RESUMEN
BACKGROUND: We sought to compare two techniques, microdialysis and repeated blood withdrawal, for serial assessment of hepatic and systemic nitric oxide (NO) biosynthesis in septic rats. METHODS: Rats were randomly allocated to either microdialysis or blood withdrawal groups. Two microdialysis probes, one in liver and the other in right atrium, were placed in rats in the microdialysis group. Half of the rats from each group were then given lipopolysaccharide (LPS) to induce NO production. The other half of the rats from each group were injected with vehicle (normal saline) to serve as controls. In the microdialysis group, dialysate (30 microl) was collected every 30 min. In the blood withdrawal group, 0.3 ml of blood was drawn every 30 min. Sampling was performed up to 6 h after injection of LPS or vehicle. Hemodynamics, hepatic and systemic NO concentrations, and iNOS expression in harvested liver tissues were assayed. RESULTS: Repeated blood withdrawal by itself caused a significant decrease in blood pressure and induced hepatic iNOS expression. Microdialysis, on the contrary, reliably detected LPS-induced NO production without resulting either in hemodynamic changes or in iNOS induction in liver tissue. CONCLUSIONS: Microdialysis provides serial measure of hepatic and systemic NO concentrations in LPS-treated rats without the need for removal of tissue.
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Hígado/metabolismo , Óxido Nítrico/biosíntesis , Sepsis/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Immunoblotting , Lipopolisacáridos/farmacología , Mediciones Luminiscentes , Masculino , Microdiálisis , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa de Tipo II , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estimulación QuímicaRESUMEN
BACKGROUND: Endotoxemia stimulates nitric oxide (NO) biosynthesis through induction of inducible NO synthase (iNOS). Cellular uptake of L-arginine, the sole substrate for iNOS, is an important mechanism regulating NO biosynthesis by iNOS. The isozymes of type-2 cationic amino acid transporters, including CAT-2, CAT-2A, and CAT-2B, constitute the most important pathways responsible for trans-membrane L-arginine transportation. Therefore, regulation of CAT-2 isozymes expression may constitute one of the downstream regulatory pathways that control iNOS activity. We investigated the time course of enzyme induction and the role of nuclear factor-kappaB (NF-kappaB) in CAT-2 isozymes expression in lipopolysaccharide-(LPS) treated rat lungs. METHODS: Adult male Sprague-Dawley rats were randomly given intravenous injections of normal saline (N/S), LPS, LPS plus NF-kappaB inhibitor pre-treatment (PDTC, dexamethasone, or salicylate), or an NF-kappaB inhibitor alone. The rats were sacrificed at different times after injection and enzyme expression and lung injury were examined. Pulmonary and systemic NO production were also measured. RESULTS: LPS co-induced iNOS, CAT-2, and CAT-2B but not CAT-2A expression in the lungs. Furthermore, NF-kappaB actively participated in LPS-induction of iNOS, CAT-2, and CAT-2B. LPS induced pulmonary and systemic NO overproduction and resulted in lung injuries. Attenuation of LPS-induced iNOS, CAT-2, and CAT-2B induction significantly inhibited NO biosynthesis and lessened lung injury. CONCLUSION: NF-kappaB actively participates in the induction of CAT-2 and CAT-2B in intact animals. Our data further support the idea that CAT-2 and CAT-2B are crucial in regulating iNOS activity.
Asunto(s)
Transportador de Aminoácidos Catiônicos 2/biosíntesis , Lipopolisacáridos/farmacología , Pulmón/metabolismo , FN-kappa B/fisiología , Animales , Endotoxinas/farmacología , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Pulmón/efectos de los fármacos , Masculino , FN-kappa B/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico Sintasa de Tipo II , Tamaño de los Órganos/fisiología , Peroxidasa/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Respiración Artificial , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estimulación QuímicaRESUMEN
OBJECTIVE: Sepsis stimulates renal nitric oxide (NO) biosynthesis through up-regulation of inducible NO synthase (iNOS) expression. Type-2 cationic amino acid transporter (CAT-2) mediation of trans-membrane L-arginine (L-Arg) transportation has been identified as one of the crucial regulatory mechanisms involved in the formation of NO by iNOS. We had previously shown that CAT-2B, a high-affinity alternative-spliced transcript of the CAT-2, is involved in induced NO biosynthesis by iNOS (Nitric Oxide, 2002). In this present study, we sought to assess the effects of sepsis on the expression of CAT-2B in lipopolysaccharide (LPS)-stimulated rat kidney. METHODS: Forty rats were randomized to either a normal saline (N/S)-treated group or a LPS-treated group. Renal NO production was determined using chemiluminescence. Semi-quantitative RT-PCR was used to determine the mRNA concentrations of iNOS and L-Arg transporters (CAT-1, CAT-2 and CAT-2B) in kidney. RESULTS: Lipopolysaccharide-coinduced iNOS, CAT-2 and CAT-2B mRNA expression in kidney and caused renal NO overproduction. A significant linear regression relationship was defined between renal NO concentrations and iNOS, CAT-2 and CAT-2B, respectively. On the contrary, CAT-1 expression was not affected by LPS-stimulation. CONCLUSIONS: We provide the first evidence to illustrate that sepsis/septic shock induces the transcription of high-affinity CAT-2B in renal tissues. Transcription of iNOS, CAT-2 and CAT-2B correlates well with renal NO biosynthesis. Regulation of L-Arg uptake by modulating the expression regulation of induced CAT-2 and CAT-2B might be a potential target for therapies against renal pathologic conditions related to NO overproduction.
Asunto(s)
Transportador de Aminoácidos Catiônicos 2/análisis , Riñón/metabolismo , Lipopolisacáridos/farmacología , Transcripción Genética/genética , Regulación hacia Arriba , Animales , Nitrógeno de la Urea Sanguínea , Transportador de Aminoácidos Catiónicos 1/análisis , Transportador de Aminoácidos Catiónicos 1/genética , Transportador de Aminoácidos Catiônicos 2/genética , Creatinina/sangre , Endotoxemia/enzimología , Endotoxemia/metabolismo , Escherichia coli , Riñón/enzimología , Modelos Lineales , Masculino , Óxido Nítrico/análisis , Óxido Nítrico/genética , Óxido Nítrico Sintasa/análisis , Óxido Nítrico Sintasa/genética , ARN Mensajero/análisis , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Sepsis/enzimología , Sepsis/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
Pyruvate is an energy substrate that has both inotropic and antioxidant properties. In this study, we tested the hypothesis that survivorship would be better after resuscitation with 1.7% sodium pyruvate than 0.9% sodium chloride in a profound hemorrhagic shock model. The study was performed in a blinded manner. Rats were randomly assigned into two groups (ten in each group), a sodium chloride resuscitation group and a sodium pyruvate resuscitation group. After a 60-min shock period, we infused 80 ml/kg of a resuscitation solution. We continuously monitored mean arterial pressure and heart rate for 50 min after resuscitation. We recognized death by the disappearance of blood pressure pulsation and precordial movement. We performed a comparison of survivorship at 50 min post resuscitation using a Z-test of proportions. Nine (90%) of the animals that received sodium pyruvate were living 50 min after resuscitation, whereas only three (30%) of the animals that received sodium chloride survived to the same time point. We conclude that sodium pyruvate is better than sodium chloride as a resuscitation solution in a model of profound hemorrhagic shock.
Asunto(s)
Cardiotónicos/uso terapéutico , Ácido Pirúvico/uso terapéutico , Resucitación , Choque Hemorrágico/tratamiento farmacológico , Choque Hemorrágico/mortalidad , Cloruro de Sodio/uso terapéutico , Animales , Glucemia/análisis , Modelos Animales de Enfermedad , Ácido Láctico/sangre , Masculino , Ratas , Ratas Sprague-Dawley , Choque Hemorrágico/sangre , Tasa de SupervivenciaRESUMEN
OBJECTIVE: To test the hypothesis that nitric oxide inhalation facilitates CO2 elimination by decreasing alveolar deadspace in an ovine model of acute lung injury. DESIGN: Prospective, placebo-controlled, randomized, crossover model. SETTING: University research laboratory. SUBJECTS: Eleven mixed-breed adult sheep. INTERVENTIONS: To induce acute lung injury, hydrochloric acid was instilled into the tracheas of paralyzed sheep receiving controlled mechanical ventilation. Each sheep breathed 0 ppm, 5 ppm, and 20 ppm nitric oxide in random order. MEASUREMENTS AND MAIN RESULTS: Estimates of alveolar deadspace volumes and arterial-to-end tidal CO2 partial pressure differences were used as indicators of CO2 elimination efficiency. At a constant minute ventilation, nitric oxide inhalation caused dose-independent decreases in Paco2 (p <.05), alveolar deadspace (p <.01), and arterial-to-end tidal CO2 partial pressure differences (p <.01). We found that estimates of arterial-to-end tidal CO2 partial pressure differences may be used to predict alveolar deadspace volume (r2 =.86, p <.05). CONCLUSIONS: Estimates of arterial-to-end tidal CO2 partial pressure differences are reliable indicators of alveolar deadspace. Both values decreased during nitric oxide inhalation in our model of acutely injured lungs. This finding supports the idea that nitric oxide inhalation facilitates CO2 elimination in acutely injured lungs. Future studies are needed to determine whether nitric oxide therapy can be used to reduce the work of breathing in selected patients with cardiopulmonary disorders.
Asunto(s)
Dióxido de Carbono/metabolismo , Lesión Pulmonar , Óxido Nítrico/farmacología , Alveolos Pulmonares/metabolismo , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Espacio Muerto Respiratorio , Administración por Inhalación , Análisis de Varianza , Animales , Estudios Cruzados , Modelos Animales de Enfermedad , Hemodinámica , Ácido Clorhídrico , Pulmón/metabolismo , Óxido Nítrico/administración & dosificación , Distribución Aleatoria , OvinosRESUMEN
Binding of NO to heavy metal-containing proteins probably accounts for many of its physiologic actions. NO inhalation is a promising new treatment for various disorders of neonates. The therapy is most likely to benefit premature neonates who are hypoxemic despite breathing pure oxygen and those who suffer from impaired carbon dioxide elimination. Newborn infants who have congenital heart disease may benefit from inhaled NO therapy if their disease involves some form of pulmonary venous hypertension or if they have recently undergone surgery involving cardiopulmonary bypass grafting. The use of NO in infants with PPHN might obviate the need for ECMO or other invasive treatment methods. Neonates with CDH seem likely to benefit marginally from NO therapy. Minimizing the toxicities of NO inhalation therapy requires that the physicians understand the nuances of infant care. The therapeutic value of increasing carbon dioxide elimination with NO inhalation warrants further investigation.
Asunto(s)
Enfermedades del Recién Nacido/tratamiento farmacológico , Óxido Nítrico/administración & dosificación , Administración por Inhalación , Dióxido de Carbono/análisis , Cardiopatías Congénitas/tratamiento farmacológico , Hernia Diafragmática/tratamiento farmacológico , Humanos , Recién Nacido , Óxido Nítrico/farmacología , Presión Parcial , Síndrome de Circulación Fetal Persistente/tratamiento farmacológico , Respiración/efectos de los fármacosRESUMEN
OBJECTIVE: Infusing nitric oxide at a constant rate into a breathing circuit with intermittent mainstream flow causes formation of nitric oxide pools between successive breaths. We hypothesized that incomplete mixing of these pools can confound estimates of delivered nitric oxide concentrations. METHODS: Nitric oxide flowed at a constant rate into the upstream end of a standard adult breathing circuit connected to a lung model. One-milliliter gas samples were obtained from various sites within the breathing system and during various phases of the breathing cycle. These samples were aspirated periodically by a microprocessor controlled apparatus and analyzed using an electrochemical sensor. RESULTS: The pools of nitric oxide distorted into hollow parabolic cone shapes and remained unmixed during their propagation into the lungs. In our preparation, time-averaged nitric oxide concentrations were minimal 60 cm downstream of the infusion site (18 ppm) and maximal 15 cm upstream of the Y-piece (36 ppm). The concentrations were mid-range within the lung (23 ppm), yet were substantially less than predicted by assuming homogeneity of the gases (31 ppm). Generally, nitric oxide concentrations within the lung were different from all other sites tested. CONCLUSION: Incomplete mixing of nitric oxide confounds estimates of delivered nitric oxide concentrations. When nitric oxide is infused at a constant rate into a breathing circuit, we doubt that any sampling site outside the patient's lungs can reliably predict delivered nitric oxide concentrations. Strategies to ensure complete mixing and representative sampling of nitric oxide should be considered carefully when designing nitric oxide delivery systems.
Asunto(s)
Óxido Nítrico/administración & dosificación , Respiración Artificial/instrumentación , Adulto , Humanos , Pulmón/irrigación sanguínea , Pulmón/fisiología , Monitoreo Fisiológico/métodos , Óxido Nítrico/análisis , Óxido Nítrico/farmacocinética , Respiración Artificial/métodos , Capacitancia VascularRESUMEN
Vascular resistance calculations often affect decisions regarding therapeutic options encountered by physicians and their patients. However, many of the terms, units, and methods used when calculating vascular resistances are ambiguous. This report attempts to clarify some of these ambiguities and suggests methods for predicting normal vascular resistances.
Asunto(s)
Vasos Sanguíneos/fisiología , Resistencia Vascular , Velocidad del Flujo Sanguíneo , Humanos , Matemática , Terminología como AsuntoRESUMEN
OBJECTIVES: This study was designed to test the hypothesis that the practice of infusing nitric oxide at constant flow rates directly into breathing circuits with intermittent (pulsatile) flow can lead to streaming and tidal pooling of the nitric oxide. This study was also designed to show the extent to which streaming and tidal pooling of nitric oxide affect nitric oxide delivery. DESIGN: A series of five in vitro experiments was performed. For each experiment, either one or two features of the nitric oxide delivery/sampling system were varied, and the effects of these variations were evaluated with regard to measured nitric oxide concentration changes. The results from each experiment were analyzed using either one- or two-factor analysis of variance. SETTING: University research laboratory. SUBJECTS: Breaths were provided by a mechanical ventilator that was connected to a lung model. A standard, corrugated, adult breathing circuit was used. Gas samples were obtained from either the lung model's bellows or selected sites within the breathing circuit. Nitric oxide concentrations were measured, using an electrochemical gas analyzer. INTERVENTIONS: The system features that were varied included the cross-sectional position of the sampling site within the breathing circuit, the distance between the infusion port and the sampling site, the breathing frequency, the distance between the Y-piece and the infusion port, and the airway (deadspace) volume. MEASUREMENTS AND MAIN RESULTS: Streaming of nitric oxide within the breathing circuit was detected as far as 25 cm downstream of the infusion site (p < .0001). Pooling of nitric oxide was detected both near and downstream of the infusion site (p < .0001). Increasing the breathing frequency from 5 to 30 breaths/min increased mixing thoroughness (p < .005). Increasing the distance between the Y-piece and the infusion port from 15 to 180 cm decreased nitric oxide delivery to our lung model (p < .0001). Interestingly, increasing airway (deadspace) volume from 150 to 450 mL decreased nitric oxide delivery to our lung model (p < .0001). CONCLUSIONS: Estimates of nitric oxide delivery using a constant flow rate of nitric oxide infused directly into a breathing circuit during controlled mechanical ventilation can be confounded by streaming and tidal propagation of nitric oxide pools. Improved reproducibility of reported dose-response relationships is likely to be achieved through further study of nitric oxide behavior within the breathing circuits. Reduced toxicity associated with nitric oxide inhalation may also be achieved through a better understanding of this nitric oxide behavior.
Asunto(s)
Pulmón/efectos de los fármacos , Óxido Nítrico/administración & dosificación , Óxido Nítrico/farmacología , Respiración Artificial/métodos , Administración por Inhalación , Adulto , Análisis de Varianza , Pruebas Respiratorias , Factores de Confusión Epidemiológicos , Relación Dosis-Respuesta a Droga , Análisis Factorial , Humanos , Modelos Biológicos , Flujo PulsátilRESUMEN
BACKGROUND: Cardiopulmonary bypass can increase pulmonary vascular tone and decrease ventilation-perfusion matching by impairing the pulmonary endothelial production of nitric oxide. OBJECTIVES: We tested the hypothesis that inhalation of exogenous nitric oxide decreases the ratio of mean pulmonary arterial pressure to mean system arterial pressure and the intrapulmonary shunt fraction and increases the ratio of arterial blood oxygen tension to fraction of inspired oxygen in patients in whom the ratio of mean pulmonary arterial pressure to mean systemic arterial pressure is more than 0.50, and the ratio of arterial blood oxygen tension to fraction of inspired oxygen is less than 300 mm Hg in the first 24 hours after cardiopulmonary bypass surgery. METHODS: Only those patients who had estimates of the ratio of mean pulmonary arterial pressure to mean systemic arterial pressure and the ratio of arterial blood oxygen tension to fraction of inspired oxygen determined preoperatively were enrolled. Hemodynamic variables were recorded, and blood samples were obtained for oximetric analysis 5 minutes before and 30 minutes after inhalation of nitric oxide began. The concentration of nitric oxide inhaled was maintained at 20 parts per million. The data were analyzed by using Friedman's repeated measures analysis of variance. RESULTS: Thirteen patients were enrolled in the study. The mean preoperative ratio of mean pulmonary arterial pressure to mean systemic arterial pressure was 0.63 +/- 0.08 (standard error of the mean), and the mean preoperative ratio of arterial blood oxygen tension to fraction of inspired oxygen was 131 +/- 15 mm Hg. No differences between preoperative and postoperative values were detected. Inhalation of nitric oxide decreased the ratio of mean pulmonary arterial pressure to mean systemic arterial from 0.53 +/- 0.07 to 0.39 +/- 0.5 and increased the ratio of arterial blood oxygen tension to fraction of inspired oxygen from 167 +/- 35 mm Hg to 235 +/- 45 mm Hg. Inhalation of nitric oxide also decreased the intrapulmonary shunt fraction from 0.29 +/- 0.05 to 0.19 +/- 0.04. CONCLUSIONS: Inhalation of nitric oxide selectively decreases pulmonary vascular tone and increases ventilation-perfusion matching in patients with persistent pulmonary hypertension and hypoxemia after surgery requiring cardiopulmonary bypass. Inhalation of nitric oxide may be a valuable adjunctive therapy for these patients.
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Puente Cardiopulmonar , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Óxido Nítrico/uso terapéutico , Administración por Inhalación , Adolescente , Adulto , Arterias , Niño , Preescolar , Hemodinámica/efectos de los fármacos , Humanos , Lactante , Recién Nacido , Persona de Mediana Edad , Oxígeno/sangre , Periodo Posoperatorio , Resistencia Vascular/efectos de los fármacos , Relación Ventilacion-Perfusión/efectos de los fármacosRESUMEN
This study was designed to test the hypothesis that A2 adenosine receptors mediate the hemodynamic responses to intravenous infusions of dipyridamole. We tested the hypothesis using theophylline, which has been reported to block A2 adenosine receptors and thereby attenuate the vasodilation caused by adenosine. Twenty-four anesthetized lambs that were between 7 and 17 days of age were used. Basal vascular tone of each animal was increased with the thromboxane mimetic U-46619. A theophylline dose commonly used in humans (5.0 mg/kg infused over 30 min followed by 1.0 mg x kg(-1) x h(-1)) resulted in negligible changes in the vasodilation caused by either dipyridamole or adenosine. However, a 10-fold greater theophylline dose significantly attenuated the vasodilation caused by adenosine, yet the attenuation in vasodilation caused by dipyridamole remained negligible. In addition, dipyridamole caused a weakly preferential pulmonary vasodilation, whereas adenosine caused a strongly preferential systemic vasodilation. These findings suggest that dipyridamole dilates effectively both the pulmonary vasculature and the systemic vasculature via predominantly adenosine-independent mechanisms.
Asunto(s)
Adenosina/farmacología , Circulación Sanguínea/efectos de los fármacos , Dipiridamol/farmacología , Circulación Pulmonar/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Animales Recién Nacidos , Relación Dosis-Respuesta a Droga , Infusiones Intravenosas , OvinosRESUMEN
OBJECTIVE: This study was designed to test the hypothesis that nitric oxide inhalation increases systemic arterial blood oxygen tension of prematurely delivered infants with respiratory distress syndrome. METHODS: Nitric oxide was administered to 23 preterm infants with a diagnosis of respiratory distress syndrome. The infants were randomly assigned to receive either 5 or 20 ppm of nitric oxide and were studied between 24 and 168 hours after delivery. The treatment period for each infant lasted 15 minutes and was preceded by and followed by a 15-minute control period. We evaluated all outcome variables by using two-way repeated measures analysis of variance; p values less than 0.01 were considered significant. RESULTS: Nitric oxide inhalation caused significant increases in the following: arterial blood oxygen tension, directly measured arterial oxyhemoglobin saturation, and transcutaneously measured arterial oxyhemoglobin saturation. No differences between the effects of the two nitric oxide concentrations were detected, nor were residual effects detected 15 minutes after either dose of nitric oxide was discontinued. CONCLUSIONS: Inhalation of both 5 and 20 ppm nitric oxide causes concentration-independent increases in the blood oxygen tensions of preterm infants with respiratory distress syndrome. We speculate that nitric oxide inhalation may be a useful adjunctive therapy for these patients.
Asunto(s)
Óxido Nítrico/administración & dosificación , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Fármacos del Sistema Respiratorio/administración & dosificación , Administración por Inhalación , Análisis de Varianza , Terapia Combinada , Relación Dosis-Respuesta a Droga , Humanos , Recién Nacido , Recien Nacido Prematuro , Terapia por Inhalación de Oxígeno , Estudios Prospectivos , Respiración Artificial , Síndrome de Dificultad Respiratoria del Recién Nacido/sangre , Resultado del TratamientoRESUMEN
This study was designed to determine indirectly if the changes in ovine fetal pulmonary vascular tone caused by i.v. injections of nitric oxide-containing solutions are mediated by cGMP. We first characterized the dose-response relationship of bolus intrapulmonary injections of zaprinast (a cGMP-selective phosphodiesterase inhibitor) and nitric oxide solutions. Injections of nitric oxide solutions as well as zaprinast solutions resulted in dose-dependent decreases in pulmonary arterial pressure that were greater than reductions in systemic arterial pressure. We also evaluated the effects of simultaneous infusions of zaprinast and U46619 (a thromboxane mimetic) on the response to bolus injections of 1.0 micrograms of acetylcholine, 100 ng of endothelin-1, and 10.0 microL of ethanol saturated with nitric oxide. Zaprinast was infused at a rate of 1.5 mg/min, and the concentration of U46619 was titrated to raise mean left pulmonary arterial pressure (LPAP) to the steady state level that was present before infusing zaprinast. All bolus injections reduced left pulmonary arterial pressure more than they reduced mean systemic arterial pressure. However, neither the response magnitudes nor the response durations were affected by simultaneous infusions of zaprinast and U46619. We therefore suggest that modulation of fetal pulmonary vascular tone by endogenously produced nitric oxide may involve mechanisms other than raising smooth muscle cytoplasmic cGMP concentrations.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Óxido Nítrico/farmacología , Endoperóxidos de Prostaglandinas Sintéticos/farmacología , Arteria Pulmonar/efectos de los fármacos , Purinonas/farmacología , Tromboxano A2/análogos & derivados , Vasodilatadores/farmacología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Animales , Relación Dosis-Respuesta a Droga , Feto/efectos de los fármacos , Infusiones Intraarteriales , Arteria Pulmonar/fisiopatología , Circulación Pulmonar/efectos de los fármacos , Ovinos , Tromboxano A2/farmacologíaRESUMEN
Nitric oxide (.NO) is a free radical, and as such may damage the pulmonary surfactant system. To determine the potential toxicity of .NO in vivo, we exposed 35 newborn lambs to 0, 20, 80 or 200 ppm .NO in either 21 or 60% O2 for 6 h. At the end of the exposure, lambs had normal values of arterial Po2, Pco2, and pH; total protein concentration in the bronchoalveolar lavage was also at normal levels. There were no differences in the surface properties of surfactant among the air or 60% O2 groups. Pulmonary surfactant samples, isolated from the bronchoalveolar lavage of lambs breathing air or 20 ppm .NO and reconstituted at a lipid concentration of 3 mg/ml, reached a low minimum surface tension (Tmin < 3 mN/m) in a pulsating bubble surfactometer. On the other hand, abnormal surface properties were observed in 36 and 60% of surfactant samples isolated from lungs of lambs that breathed 80 or 200 ppm .NO, respectively. These findings were confirmed using a captive bubble surfactometer. Surfactant protein A, isolated from the lungs of lambs that breathed 200 ppm .NO, exhibited decreased ability to aggregate lipids in vitro. These data are consistent with injury to the surfactant apoproteins during inhalation of either 80 or 200 ppm .NO for 6 h.
Asunto(s)
Animales Recién Nacidos/fisiología , Óxido Nítrico/administración & dosificación , Surfactantes Pulmonares/efectos de los fármacos , Administración por Inhalación , Animales , Western Blotting , Electroforesis en Gel de Poliacrilamida , Óxido Nítrico/farmacología , Concentración Osmolar , Proteolípidos/química , Proteolípidos/fisiología , Proteínas Asociadas a Surfactante Pulmonar , Surfactantes Pulmonares/química , Surfactantes Pulmonares/fisiología , Ovinos , Relación Estructura-Actividad , Tensión SuperficialRESUMEN
Others have shown that inhaled nitric oxide causes reversal of pulmonary hypertension in anaesthetized perinatal sheep. The present study examined haemodynamic responses to inhaled NO in the normal and constricted pulmonary circulation of unanaesthetized newborn lambs. Three experiments were conducted on each of 7 lambs. First, to determine a minimum concentration of NO which could reverse acute pulmonary hypertension caused by infusion of the thromboxame mimic U46619, the haemodynamic effects of 5 different doses of inhaled NO were examined. Second, the effects of inhaling 80 ppm NO during hypoxic pulmonary vasoconstriction were examined. Finally, to determine if tachyphalaxis occurs during NO inhalation, lambs were exposed to 80 ppm NO for 3 h during which time pulmonary arterial pressure was doubled by infusion of U46619. Breathing NO (80 ppm) caused a slight but significant decrease in pulmonary vascular resistance (PVR) in lambs with normal pulmonary arterial pressure (PAP). Nitric oxide, inhaled at concentrations between 10 and 80 ppm for 6 min (F1O2 = 0.60), caused decreases in PVR when PAP was elevated with U46619. Nitric oxide acted selectively on the pulmonary circulation, i.e. no changes occurred in systemic arterial pressure or any other measured variable. Breathing 80 ppm NO for 6 min reversed hypoxic pulmonary vasoconstriction. In the chronic exposure study, inhaling 80 ppm NO for 3 h completely reversed U46619-induced pulmonary hypertension. Although arterial methaemoglobin increased during the 3-h exposure to 80 ppm NO, there was no indication that this concentration of NO impairs oxygen loading. These data demonstrate that NO, at concentrations as low as 10 ppm, is a potent, rapid-action, and selective pulmonary vasodilator in unanaesthetized newborn lambs with elevated pulmonary tone. Furthermore, these data support the use of inhaled NO for treatment of infants with pulmonary hypertension.
Asunto(s)
Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Óxido Nítrico/uso terapéutico , Vasodilatadores/uso terapéutico , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Administración por Inhalación , Animales , Animales Recién Nacidos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Hipertensión/inducido químicamente , Hipertensión Pulmonar/inducido químicamente , Hipoxia/tratamiento farmacológico , Endoperóxidos de Prostaglandinas Sintéticos/antagonistas & inhibidores , Ovinos , Tromboxano A2/análogos & derivados , Tromboxano A2/antagonistas & inhibidores , Vasoconstrictores/antagonistas & inhibidoresRESUMEN
Nitric oxide (NO) gas is known as both a vasodilator and a toxin. It can react with oxygen to form compounds more toxic than itself, such as nitrogen dioxide (NO2). The reactions are time dependent; thus, infusing NO into breathing circuits as close to ventilated subjects as possible may help minimize toxic byproduct exposure. Unfortunately, flow rates commonly used with mechanical ventilation favor laminar gas flow (streaming) within the breathing circuits. Streaming could delay mixing of NO with other inhaled gases. This mixing delay may interfere with accurate monitoring and/or delivery of NO. We tested the hypothesis that streaming of NO infused by constant flow into the inspiratory limb of a constant-flow mechanical ventilation system can lead to NO concentration delivery estimate errors. We then compared the NO2 concentrations at the ventilator Y-piece with three different NO mixing methods: blending the gases before they reach the breathing circuit inspiratory limb, infusing NO directly into the breathing circuit inspiratory limb far enough from the Y-piece to ensure thorough mixing, and infusing NO directly into the breathing circuit inspiratory limb immediately before the gases reach an in-line mixing device placed close to the Y-piece. Our results indicate that streaming can lead to NO concentration delivery estimate errors and that these errors can be characterized by measuring NO concentration variations across the inspiratory tubing's luminal diameter. NO2 concentration measured at the ventilator Y-piece were dependent on NO concentrations (p < 0.0001), NO delivery methods (p < 0.0001), and interactions between NO concentrations and NO delivery methods (p < 0.0001). We conclude that gas streaming and toxic byproduct exposure should be considered together when choosing an NO delivery method.
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Óxido Nítrico/administración & dosificación , Respiración Artificial/métodos , Vasodilatadores/administración & dosificación , Relación Dosis-Respuesta a Droga , Diseño de Equipo , Estudios de Evaluación como Asunto , Humanos , Intubación Intratraqueal/instrumentación , Óxido Nítrico/efectos adversos , Dióxido de Nitrógeno/análisis , Respiración Artificial/instrumentación , Respiración Artificial/estadística & datos numéricos , Vasodilatadores/efectos adversos , Ventiladores MecánicosRESUMEN
Three pediatric patients underwent successful transcatheter coronary artery fistula occlusion using the Debrun system. This latex balloon system offers several advantages over other occlusion systems. First, the balloon delivery and release is controlled. Second, "test occlusions" can be performed that allow simultaneous balloon inflation, coronary cineangiography, and electrocardiographic monitoring. Third, because the balloons are flow-directed, they are easily positioned in properly chosen locations. Finally, the balloons can be constructed to suit the size of the fistula. In this study, two patients received only one balloon; in the other patient two balloons were placed in the same fistula. All fistulas drained into either the right atrium or ventricle and were successfully occluded. After a follow-up period of up to 3 years, no local or systemic reactions to the balloons were recognized. We conclude that detachable balloon occlusion of coronary artery fistulas is a safe, effective alternative to surgical ligation in selected pediatric patients.
Asunto(s)
Angioplastia Coronaria con Balón/métodos , Enfermedad Coronaria/terapia , Vasos Coronarios , Fístula/terapia , Adolescente , Preescolar , Humanos , Lactante , Resultado del TratamientoRESUMEN
This study was designed to test the hypothesis that inhalation of nitric oxide by lambs delivered prematurely would result in increased systemic arterial blood oxygen tension and decreased pulmonary vascular resistance. Eleven premature fetal lambs were delivered by cesarean section at 126-127 d gestation. One hundred min after the onset of ventilation, nitric oxide gas was added to the lambs' breathing mixture. The animals were exposed in random order to 5 ppm for 10 min, 20 ppm for 10 min, and 20 ppm for 20 min. Each treatment period was preceded by and followed by a 10-min washout period. When compared with the washout (control) periods, all three treatment periods resulted in an improvement in both the systemic arterial blood oxygen tension and the physiologic intrapulmonary shunt. Inhalation of nitric oxide also resulted in a selective decrease in pulmonary arterial blood pressure. Comparisons between the different treatment groups revealed a further improvement in blood oxygenation and pulmonary hemodynamics when using the higher concentration of nitric oxide. Interestingly, the rise in arterial blood oxygenation continued after inhaling 20 ppm nitric oxide for more than 10 min.
Asunto(s)
Óxido Nítrico/farmacología , Circulación Pulmonar/efectos de los fármacos , Administración por Inhalación , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Recién Nacido , Óxido Nítrico/administración & dosificación , Oxígeno/sangre , Embarazo , Circulación Pulmonar/fisiología , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológico , Síndrome de Dificultad Respiratoria del Recién Nacido/etiología , Síndrome de Dificultad Respiratoria del Recién Nacido/fisiopatología , Ovinos , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiologíaRESUMEN
The case of a neonate reported herein demonstrates a congenital fistula between the left circumflex coronary artery and the right ventricle. Intraoperative stress to the patient's heart suggested a coronary "steal phenomenon."