RESUMEN
Memories of our personal past are not exact accounts of what occurred. Instead, memory reconstructs the past in adaptive-though not always faithful-ways. Using a naturalistic design, we asked how the visual perspective adopted in the mind's eye when recalling the past-namely, an "own eyes" versus "observer" perspective-relates to the stability of autobiographical memories. We hypothesized that changes in visual perspective over time would predict poorer consistency of memories. Young adults (N = 178) rated the phenomenology of and freely recalled self-selected memories of everyday events at two time points (10 weeks apart). Multilevel linear modeling revealed, as expected, that greater shifts in visual perspective over time predicted lower memory consistency, particularly for emotional details. Our results offer insight into the factors that predict the fidelity of memories for everyday events. Moreover, our results may elucidate new metrics that are useful in interpreting eyewitness testimony or experiences relayed in clinical contexts.
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Emociones , Memoria Episódica , Adulto Joven , Humanos , Recuerdo Mental , MatrimonioRESUMEN
BACKGROUND: It has been proposed that fibrin tissue adhesive (FTA) can act as an effective alternative to nasal packing in managing the postoperative symptoms of endoscopic nasal surgery. METHODOLOGY: MEDLINE, Embase, Cochrane Library, The Cumulative Index to Nursing and Allied Health Literature and ClinicalTrials.gov were searched for randomised controlled trials comparing FTA with nasal packing in endoscopic nasal surgery. The primary outcome of interest was bleeding; secondary outcomes included pain, nasal obstruction, infection, adhesions and the formation of granulation tissue. All trials underwent a risk of bias assessment, and a meta-analysis was performed using a random effects model. RESULTS: 315 studies were found, of which four were eligible for inclusion (n = 152). Bleeding was reported in all, with the meta-analysis favouring the packing group, although this was not significant. Nasal obstruction and granulation severity were significantly lower in the FTA group, however, no difference was noted for the outcomes of pain, infection or adhesions. CONCLUSION: Our results indicate minor advantages for using FTA over nasal packing. Unfortunately, the included studies show significant heterogeneity and risk of bias. Based on the available evidence, clinicians must balance the higher cost of FTA against the limited advantages for the patient.
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Endoscopía , Epistaxis , Adhesivo de Tejido de Fibrina , Procedimientos Quírurgicos Nasales , Epistaxis/terapia , Adhesivo de Tejido de Fibrina/uso terapéutico , Humanos , NarizRESUMEN
OBJECTIVES: Accumulating evidence suggests that gender affects the incidence and severity of several pulmonary diseases. Previous studies on mice have shown gender differences in susceptibility to naphthalene-induced lung injury, where Clara cell damage was found to occur earlier and to be more extensive in females than in males. However, very little is known about whether there are any gender differences in subsequent lung repair responses. The aim of this study was to investigate whether gender plays an important role in pulmonary regenerative response to naphthalene-induced Clara cell ablation. MATERIALS AND METHODS: Adult male and female mice were injected with a low, medium, or high dose of naphthalene, and lung tissue regeneration was examined by immunohistochemical staining for cell proliferation marker (Ki-67) and mitosis marker (phosphohistone-3). RESULTS: Histopathological analysis showed that naphthalene-induced Clara cell necrosis was more prominent in the lungs of female mice as compared to male mice. Cell proliferation and mitosis in both the distal bronchiolar airway epithelium and peribronchiolar interstitium of female mice was significantly greater than that of male mice after treatment with the low and medium doses. However, after treatment with high dose of naphthalene, lung regeneration was delayed in female mice, while male mice mounted a timely regenerative response. CONCLUSIONS: These findings show that there are clear gender differences in naphthalene-induced lung injury and repair.
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Lesión Pulmonar Aguda , Naftalenos/toxicidad , Mucosa Respiratoria/patología , Mucosa Respiratoria/fisiología , Caracteres Sexuales , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/fisiopatología , Factores de Edad , Animales , Bronquiolos/patología , Bronquiolos/fisiopatología , División Celular/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Antígeno Ki-67/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mitosis/fisiología , Necrosis , Regeneración/fisiología , Índice de Severidad de la EnfermedadRESUMEN
Adenoviral vector-mediated gene delivery has been vastly investigated for cystic fibrosis (CF) gene therapy; however, one of its drawbacks is the low efficiency of gene transfer, which is due to basolateral colocalization of viral receptors, immune responses to viral vectors and the presence of a thick mucus layer in the airways of CF patients. Therefore, enhancement of gene transfer can lead to reduction in the viral dosage, which could further reduce the acute toxicity associated with the use of adenoviral vectors. Nacystelyn (NAL) is a mucolytic agent with anti-inflammatory and antioxidant properties, and has been used clinically in CF patients to reduce mucus viscosity in the airways. In this study, we show that pretreatment of the airways with NAL followed by administration of adenoviral vectors in complex with DEAE-Dextran can significantly enhance gene delivery to the airways of mice without any harmful effects. Moreover, NAL pretreatment can reduce the airway inflammation, which is normally observed after delivery of adenoviral particles. Taken together, these results indicate that NAL pretreatment followed by adenoviral vector-mediated gene delivery can be beneficial to CF patients by increasing the efficiency of gene transfer to the airways, and reducing the acute toxicity associated with the administration of adenoviral vectors.
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Acetilcisteína/análogos & derivados , Adenoviridae/genética , Expectorantes/uso terapéutico , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Pulmón/metabolismo , Lisina/análogos & derivados , Acetilcisteína/uso terapéutico , Animales , Línea Celular , DEAE Dextrano/administración & dosificación , Expresión Génica , Operón Lac , Pulmón/virología , Lisina/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Coloración y Etiquetado , Transducción Genética/métodosRESUMEN
West Indian land mammals have suffered the most severe extinctions of any Holocene mammal faunas. However, 'last-occurrence' dates based on radiometric or robust stratigraphic data remain unavailable for most West Indian species, making it impossible to identify factors responsible for these extinctions. Here, we present new radiometric dates from archaeological and palaeontological sites on Puerto Rico, the only Greater Antillean island to have lost all native land mammals. Although it has been suggested that these species died out earlier than other West Indian mammals, we demonstrate that Puerto Rican mammal last-occurrence dates are in close agreement with those from other Antillean islands, as several species in fact persisted for millennia following Amerindian arrival. Echimyid rodents and nesophontid 'island-shrews' were still present on Puerto Rico approximately 1000 years BP, and probably became extinct following European arrival. The large (13kg) heptaxodontid rodent Elasmodontomys obliquus also appears to have survived for over 2000 years after Amerindian colonization, suggesting that at least some large West Indian mammals became extinct in protracted pre-European 'sitzkrieg'-style events rather than 'blitzkrieg'-style overkill.
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Extinción Biológica , Mamíferos , Paleontología , Animales , Isótopos de Carbono/análisis , Fósiles , Mandíbula/anatomía & histología , Espectrometría de Masas , Puerto RicoRESUMEN
Impaired regulation of salt and water balance in left ventricular dysfunction and heart failure can lead to pulmonary and peripheral edema and hyponatremia. Previous studies of disordered water regulation in heart failure have used models of low cardiac output with normal cardiac function (e.g., inferior vena cava ligation). We investigated thirst and vasopressin (AVP) secretion in a rat myocardial infarction model of chronic left ventricular dysfunction/heart failure in response to a 24-h water deprivation period. Thirst (implied from water drunk), hematocrit, plasma renin activity, and plasma AVP concentrations increased with water deprivation vs. ad libitum water access. Thirst and plasma AVP concentrations were significantly positively correlated with infarct size after 24-h water deprivation but not under ad libitum water access conditions. The mechanism by which this occurs is unclear but could involve increased osmoreceptor sensitivity, altered stimulation of baroreceptors, the renin-angiotensin system, or altered central neural control.
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Infarto del Miocardio/fisiopatología , Sed/fisiología , Vasopresinas/metabolismo , Animales , Peso Corporal , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Infarto del Miocardio/sangre , Infarto del Miocardio/patología , Tamaño de los Órganos , Ratas , Ratas Sprague-Dawley , Vasopresinas/sangre , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatología , Privación de Agua/fisiología , Equilibrio Hidroelectrolítico/fisiologíaRESUMEN
1. Angiotensin (Ang) II causes cardiac hypertrophy in vitro and in vivo. It also stimulates the release of endothelin (ET)-1. Endothelin-1 induces hypertrophy of cardiomyocytes in vitro. 2. In the present study, we examined whether the cardiac hypertrophic action of AngII in vivo was mediated by ET-1 via ETA receptors. We also determined whether arginine vasopressin (AVP), another ET-1 stimulator, could cause cardiac hypertrophy in vivo through an ET-1-dependent pathway. 3. In Sprague-Dawley rats (n = 8 per group), we determined whether the orally administered ETA receptor antagonist BMS 193884 could attenuate the cardiac hypertrophic effect of: (i) i.v. AngII infusion at either 100 or 200 ng/kg per min, i.v., for 1 week; (ii) AngII infusion at 100 ng/kg per min, i.v., for 2 weeks; and (iii) AVP infusion at either 2 or 10 ng/kg per min, i.v., for 1 week. Mean arterial pressure and heart rate were also measured. 4. Infusion with AngII for both 1 and 2 weeks increased left ventricular weight. Only AngII infusion at 200 ng/kg per min for 1 week increased blood pressure. Endothelin ETA receptor blockade did not attenuate the left ventricular hypertrophy, even though it reduced the hypertensive effect of AngII. Arginine vasopressin increased blood pressure, but did not cause cardiac hypertrophy. 5. We showed that AngII can cause cardiac hypertrophy through a direct, blood pressure-independent effect on the heart. Endothelin-1 did not mediate the cardiac hypertrophic effect of AngII through ETA receptors. This may indicate the involvement of ETB receptors in this model of cardiac hypertrophy. Arginine vasopressin did not cause cardiac hypertrophy in vivo.
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Angiotensina II/fisiología , Cardiomegalia/patología , Antagonistas de los Receptores de la Endotelina A , Endotelina-1/fisiología , Aldosterona/sangre , Animales , Arginina Vasopresina/farmacología , Presión Sanguínea/efectos de los fármacos , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Ventrículos Cardíacos/efectos de los fármacos , Infusiones Intravenosas , Masculino , Oxazoles/farmacología , Ratas , Ratas Sprague-Dawley , Renina/sangre , Sulfonamidas/farmacologíaRESUMEN
Single cell studies have identified intraclonal heterogeneity of cytokine production by activated T cells. To investigate implications of cytokine heterogeneity for cell fate, an interleukin (IL)-2 promoter-green fluorescent protein (GFP) reporter transgenic model was developed to track IL-2+ and IL-2- T cells during differentiation from naive precursors. Antigen-activated IL-2+ and IL-2- cells had comparable proliferative capacities in primary responses. However, T cells that expressed IL-2 in primary responses demonstrated enhanced antigenic sensitivity and increased expression of effector cytokines in secondary responses in vitro and in vivo. Thus, heterogeneity of activation during a primary response translates into heterogeneous secondary responses, in which enhanced memory/effector function is linked to cells that previously exceeded an activation threshold associated with IL-2 gene transcription.
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Memoria Inmunológica/inmunología , Interleucina-2/biosíntesis , Linfocitos T/inmunología , Animales , Antígenos CD2/genética , Diferenciación Celular , Células Cultivadas , Femenino , Expresión Génica , Proteínas Fluorescentes Verdes , Interleucina-2/genética , Proteínas Luminiscentes/genética , Subgrupos Linfocitarios/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Ovalbúmina/inmunología , Regiones Promotoras Genéticas , Linfocitos T/citología , Células TH1/citología , Células TH1/inmunología , Células Th2/citología , Células Th2/inmunología , TransgenesRESUMEN
OBJECTIVE: The vasoconstrictor effect of endothelins (ET) is mediated by endothelin A (ETA) and endothelin B (ETB) receptors. Furthermore, ETB receptor stimulation results in release of vasodilators. Hence, ETA receptor antagonists should attenuate ET-mediated vasoconstriction. The aim of the present study was to evaluate and compare the effects of BQ-123, an ETA receptor antagonist, and bosentan, an ETA and ETB receptor antagonist, on coronary vasomotor tone, left ventricular systolic function and ET-1 efflux in the presence or absence of myocardial ischaemia/reperfusion. METHODS: Isolated rat hearts were perfused using a Langendorff preparation. Global ischaemia was induced on average by 68 +/- 2% (+/- standard error of the mean) reduction of a baseline perfusion flow-rate 10 min after introduction of ET antagonists. Thirty minutes of ischaemia was followed by 30 min reperfusion. ET-1 efflux in coronary perfusate was measured by radioimmunoassay. RESULTS: In non-ischaemic hearts (n = 7), BQ-123 (10(-6) M) perfusion induced a progressive decrease in coronary flow-rate compared with control group. This flow reduction persisted after wash-out of BQ-123. In contrast, bosentan (10(-5) M, n = 7) induced no change in perfusion rate. In the absence of ET antagonists (n = 16), there was a 22 +/- 6% post-ischaemic increase in perfusion flow-rate. BQ-123 (n = 5) but not bosentan (n = 12) abolished this post-ischaemic increase in flow-rate. Neither BQ-123 nor bosentan induced significant variation in force of contraction. In ischaemic hearts, ischaemia per se induced a transient decrease in force of contraction. Bosentan significantly (P < 0.05) accentuated and BQ-123 tended to accentuate (P = 0.06) this decrease in force of contraction during ischaemia. Bosentan but not BQ-123 significantly impaired the recovery of systolic function during reperfusion (P < 0.05). Both BQ-123 and bosentan perfusion increased ET-1 efflux rate to 730 +/- 188% and 315 +/- 81% respectively. This effect was abolished during ischaemia for BQ-123, but not for bosentan. CONCLUSIONS: In isolated perfused rat hearts, both BQ-123 and bosentan increased ET-1 efflux, but only BQ-123 exerted vasoconstrictor effects. These results thus generated the hypothesis that: (1) ET-1 release within the coronary vascular bed may be physiologically subject to negative feedback regulation mediated via ETA receptors; (2) ETA receptor antagonists increase ET-1 efflux, which may lead to net vasoconstriction via unopposed ETB stimulation. Furthermore, the negative inotropic effects observed during ischaemia suggest that ET is critical to the maintenance of systolic function during ischaemia.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Endotelina-1/metabolismo , Isquemia Miocárdica/metabolismo , Péptidos Cíclicos/farmacología , Receptores de Endotelina/metabolismo , Vasoconstricción/efectos de los fármacos , Animales , Antihipertensivos/farmacología , Bosentán , Masculino , Contracción Miocárdica/efectos de los fármacos , Isquemia Miocárdica/fisiopatología , Perfusión , Ratas , Ratas Endogámicas , Receptor de Endotelina A , Receptor de Endotelina B , Flujo Sanguíneo Regional/efectos de los fármacos , Sulfonamidas/farmacología , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Previous studies have shown that i.v. endotoxin infusion causes gastrointestinal dysfunction and intestinal injury in piglets. The aim of this study was to investigate the effects of endotoxin on intestinal myoelectric activity in newborn swine and to correlate this with gastrointestinal and hemodynamic events. Three pairs of electrodes were implanted in the jejunal wall of piglets, and after recovery, intestinal myoelectric activity was continuously recorded in the conscious, fasted condition. The intestinal myoelectric activity on the control day showed regular, repeating migrating myoelectric complex (MMC) cycles, each of which was composed of the classic phases I, II, and III. Mean cycle duration was 67.0 +/- 18.7 min (+/- SD), and phase III comprised 9.1 +/- 2.2% of each cycle. On the next day, infusion of 30 micrograms/kg endotoxin caused an initial, prolonged quiescent period and delayed the appearance of the first postendotoxin phase III complex. After the quiescent period, there was a period of irregular spiking activity followed by several shortened MMC cycles (47.9 +/- 22.7 min, p < 0.01 versus control) with a prolongation of the percentage of time spent in phase III (15.4 +/- 11.3%, p < 0.01). Endotoxin thus produced biphasic alterations in intestinal myoelectric activity characterized by an initial quiescence followed by increased gastrointestinal smooth muscle activity. Animals developed diarrhea, hypotension, and tachycardia about 1 h after endotoxin infusion in temporal association with increased spiking activity and MMC cycling. These studies are the first to show this biphasic response to endotoxin.
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Ciclos de Actividad , Duodeno/fisiología , Endotoxinas/toxicidad , Hemodinámica/efectos de los fármacos , Complejo Mioeléctrico Migratorio/efectos de los fármacos , Animales , Animales Recién Nacidos , Presión Sanguínea/efectos de los fármacos , Duodeno/efectos de los fármacos , Duodeno/inervación , Escherichia coli , Ayuno , Frecuencia Cardíaca/efectos de los fármacos , Infusiones Intravenosas , Músculo Liso/efectos de los fármacos , Músculo Liso/inervación , Músculo Liso/fisiología , PorcinosRESUMEN
The early phase of endotoxin-induced acute hemodynamic disturbances and hypoxemia is mediated by various factors, including eicosanoids and tumor necrosis factor-alpha (TNF alpha). Thromboxane A2 is the major mediator of the early pulmonary hypertension associated with endotoxemia, but the mechanisms underlying the prolonged hemodynamic disturbances observed in ongoing endotoxemia are not well understood. The authors used a chronically instrumental young piglet model to determine the roles of several eicosanoids and of TNF alpha in the prolonged endotoxin-induced pulmonary hypertension and other cardiovascular derangements. Animals were given 40 micrograms/kg endotoxin intravenously per hour for 30 minutes, followed by 20 micrograms/kg per hour. In all animals, persistent pulmonary hypertension, lowered cardiac output, any hypoxemia developed during endotoxin infusion. After 3 hours of endotoxin infusion, randomly ordered infusions of 1 mg/kg dazmegrel (a thromboxane A2 synthesis inhibitor), 5mg/kg nordihydroguaiaretic acid (a 5-lipoxygenase inhibitor), and 20 mg/kg pentoxifylline (A TNF alpha inhibitor) were given intravenously at 30-to-60-minute intervals. Dazmegrel and pentoxifylline lowered pulmonary arterial pressure and resistance and raised arterial oxygen tension. Cardiac output increased significantly after pentoxifylline. These hemodynamic effects persisted for 30-60 minutes, despite continued endotoxin infusion. The elevated plasma concentrations of thromboxane B2 and TNF alpha returned toward preendotoxin baseline values after dazmegrel and pentoxifylline treatment, respectively. No beneficial effects were noted after administration of nordihydroguaiaretic acid. Based on these results, both thromboxane A2 and TNF alpha, but not 5-lipoxygenase products, play active roles in prolonged endotoxin-induced pulmonary hypertension and hypoxemia in young piglets. Combined thromboxane A2 and TNF alpha blockade may be clinically useful in treatment of advanced sepsis in neonates.
Asunto(s)
Endotoxinas/toxicidad , Hipertensión Pulmonar/etiología , Leucotrienos/fisiología , Sepsis/fisiopatología , Tromboxano A2/fisiología , Factor de Necrosis Tumoral alfa/fisiología , 6-Cetoprostaglandina F1 alfa/sangre , Animales , Endotoxinas/administración & dosificación , Endotoxinas/sangre , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Hipertensión Pulmonar/fisiopatología , Imidazoles/farmacología , Antagonistas de Leucotrieno , Leucotrienos/metabolismo , Lipooxigenasa/metabolismo , Masoprocol/farmacología , Pentoxifilina/farmacología , Sepsis/complicaciones , Porcinos , Tromboxano A2/antagonistas & inhibidores , Tromboxano A2/sangre , Tromboxano B2/sangre , Tromboxano-A Sintasa/antagonistas & inhibidores , Toxemia , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: To compare different aspects of intermediary metabolism in self perceived 'small-eating' females and self-perceived near normal weight 'large-eating' females and relate the data to those reported for Pima Indians who have the world's highest prevalence of non-insulin dependent diabetes mellitus and obesity. DESIGN: Make repeat measurements of rates of oxygen consumption, carbon dioxide production and blood metabolites in 'large-' and 'small-eating' females at rest, during different activities and after ingestion of a standardised liquid meal. SUBJECTS: Nine self perceived, 'large-eating' females and nine self perceived 'small-eating' females. MEASUREMENTS: Resting metabolic rates (RMR), respiratory quotient (RQ) values and plasma insulin, glucagon insulin-like growth factor (IGF-1), dehydroepiandrosterone sulphate (DHEA-SO4) and glucose. RESULTS: RMR (adjusted for FFM) averaged 3891 +/- 93 J/min in the 'small-eaters' and 3375 +/- 107 J/min in the 'large-eaters' for ten consecutive measurements conducted at 30 min intervals during the control period for the measurement of the thermic effect of food. Over this period the average RQ for the 'small-eating' women (0.81) was significantly greater than that of the 'large-eating' women (0.78). The two groups responded similarly to an oral glucose tolerance test but the concentration of DHEA-SO4 in plasma was 35% higher in the 'small-eaters'. CONCLUSION: The 'small-eating' women may have a greater risk of weight gain but they counteract this tendency by maintaining high activity levels.
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Apetito/fisiología , Ingestión de Alimentos/fisiología , Metabolismo Energético/fisiología , Autoimagen , Adulto , Metabolismo Basal/fisiología , Calorimetría Indirecta , Dióxido de Carbono/metabolismo , Deshidroepiandrosterona/análogos & derivados , Deshidroepiandrosterona/sangre , Sulfato de Deshidroepiandrosterona , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/psicología , Femenino , Glucagón/sangre , Humanos , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Persona de Mediana Edad , Obesidad/fisiopatología , Obesidad/psicología , Consumo de Oxígeno/fisiología , Descanso/fisiologíaRESUMEN
The distribution of somatostatin immunoreactivity was determined throughout the hypothalamus of the sheep and comparisons were made with the known distribution of somatostatin immunoreactivity in the rat. Immunopositive perikarya were present in the sheep periventricular region from as far rostral as the supraoptic recess of the third ventricle to the posterior optic chiasm. In the basal hypothalamus, a thick shell of immunopositive neurons surrounded the ventromedial nucleus (VMH), and there were also neurons in the caudal arcuate nucleus. Somatostatin immunoreactive fibres were concentrated in the dorsal VMH and arcuate nucleus as well as in the median eminence. The distribution in sheep was similar to that in rats, but immunoreactive neurons around sheep VMH were distinctive, a characteristic that might relate to differences in growth hormone physiology in this species.
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Hipotálamo/metabolismo , Somatostatina/metabolismo , Animales , Bovinos , Hipotálamo/ultraestructura , Procesamiento de Imagen Asistido por Computador , Técnicas para Inmunoenzimas , Ratas , Ovinos , Núcleo Hipotalámico Ventromedial/metabolismo , Núcleo Hipotalámico Ventromedial/ultraestructuraRESUMEN
The parasympathetic nervous system actively participates in the regulation of pathophysiologic responses in circulatory shock. To determine the effects of cholinergic blockade in endotoxic shock in newborn piglets, 16 chronically instrumented newborn piglets were infused with 10 mg/kg of endotoxin over 10 min. Eight animals were injected intravenously with 10 mg/kg of anisodamine, an anticholinergic drug, 10 min before endotoxin and then with escalating doses of 2, 5, 10, and 20 mg/kg every 10 min, beginning 60 min after endotoxin. The other eight animals were given saline as a control. Endotoxin infusion caused elevations in mean pulmonary artery pressure and vascular resistance index and an initial increase in systemic artery pressure followed by hypotension. Heart rate was stable for 45 min and then increased. Cardiac index fell from a baseline of 173 +/- 20 (mean +/- S.E.) to 136 +/- 23 mL.min-1.kg-1 60 min after endotoxin. Pretreatment with anisodamine increased heart rate from 163 +/- 15 to 289 +/- 10 beats.min-1 and cardiac index from 195 +/- 15 to 238 +/- 14 mL.min-1.kg-1 before endotoxin infusion. These variables remained at higher levels than in the control group until 60 min after endotoxin infusion; thereafter, the two groups were similar. The changes in pulmonary and systemic artery pressures were not significantly altered by anisodamine. After 60 min, additional doses of anisodamine caused no significant hemodynamic responses, and the differences between the two groups were not significant. Arterial plasma thromboxane B2 levels rose immediately and tumor necrosis factor-alpha levels increased 60 min after endotoxin infusion; no significant differences were noted between groups at any time.(ABSTRACT TRUNCATED AT 250 WORDS)
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Hemodinámica/fisiología , Parasimpatolíticos/farmacología , Choque Séptico/fisiopatología , Alcaloides Solanáceos/farmacología , Análisis de Varianza , Animales , Animales Recién Nacidos , Presión Sanguínea/efectos de los fármacos , Dióxido de Carbono/sangre , Gasto Cardíaco/efectos de los fármacos , Diarrea , Sistema Digestivo/patología , Relación Dosis-Respuesta a Droga , Endotoxinas , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Oxígeno/sangre , Presión Parcial , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Choque Séptico/patología , Volumen Sistólico/efectos de los fármacos , Porcinos , Tromboxano B2/sangre , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismo , Resistencia Vascular/efectos de los fármacos , VómitosRESUMEN
The GABA agonist muscimol, injected into the depressor area of the caudal ventrolateral medulla, increased blood pressure and increased the expression of the immediate early gene c-fos in the rostral ventral medulla (RVM) of the rat. The number of Fos-immunoreactive (Fos-IR) neurons seen in the RVM was increased 3-fold after muscimol compared to Fos-IR after vehicle treatment. In the rostral aspect of the RVM approximately half of the Fos-IR neurons were identified as spinally projecting after the injection of the retrograde tracer cholera toxin B subunit into the upper thoracic spinal cord. These bulbospinal Fos-IR neurons were identified in the lateral aspects of the RVM, in the area where baroreceptor-sensitive neurons have been identified in electrophysiological studies, and also in more medial areas of the RVM. Fos-IR neurons were also identified in the intermediolateral cell column of the thoracic spinal cord after muscimol injection, but were rarely observed in this area after vehicle treatment. This study demonstrates the functional connectivity of the caudal and rostral areas of the medulla oblongata and the spinal cord, supporting the view that the caudal ventrolateral medulla contains neurons that provide a tonic inhibitory control over neurons in the RVM and that, in turn, the spinally projecting neurons in the RVM provide an excitatory input to the spinal cord sympathetic preganglionic neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
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Presión Sanguínea/fisiología , Bulbo Raquídeo/fisiología , Inhibición Neural , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Médula Espinal/metabolismo , Animales , Toxina del Cólera , Inmunohistoquímica , Masculino , Bulbo Raquídeo/citología , Muscimol/farmacología , Fragmentos de Péptidos , Ratas , Ratas Endogámicas WKY , Médula Espinal/citologíaRESUMEN
OBJECTIVE: The aim was to investigate (1) the relationship between atrial natriuretic factor (ANF) release and the extent of ischaemia-hypoxia, and (2) the potential role of eicosanoids in ANF release during global ischaemia, particularly the cyclo-oxygenase derivatives (prostaglandins) and the lipoxygenase derivatives (leukotrienes). METHODS: Using an isolated perfused, spontaneously beating rat heart, global ischaemia was achieved by the reduction of perfusion flow rate relative to basal flow rate. ANF was measured by radioimmunoassay. RESULTS: A decrease in perfusion flow rate by 75-80% to a final value of 2-2.5 ml.min-1.g-1 heart (n = 6) caused a gradual but sustained increase of ANF release which reached a plateau after 12 min, attaining a peak value of 89.9 (SEM 26.6)% over baseline. A decrease in perfusion flow rate by 55-60% (n = 5) also resulted in an increased ANF secretion, with a peak of 125.6(23.2)% over baseline at 14 min. A decrease in perfusion flow rate by 25-30% to a final value of 5-6.75 ml.min-1.g-1 heart (n = 4) showed no change in ANF release. The mean basal value of ANF release was 8.23(2.39) ng.min-1.g-1 heart (n = 26). In a separate series of experiments using a reduction of 55-60% in perfusion flow rate but with the addition to the perfusion medium of the specific cyclo-oxygenase inhibitor meclofenamate 10 microM (n = 5) or the lipoxygenase inhibitor nordihydroguaiaretic acid 10 microM (n = 5), no increase in ANF release occurred during the period of global ischaemia. Neither inhibitor affected ANF release during basal perfusion rates (7-9 ml.min-1.g-1 heart). CONCLUSIONS: ANF released in response to global ischaemia is likely to be mediated by prostanoids generated via the cyclo-oxygenase pathway and leukotrienes generated via the lipoxygenase pathway. Both pathways may provide important paracrine/autacoid regulatory roles for the protection of the heart during ischaemia by stimulating ANF release, with the subsequent beneficial effects of the peptide on peripheral tissues, ultimately leading to a reduction in load on the heart.
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Factor Natriurético Atrial/biosíntesis , Diterpenos , Eicosanoides/fisiología , Isquemia Miocárdica/metabolismo , Miocardio/metabolismo , Animales , Modelos Animales de Enfermedad , Ginkgólidos , Frecuencia Cardíaca/efectos de los fármacos , Lactonas/farmacología , Masculino , Masoprocol/farmacología , Ácido Meclofenámico/farmacología , Contracción Miocárdica/efectos de los fármacos , Perfusión , Factor de Activación Plaquetaria/antagonistas & inhibidores , Ratas , Ratas Endogámicas , Tasa de Secreción/efectos de los fármacosRESUMEN
Platelet-activating factor (PAF) and the prostaglandins have recently been shown to stimulate atrial natriuretic factor (ANF) secretion from the heart. As PAF also potentiates the release of cyclooxygenase products from isolated hearts, the role of these substances in PAF-induced ANF secretion was investigated. Using an isolated perfused rat heart preparation, cyclooxygenase inhibition by indomethacin or meclofenamic acid (10 microM for each) significantly attenuated the rise in ANF associated with PAF administration (2.5 nmol). Prostaglandin F2 alpha (PGF) produced an immediate and dose-dependent increase in ANF secretion, which was significant at 0.01 mumol and reached 348 +/- 66% over baseline values after a 1-mumol injection. Prostaglandin E2 (PGE) generated a much smaller 98 +/- 25% increase after a 1-mumol administration. Furthermore, PGF but not PGE was released from isolated hearts immediately after PAF administration. PGF release reached a maximum of 0.06 nmol/min g Heart-1 1 min after PAF stimulation and had returned to undetectable baseline values by 6 min. Cyclooxygenase inhibition abolished the release of PGF after PAF, in addition to attenuating (by 60-70%) the increased secretion of ANF after PAF injection. These results demonstrate very clearly that PGF is the major mediator for PAF-stimulated ANF secretion. Such an interaction may provide an alternative mechanism to atrial distension for the secretion of ANF in pathologies such as myocardial infarction, where autacoids such as PAF and the PGs are released from damaged cardiac muscle and elevated plasma levels of ANF are observed.
Asunto(s)
Factor Natriurético Atrial/metabolismo , Dinoprost/farmacología , Corazón/fisiología , Factor de Activación Plaquetaria/farmacología , Animales , Dinoprostona/farmacología , Corazón/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Indometacina/farmacología , Cinética , Masculino , Ácido Meclofenámico/farmacología , Contracción Miocárdica/efectos de los fármacos , Perfusión , Prostaglandinas E/metabolismo , Prostaglandinas F/metabolismo , RatasRESUMEN
Newborn endotoxic shock syndrome is associated with high morbidity and mortality, yet presents with different clinical manifestations than in older patients. To determine the influence of age on hemodynamic and metabolic responses to endotoxin, we developed a chronically instrumented endotoxic shock model using eight 1-3-day-old and seven 2-3-week-old piglets. Three days after surgery, 10 mg/kg of endotoxin was infused intravenously over 10 min in the younger group, and 5-10 mg/kg was given to the older animals. Two older piglets died immediately after infusion of 5 mg/kg of endotoxin, and five of the seven died within 4 hr, while all eight younger animals lived longer than 4 hr. Pulmonary artery pressure increased significantly after endotoxin in both groups, and there were no differences between groups. Systemic artery pressure and cardiac index fell by 44 +/- 10% and 70 +/- 15%, respectively, 5 min after endotoxin infusion in the older group, while these values did not change significantly in the younger group. Endotoxin infusion also caused greater elevation in pulmonary vascular resistance index in the older animals. In the later phase, which began 30 min after endotoxin, both groups displayed systemic hypotension and pulmonary hypertension, and the groups did not differ from one another in this regard. With progression of endotoxic shock, more severe metabolic acidosis developed in the older animals than in the younger animals. Plasma thromboxane B2 levels in the older group were about double those in younger piglets. Plasma 6-keto-PGF1 alpha and TNF alpha levels in both groups were similar and were significantly increased in the later phase.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Envejecimiento/fisiología , Animales Recién Nacidos/fisiología , Hemodinámica , Choque Séptico/fisiopatología , 6-Cetoprostaglandina F1 alfa/sangre , Animales , Presión Sanguínea , Endotoxinas/administración & dosificación , Escherichia coli , Femenino , Cinética , Oxígeno/sangre , Arteria Pulmonar/fisiopatología , Choque Séptico/etiología , Porcinos , Tromboxano B2/sangre , Factor de Necrosis Tumoral alfa/metabolismo , Resistencia VascularRESUMEN
Capsular type-specific polysaccharide is thought to be an important pathogenetic factor in Group B streptococcus (GBS) sepsis. To determine the effects of capsular type-specific polysaccharide on GBS-induced hemodynamic responses, anesthetized infant piglets were infused for 3 h with three related GBS Type lb strains that express different amounts of capsular type-specific polysaccharide. A larger capsule strain and a smaller capsule strain were isolated from an infected infant and its mother, respectively. A capsule-deficient mutant was then made from the larger capsule strain by transposon insertion mutagenesis. The smaller capsule strain and capsule-deficient mutant caused similar elevations in mean pulmonary artery pressure and pulmonary vascular resistance index and reductions in cardiac index. The larger capsule strain caused moderate pulmonary hypertension, but this response was smaller than for the other two GBS strains. Further comparisons in responses between the large capsule strain and its capsule-deficient mutant were then performed using unanesthetized piglets. The mutant caused significantly greater pulmonary hypertension and arterial plasma thromboxane B2 levels than the large capsule strain. The pulmonary hypertension induced by both strains was reversed by dazmegrel, a thromboxane A2 synthase inhibitor. These results suggest that (1) capsular type-specific polysaccharide is not an essential component in the generation of acute hemodynamic responses; (2) expression of large amounts of capsular type-specific polysaccharide on the organism surface partially inhibits GBS-induced pulmonary hypertension; and (3) the inhibition of the pulmonary responses is due to reduced thromboxane A2 release.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Cápsulas Bacterianas/toxicidad , Hipertensión Pulmonar/etiología , Polisacáridos Bacterianos/toxicidad , Infecciones Estreptocócicas/etiología , Streptococcus agalactiae/efectos de los fármacos , Streptococcus agalactiae/patogenicidad , 6-Cetoprostaglandina F1 alfa/sangre , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Hemodinámica/efectos de los fármacos , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/fisiopatología , Imidazoles/uso terapéutico , Infecciones Estreptocócicas/sangre , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/epidemiología , Infecciones Estreptocócicas/fisiopatología , Streptococcus agalactiae/aislamiento & purificación , Porcinos , Tromboxano B2/sangre , Tromboxano-A Sintasa/antagonistas & inhibidoresRESUMEN
Plasma levels of atrial natriuretic factor (ANF) and norepinephrine are markedly elevated during episodes of ventricular tachycardia. Although atrial distention appears to be the major stimulus for ANF release, reflex changes in autonomic tone might also contribute. Plasma ANF and norepinephrine levels, sinus node cycle length, systolic blood pressure, and mean right atrial pressure were therefore assessed during rapid right ventricular pacing at 150 beats/min for 10 minutes. In five patients (group 1) observations were made without autonomic blockade, and another five patients (group 2) had ventricular pacing after cardiac autonomic blockade. In group 1 systolic blood pressure fell during ventricular pacing from 122 +/- 4 to 105 +/- 5 mm Hg (p < 0.02), norepinephrine levels increased from 195 +/- 26 to 411 +/- 71 pg/ml (p < 0.02), and sinus node cycle length decreased from 936 +/- 99 to 688 +/- 58 msec (p < 0.02). Right atrial pressure was elevated from 2.6 +/- 0.6 to 7.4 +/- 0.6 mm Hg (p < 0.02), and ANF levels increased from 161 +/- 23 to 240 +/- 26 pg/ml (p < 0.05). Whereas systolic blood pressure, norepinephrine, sinus cycle length, and right atrial pressure returned promptly to baseline levels when ventricular pacing was stopped, ANF levels continued to rise (296 +/- 37 pg/ml; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)