PAF antagonist, in a rat model of traumatic shock. Pentobarbital anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, significant increases in plasma cathepsin D (4.2-fold), free amino-nitrogen (2.8-fold) and myocardial depressant factor (4.7-fold) activities and a survival time of 1.62 +/- 0.16 h. Treatment with BN 50739 (10 mg/kg, i.v.) 10 min post-trauma prolonged survival time to 3.14 +/- 0.44 h (p less than 0.01) and attenuated the accumulations of cathepsin D (5.8 vs. 12.5 U/ml, p less than 0.01), free amino-nitrogen (4.6 vs. 12.5 U/ml, p less than 0.001) and myocardial depressant factor (19.4 vs. 65.1 U/ml, p less than 0.001). Moreover, in washed rabbit platelets, BN 50739 inhibited PAF (1.85 nM)-induced aggregation (IC50: 50 nM) without affecting ADP (5 microM)-induced aggregation. In anesthetized rats, BN 50739 (10 mg/kg, i.v.) attenuated PAF (10-30 ng/kg, i.v.)-induced hypotension for longer than 5 h, without influencing acetylcholine (10 micrograms/kg, i.v.)-induced hypotension. These findings indicate that BN 50739 is a specific PAF receptor antagonist with a long duration of action in vivo. The beneficial effects of PAF antagonism on traumatic shock are significant in the present study, and are consistent with the concept that PAF is involved in the pathogenesis of traumatic shock.
Assuntos
Azepinas/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Glicoproteínas da Membrana de Plaquetas , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G , Choque Traumático/tratamento farmacológico , Triazóis/uso terapêutico , Animais , Azepinas/sangue , Pressão Sanguínea/efeitos dos fármacos , Catepsina D/sangue , Técnicas In Vitro , Masculino , Fator Depressor Miocárdico/sangue , Nitrogênio/sangue , Inibidores da Agregação Plaquetária/sangue , Coelhos , Ratos , Ratos Endogâmicos , Choque Traumático/fisiopatologia , Tromboxano B2/sangue , Triazóis/sangueRESUMO
Leukocytes release cytokines and oxygen derived free radicals upon activation. Both superoxide (O2) and tumor necrosis factor (TNF) inhibit endothelium-dependent vasodilation in the intact circulation as well as in isolated blood vessels. Superoxide inactivates endothelium-derived relaxing factor (EDRF) rapidly, whereas TNF required 2 h to block EDRF release due to synthesis of adhesive proteins on the surface of neutrophils and/or the expression of their ligands on endothelial cells. Thus, vasodilation to acetylcholine is markedly attenuated by either O2 or TNF, whereas the vasodilation to NaNO2 at pH 2.0 or to nitroglycerin is not affected. Superoxide dismutase restores acetylcholine responses to myocardial ischemia followed by reperfusion, whereas cycloheximide restores acetylcholine responses to TNF. This occurs both in the isolated perfused rat heart (perfused without plasma or blood cells) and in isolated perfused cat carotid arteries. EDRF may be important in preserving integrity of vital tissues during ischemic states.
Assuntos
Doença das Coronárias/fisiopatologia , Endotélio Vascular/fisiologia , Leucócitos/fisiologia , Vasodilatação , Acetilcolina/farmacologia , Animais , Endotélio Vascular/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Superóxidos/farmacologia , Vasodilatação/efeitos dos fármacosRESUMO
We have devised a perfused artery preparation, in which one can conveniently assess vasoactivity to agents (a) in the presence and absence of a functionally intact endothelium within the same vessel, and (b) when added to the luminal or abluminal (i.e., adventitial) surface of the vessel. Moreover, utilizing stainless steel cannulas of various calibers, one can routinely perfuse vessels ranging from less than 1 mm to over 4 mm in internal diameter. By moderating the pulsatile nature of the constant flow perfusion, one can retain a functionally intact endothelium (i.e., at totally damped perfusion) or one can abolish endothelial modulation of vasoactive agents (i.e., a pulsatile perfusion). The integrity of the endothelium was confirmed by histological methods. Using perfused cat carotid arteries preconstricted with U-46619, a stable prostaglandin-endoperoxide analog which maintains a stable vasoconstriction, acetylcholine dilated carotid arteries perfused at non-pulsatile flows, but not at pulsatile flows, indicating the endothelium dependent nature of the vasodilation produced by ACh. This was confirmed with the calcium ionophore A-23187, a non-receptor endothelium dependent vasodilator. However, calcium channel blockers (e.g., nimodipine) prostacyclin analogs (e.g., iloprost) or vasodilator nitrates (e.g., sodium nitrite at pH 2.0) produced equivalent dilations in the presence and absence of a functional intact endothelium. This preparation allows for convenient use of single dose application of pharmacologic agents as well as cumulative dose-response relationships.
Assuntos
Artérias/fisiologia , Vasos Sanguíneos/fisiologia , Endotélio Vascular/fisiologia , Acetilcolina/farmacologia , Animais , Artérias/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Gatos , Epoprostenol/farmacologia , Feminino , Iloprosta , Técnicas In Vitro , Masculino , Nimodipina/farmacologia , Coelhos , Ratos , Nitrito de Sódio/farmacologiaRESUMO
The effect of 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl- 3(2H)- pyridazinone (pimobendan, UD-CG 115 BS), a novel positive inotropic and vasodilator agent, was studied in a severe model of murine traumatic shock. Noble-Collip drum trauma produced a shock state characterized by a significantly reduced mean arterial blood pressure (MABP), a 5-fold increase in plasma cathepsin D and myocardial depressant factor (MDF) activities, and a survival time of 80 +/- 12 min. Administration of pimobendan (100 micrograms/kg, i.v. bolus) significantly prolonged the survival time to 175 +/- 24 min (p less than 0.01). Although plasma cathepsin D was not affected by pimobendan, this agent significantly attenuated the accumulation of MDF activity in the plasma when compared to animals receiving only its vehicle (37 +/- 6 vs 61 +/- 9 U/ml, p less than 0.05). Additionally, pimobendan inhibited platelet aggregation in cat platelet rich plasma, but failed to have an antiproteolytic effect in cat pancreatic homogenates. These results suggest that cardiotonic and vasodilator activities combined with inhibition of platelet aggregation could mediate the beneficial effects of pimobendan in traumatic shock.
Assuntos
Cardiotônicos/uso terapêutico , Piridazinas/uso terapêutico , Choque Traumático/tratamento farmacológico , Vasodilatadores/uso terapêutico , Animais , Cardiotônicos/farmacologia , Catepsina D/sangue , Gatos , Modelos Animais de Doenças , Isquemia , Masculino , Fator Depressor Miocárdico/sangue , Pâncreas/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Piridazinas/farmacologia , Ratos , Ratos Endogâmicos , Circulação Esplâncnica , Vasodilatadores/farmacologiaRESUMO
Splanchnic artery occlusion (SAO) followed by release of the occlusive clamps produces circulatory shock characterized by an abrupt hypotension, cardiac depression and high lethality. We studied the effects of the thromboxane receptor antagonist, BM-13505, in rats during SAO shock. Anesthetized rats subjected to total occlusion of the celiac and superior mesenteric arteries for 40 minutes developed a severe shock state following reperfusion, usually resulting in death within 90-120 minutes of release of the occlusion. BM-13505 was started at reperfusion for 10 minutes. SAO shock rats treated with BM-13505 (1 mg/kg) maintained post-reperfusion mean arterial blood pressure (MABP) at significantly higher values compared to those receiving only the vehicle (0.9% NaCl). Treatment with BM-13505 attenuated the plasma activity of the lysosomal protease cathepsin D (p less than 0.05 from vehicle) and the plasma accumulation of free amino-nitrogen compounds (p less than 0.01 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor was significantly lower in BM-13505 treated rats than in non-treated rats (p less than 0.01 from vehicle). SAO shock rats treated with BM-13505 also exhibited a higher survival rate than the vehicle group (75% vs. 20%). These results suggest an important role of thromboxane A2 in the pathophysiology of SAO shock.
Assuntos
Oclusão Vascular Mesentérica/fisiopatologia , Fenilacetatos/farmacologia , Choque/fisiopatologia , Sulfonamidas/farmacologia , Tromboxano A2/antagonistas & inibidores , Animais , Pressão Sanguínea/efeitos dos fármacos , Catepsina D/sangue , Modelos Animais de Doenças , Hematócrito , Masculino , Fator Depressor Miocárdico/sangue , Nitrogênio/sangue , Ratos , Ratos Endogâmicos , Circulação EsplâncnicaRESUMO
Thromboxane A2 (TxA2) production increases significantly during acute myocardial ischemia. Since TxA2 induces platelet aggregation, coronary vasoconstriction and has a direct cytolytic effect, thromboxane receptor antagonists would be expected to be beneficial in acute myocardial ischemia. A new thromboxane A2 receptor antagonist, AH-23,848, was studied in a cat model of acute myocardial ischemia. Myocardial ischemia was induced by ligation of the left anterior descending (LAD) coronary artery. Thirty minutes later, AH-23,848 or vehicle was given as a bolus (1 mg.kg-1) followed by a continuous infusion (1 mg.kg-1.h-1). AH-23,848 effectively reduced the S-T segment elevation while vehicle treated cats showed an increase. From direct myocardial biopsies, it was also seen that AH-23,848 prevented the loss of creatine kinase (CK) activity from the ischemic myocardium. Furthermore, the loss of amino-nitrogen compounds was also significantly reduced (p less than 0.05) by treatment with the receptor antagonist. This protective effect was not due to an indirect reduction of myocardial oxygen demand since blood pressure, heart rate or their product was unaltered by AH-23,848 administration. Moreover, the specificity of AH-23,848 to thromboxane receptors was confirmed in isolated cat coronary arteries and in cat platelets. These experiments demonstrate that blockade of the thromboxane receptor by AH-23,848 is an effective means of preventing acute myocardial ischemic damage in the cat, and thus thromboxane A2 plays a role in propagating the extension of ischemic damage during acute myocardial ischemia.
Assuntos
Compostos de Bifenilo/farmacologia , Doença das Coronárias/tratamento farmacológico , Receptores de Prostaglandina/efeitos dos fármacos , Doença Aguda , Animais , Gatos , Vasos Coronários/efeitos dos fármacos , Creatina Quinase/sangue , Eletrocardiografia , Radicais Livres , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , Masculino , Receptores de Tromboxanos , Tromboxano A2/análogos & derivados , Tromboxano A2/antagonistas & inibidores , Vasoconstrição/efeitos dos fármacosRESUMO
Blood was withdrawn continuously from femoral veins of anesthetized rabbits at a rate of 0.07 ml/min. Sodium citrate was pumped into the blood to prevent coagulation, and luciferin-luciferase reagent was added to permit the continuous detection of extracellular ATP. Subsequently, the red blood cells were lysed and the platelet count was recorded continuously. Injection of platelet activating factor or collagen into rabbit ear veins caused an almost immediate but short-lived increase in extracellular ATP with a simultaneous but more prolonged decrease in the platelet count. Although both the endoperoxide analog 9,11-azo-PGH2 and ADP also decreased the platelet count, little extracellular ATP was detected after the azo-PGH2 and none after ADP. These studies demonstrate that those agents that cause platelet secretion from rabbit platelets in vitro also cause secretion in vivo. The method described should be useful in evaluating the capacity of antithrombotic drugs to modify platelet secretion in vivo.