RESUMEN
BACKGROUND: Acute mesenteric ischemia following cardiovascular surgery is a rare but fatal complication. We established a new rat model for hemodynamic monitoring during mesenteric ischemia/reperfusion (I/R) and evaluated the impact of mesenteric I/R on hemodynamics and remote organ injury. METHODS: Mesenteric I/R was induced in male Wistar rats by superior mesenteric artery occlusion for 90 minutes, followed by 120 minutes of reperfusion. Before I/R, ventilation and hemodynamic monitoring including mean arterial blood pressure (MAP) and cardiac output (CO) were established. During reperfusion Geloplasma (I/R + Geloplasma, N = 6) and Ringer's solution (I/R + Ringer, N = 6) were titrated according to CO and compared with I/R without volume resuscitation (I/R only, N = 6) and a sham group (sham, N = 6). Blood samples were regularly taken for serum marker measurements. After reperfusion organs were harvested for histology studies. RESULTS: After acute mesenteric I/R, MAP and CO decreased (p < 0.01) while systemic and pulmonary vascular resistance increased (p < 0.01) continuously in the I/R group. Volume substitution according to CO initially stabilized hemodynamic parameters, but CO declined independently in the late stage. Compared with the I/R + Ringer group, the I/R + Geloplasma group required less volume for resuscitation (p < 0.01), experienced less metabolic acidosis. I/R groups had more organ injuries, more neutrophils sequestration, and higher creatine phosphokinase-MB levels than sham group. CONCLUSION: A new model for CO monitoring after mesenteric I/R injury demonstrated severe hypovolemic shock during reperfusion followed by remote myocardial and lung injury. Far less colloid volume is needed for hemodynamic stabilization after I/R compared with crystalloid volume.
Asunto(s)
Gelatina/toxicidad , Hemodinámica , Intestinos/irrigación sanguínea , Soluciones Isotónicas/toxicidad , Isquemia Mesentérica/terapia , Daño por Reperfusión/fisiopatología , Reperfusión/efectos adversos , Acidosis/sangre , Acidosis/etiología , Acidosis/fisiopatología , Animales , Presión Arterial , Biomarcadores/sangre , Gasto Cardíaco , Modelos Animales de Enfermedad , Gelatina/administración & dosificación , Intestinos/patología , Soluciones Isotónicas/administración & dosificación , Pulmón/irrigación sanguínea , Pulmón/patología , Lesión Pulmonar/etiología , Lesión Pulmonar/patología , Lesión Pulmonar/fisiopatología , Masculino , Isquemia Mesentérica/sangre , Isquemia Mesentérica/patología , Isquemia Mesentérica/fisiopatología , Miocardio/patología , Ratas Wistar , Reperfusión/métodos , Daño por Reperfusión/sangre , Daño por Reperfusión/etiología , Daño por Reperfusión/patología , Lactato de Ringer , Factores de Tiempo , Resistencia VascularRESUMEN
BACKGROUND: Acute mesenteric ischemia is often caused by embolization of the mesenteric arterial circulation. Coherent intestinal injury due to ischemia and following reperfusion get visible on macroscopic and histologic level. In previous studies, application of glycine caused an ameliorated intestinal damage after ischemia-reperfusion in rats. Because we speculated that glycine acted here as a signal molecule, we investigated whether the glycine-receptor agonist ß-alanine evokes the same beneficial effect in intestinal ischemia-reperfusion. MATERIALS AND METHODS: ß-alanine (10, 30, and 100 mg/kg) was administered intravenously. Ischemia/reperfusion of the small intestine was initiated by occluding and reopening the superior mesenteric artery in rats. After 90 min of ischemia and 120 min of reperfusion, the intestine was analyzed with regard to macroscopic and histologic tissue damage, the activity of the saccharase, and accumulation of macrophages. In addition, systemic parameters and metabolic ones (e.g., acid-base balance, electrolytes, and blood glucose) were measured at certain points in time. RESULTS: All three dosages of ß-alanine did not change systemic parameters but prevent from hyponatremia during the period of reperfusion. Most importantly, application of 100-mg ß-alanine clearly diminished intestinal tissue damage, getting visible on macroscopic and histologic level. In addition, I/R-mediated decrease of saccharase activity and accumulation of macrophages in the small intestine were ameliorated. CONCLUSIONS: The present study demonstrated that ß-alanine was a potent agent to ameliorate I/R-induced injury of the small intestine. Due to its diminishing effect on the accumulation of macrophages, ß-alanine is strongly expected to mediate its beneficial effect via glycine receptors.
Asunto(s)
Intestinos/irrigación sanguínea , Sustancias Protectoras/uso terapéutico , Daño por Reperfusión/prevención & control , beta-Alanina/uso terapéutico , Animales , Biomarcadores/metabolismo , Relación Dosis-Respuesta a Droga , Inyecciones Intravenosas , Intestinos/efectos de los fármacos , Intestinos/patología , Masculino , Sustancias Protectoras/metabolismo , Sustancias Protectoras/farmacología , Ratas , Ratas Wistar , Receptores de Glicina/metabolismo , beta-Alanina/metabolismo , beta-Alanina/farmacologíaRESUMEN
BACKGROUND: The pathophysiological role of pancreatic digestive hydrolases in intestinal ischemia-reperfusion (I/R) injury is still not clear. Here, we studied whether ischemia-induced injury to the small intestine can be explained by the autodigestion hypothesis. MATERIALS AND METHODS: Mesenteric I/R was induced in rats by superior mesenteric artery occlusion (90 min) and reopening (120 min). Thirty minutes before superior mesenteric artery occlusion, aprotinin (14.7 mg/kg), orlistat (5 mg/kg), and their combination or α1-proteinase inhibitor (60 mg/kg) were injected into the lumen of the small intestine. Systemic and vital parameters, intestinal microcirculation, and mucosal barrier function were monitored during the observation phase; markers of small intestinal injury, as well as trypsin-, chymotrypsin-, elastase-, and lipase-like activities in intestinal effluates were assessed at the end. RESULTS: The pattern of small intestinal injury correlated inversely with the local alterations in microvascular tissue perfusion and corresponded with the intestinal distribution of trypsin-like activity. Aprotinin almost completely inhibited trypsin-like activity (P < 0.05) and significantly reduced intestinal tissue injury. Combined with orlistat, it also increased the postischemic blood pressure (P < 0.05) but not the intestinal barrier function. Macroscopic as well as the histologic alterations were decreased by α1-proteinase inhibitor, which significantly improved postischemic blood pressure (P < 0.05). CONCLUSIONS: The I/R-induced pattern of small intestinal injury is likely to result from both local differences in tissue ischemia and the digestive activity of migrated pancreatic trypsin. Therefore, administration of aprotinin and orlistat into ischemic small intestines may be a therapeutic option in patients with a poor diagnosis.
Asunto(s)
Enfermedades Intestinales/enzimología , Intestino Delgado/enzimología , Daño por Reperfusión/enzimología , Tripsina/metabolismo , Animales , Aprotinina/uso terapéutico , Evaluación Preclínica de Medicamentos , Enfermedades Intestinales/tratamiento farmacológico , Intestino Delgado/irrigación sanguínea , Lactonas/uso terapéutico , Orlistat , Ratas , Daño por Reperfusión/tratamiento farmacológico , Circulación Esplácnica , Inhibidores de Tripsina/uso terapéuticoRESUMEN
Melatonin improves survival and functional impairment including hemolysis, thrombocytopenia, and hypotension when administered in a prophylactic manner or early after initiation of sepsis or endotoxemia. In the present study, melatonin was given not before first symptoms of systemic inflammation became manifest. Lipopolysaccharide was infused at a rate of 0.5 mg/kg × h to induce systemic inflammation in male Wistar rats. Melatonin (single dose 3 mg/kg × 15 min) was intravenously administered 180 and 270 min after starting of the lipopolysaccharide infusion. Systemic and vital parameters (e.g., systemic blood pressure and breathing rate) as well as blood and plasma parameters (acid-base parameters; electrolytes; parameters of tissue injury such as glucose concentration, lactate concentration, hemolysis, and aminotransferase activities; parameters of thromboelastometry; and platelet count) were determined in regular intervals. Infusion of lipopolysaccharide led to characteristic symptoms of severe systemic inflammation including hypotension, metabolic acidosis and hypoglycemia, electrolyte and hemostatic disturbances, thrombocytopenia, and hemolysis. Melatonin neither decreased mortality nor reduced lipopolysaccharide-dependent changes to vital, blood, and plasma parameters. Even though melatonin may have a beneficial effect in early stages of systemic inflammation, it can hardly be an option in therapy of manifest sepsis or endotoxemia in an intensive care unit.
Asunto(s)
Inflamación/tratamiento farmacológico , Melatonina/uso terapéutico , Animales , Endotoxemia/tratamiento farmacológico , Inflamación/inducido químicamente , Lipopolisacáridos/efectos adversos , Masculino , Melatonina/farmacología , Ratas , Ratas Wistar , Sepsis/tratamiento farmacológico , Factores de Tiempo , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Intestinal ischemia is often caused by a malperfusion of the upper mesenteric artery. Since the intestinal mucosa is one of the most rapidly proliferating organs in human body, this tissue can partly regenerate itself after the onset of ischemia and reperfusion (I/R). Therefore, we investigated whether glycine, sodium pyruvate, and resveratrol can either support or potentially harm regeneration when applied therapeutically after reperfusion injury. METHODS: I/R of the small intestine was initiated by occluding and reopening the upper mesenteric artery in rats. After 60 min of ischemia and 300 min of reperfusion, glycine, sodium pyruvate, or resveratrol was administered intravenously. Small intestine regeneration was analyzed regarding tissue damage, activity of saccharase, and Ki-67 positive cells. Additionally, systemic parameters and metabolic ones were obtained at selected periods. RESULTS: Resveratrol failed in improving the outcome after I/R, while glycine showed a partial beneficial effect. Sodium pyruvate ameliorated metabolic acidosis, diminished histopathologic tissue injury, and increased cell proliferation in the small intestine. CONCLUSION: While glycine could improve in part regeneration but not proliferation, sodium pyruvate seems to be a possible therapeutic agent to facilitate proliferation and to support mucosal regeneration after I/R injury to the small intestine.
Asunto(s)
Glicina/administración & dosificación , Ácido Pirúvico/administración & dosificación , Regeneración/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Estilbenos/administración & dosificación , Animales , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Inyecciones Intravenosas , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Intestino Delgado/efectos de los fármacos , Intestino Delgado/patología , Antígeno Ki-67/genética , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/patología , Ratas , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Resveratrol , beta-Fructofuranosidasa/genéticaRESUMEN
Melatonin has been shown to enhance the immune response under immune-compromised conditions. However, its immune-modulatory effects under inflammatory conditions are unclear at present. Both pro- and anti-inflammation has been reported. To study time-dependent effects of melatonin on the general immune response during endotoxemia in more detail, we used two models in male rats: per-acute endotoxemia was induced by lipopolysaccharide (LPS) bolus injection (2.5 mg/kg), sub-acute endotoxemia by LPS infusion (2.5 mg/kg × h). Melatonin was applied directly before and 2 h after LPS administration (3 mg/kg, each). The LPS-induced formation of the pro-inflammatory cytokines tumor necrosis factor alpha, interferon-gamma, interleukin (IL)-1α/ß, IL-5, and IL-6 and of the anti-inflammatory cytokine IL-10 was further amplified by melatonin, although it was only significant during per-acute endotoxemia. In both models, melatonin had no effect on the LPS-induced nitric oxide release. These findings show that exogenous melatonin is capable of enhancing the general immune response under inflammatory conditions.