RESUMEN
Sepsis, the leading cause of death in intensive care units, is associated with overproduction of nitric oxide (NO) due to inducible NO synthase (iNOS), responsible for some of the pathologic changes. Aminoguanidine (AG) is a selective iNOS inhibitor with reported inconsistent actions in sepsis. To investigate the influence of iNOS, we studied models of acute bacterial sepsis using acute challenges with aerobic (Escherichia coli) and anaerobic (Bacteroides fragilis) bacteria in the presence of AG. Six-week-old, 23 g, male and female BALB/c and C57Bl/6j mice, in equal proportions, were inoculated (ip) with bacteria in groups of 4 animals for each dose and each experiment in the absence or presence of AG (50 mg/kg, ip, starting 24 h before challenge and daily until day 6) and serum nitrate was measured by chemiluminescence. Both types of bacteria were lethal to mice, with an LD50 of 6 nephelometric units (U) for E. coli and 8 U for B. fragilis. Nitrate production peaked on the second day after E. coli inoculation with 8 and 6 U (P < 0.05), but was absent after non-lethal lower doses. After challenge with B. fragilis this early peak occurred at all tested doses after 24 h, including non-lethal ones (P < 0.05). AG-treated mice challenged with E. coli presented higher survival (P < 0.05) and increased LD50. AG-treated mice challenged with B. fragilis had lower LD50 and higher mortality. Control AG-treated animals presented no toxic effects. The opposite effect of iNOS blockade by AG in these models could be explained by restriction of oxygen for immune cells or an efficient action of NO in anaerobic localized infections. The antagonic role of NO production observed in our bacterial models could explain the reported discrepancy of NO action in sepsis.
Asunto(s)
Infecciones por Bacteroides/tratamiento farmacológico , Infecciones por Escherichia coli/tratamiento farmacológico , Guanidinas/uso terapéutico , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Sepsis/tratamiento farmacológico , Enfermedad Aguda , Animales , Infecciones por Bacteroides/sangre , Infecciones por Bacteroides/mortalidad , Bacteroides fragilis , Modelos Animales de Enfermedad , Infecciones por Escherichia coli/sangre , Infecciones por Escherichia coli/mortalidad , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Nitratos/sangre , Sepsis/sangre , Sepsis/microbiología , Sepsis/mortalidad , Tasa de SupervivenciaRESUMEN
Sepsis, the leading cause of death in intensive care units, is associated with overproduction of nitric oxide (NO) due to inducible NO synthase (iNOS), responsible for some of the pathologic changes. Aminoguanidine (AG) is a selective iNOS inhibitor with reported inconsistent actions in sepsis. To investigate the influence of iNOS, we studied models of acute bacterial sepsis using acute challenges with aerobic (Escherichia coli) and anaerobic (Bacteroides fragilis) bacteria in the presence of AG. Six-week-old, 23 g, male and female BALB/c and C57Bl/6j mice, in equal proportions, were inoculated (ip) with bacteria in groups of 4 animals for each dose and each experiment in the absence or presence of AG (50 mg/kg, ip, starting 24 h before challenge and daily until day 6) and serum nitrate was measured by chemiluminescence. Both types of bacteria were lethal to mice, with an LD50 of 6 nephelometric units (U) for E. coli and 8 U for B. fragilis. Nitrate production peaked on the second day after E. coli inoculation with 8 and 6 U (P < 0.05), but was absent after non-lethal lower doses. After challenge with B. fragilis this early peak occurred at all tested doses after 24 h, including non-lethal ones (P < 0.05). AG-treated mice challenged with E. coli presented higher survival (P < 0.05) and increased LD50. AG-treated mice challenged with B. fragilis had lower LD50 and higher mortality. Control AG-treated animals presented no toxic effects. The opposite effect of iNOS blockade by AG in these models could be explained by restriction of oxygen for immune cells or an efficient action of NO in anaerobic localized infections. The antagonic role of NO production observed in our bacterial models could explain the reported discrepancy of NO action in sepsis.
Asunto(s)
Animales , Masculino , Femenino , Ratones , Infecciones por Bacteroides/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Infecciones por Escherichia coli/tratamiento farmacológico , Guanidinas/uso terapéutico , Óxido Nítrico/antagonistas & inhibidores , Sepsis/tratamiento farmacológico , Enfermedad Aguda , Bacteroides fragilis , Infecciones por Bacteroides/mortalidad , Modelos Animales de Enfermedad , Infecciones por Escherichia coli/mortalidad , Ratones Endogámicos BALB C , Nitratos/sangre , Tasa de Supervivencia , Sepsis/microbiología , Sepsis/mortalidadRESUMEN
Multiple myeloma, as other neoplastic diseases, is accompanied by alterations in lipid metabolism. The metabolism of chylomicrons is unexplored in this condition, despite the importance of these lipoproteins for the energy body supply. Chylomicron metabolism in the bloodstream consists of lipolysis by lipoprotein lipase and uptake of remnants by the liver. Triglyceride-rich emulsions can mimic chylomicron metabolism in man and are a useful tool to evaluate this metabolic pathway. A double-labeled chylomicron-resembling emulsion was injected into 20 patients with multiple myeloma and 30 normolipidemic healthy subjects. The plasma kinetic curves of the emulsion 3H-triglyceride and 14C-cholesteryl ester were determined in plasma samples collected over 60 minutes. The fractional clearance rate (FCR) of triglycerides in multiple myeloma was not changed compared to controls. However, FCR of cholesteryl esters was smaller in multiple myeloma (0.025 +/- 0.003 and 0.061 +/- 0.010 min(-1), respectively). These results indicate that chylomicron lipolysis is not affected in multiple myeloma, whereas remnant removal is diminished.
Asunto(s)
Ésteres del Colesterol/farmacocinética , Quilomicrones/metabolismo , Emulsiones Grasas Intravenosas/farmacocinética , Mieloma Múltiple/metabolismo , Triglicéridos/farmacocinética , Adulto , Anciano , Apolipoproteínas/sangre , Colesterol/deficiencia , Ésteres del Colesterol/sangre , Femenino , Humanos , Hipolipoproteinemias/etiología , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Triglicéridos/sangreRESUMEN
1. Seven patients submitted to myocardial revascularization surgery with cardiopulmonary bypass were studied. Blood samples were obtained immediately before and 24 h after surgery. The parameters studied were the production of platelet activating factor (PAF-acether) and superoxide anion, cellular beta-glucuronidase activity as well as polymorphonuclear cell (PMN) and platelet counts. 2. Twenty-four h after surgery, there was a 54% decrease in platelet number (P less than 0.005), a 121% increase in PMN number (P less than 0.005), a 353% increase in PAF-acether (P less than 0.01), a 211% increase in superoxide anion (O2-) and a 104% increase in beta-glucuronidase (P less than 0.05) levels when compared with the pre-surgery levels. 3. The present results indicate that PMN are more reactive after surgery with cardiopulmonary bypass.
Asunto(s)
Puente Cardiopulmonar , Glucuronidasa/sangre , Revascularización Miocárdica , Neutrófilos/fisiología , Factor de Activación Plaquetaria/biosíntesis , Superóxidos/sangre , Recuento de Células Sanguíneas , Humanos , Persona de Mediana Edad , Recuento de PlaquetasRESUMEN
Seven patients submitted to myocardial revascularization surgery with cardiopulmonary bypass were studied. Blood samples were obtained immediately before and 24 h after surgery. The parameters studied were the production of platelet activating factor (PAF-acether) and superoxide anion, cellular beta-glucuronidase activity as well as polymorphonuclear cell(PMN) and platelet count. Twenty-four h after surgery, there was a 54% decrease in platelet number (P<0.005), a 121% increase in PMN number (P<0.005), a 353% increase in PAF-acether (P<0.01), a 211% increase in superoxide anion (O2-) and a 104% increase in beta-glucuronidase (P<0.05) levels when compared with the pre-surgery levels. The present results indicate that PMN are more reactive after surgery with cardiopulmonary bypass