RESUMEN
BACKGROUND: Nonselective nitric oxide synthase (NOS) inhibition has detrimental effects in sepsis because of inhibition of the physiologically important endothelial NOS (eNOS). The authors hypothesized that selective inducible NOS (iNOS) inhibition would maintain eNOS vasodilation but prevent acetylcholine- and bradykinin-mediated vasoconstriction caused by lipopolysaccharide-induced endothelial dysfunction. METHODS: Rats were administered intraperitoneal lipopolysaccharide (15 mg/kg) with and without the selective iNOS inhibitors L-N6-(1-iminoethyl)-lysine (L-NIL, 3 mg/kg), dexamethasone (1 mg/kg), or the nonselective NOS inhibitor Nomega-nitro-L-arginine methylester (L-NAME, 5 mg/kg). Six hours later, the lungs were isolated and pulmonary vasoreactivity was assessed with hypoxic vasoconstrictions (3% O2), acetylcholine (1 microg), Biochemical Engineering, and bradykinin (3 microg). In additional lipopolysaccharide experiments, L-NIL (10 microM) or 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, 100 microM), a selective muscarinic M3 antagonist, was added into the perfusate. RESULTS: Exhaled nitric oxide was higher in the lipopolysaccharide group (37.7+/-17.8 ppb) compared with the control group (0.4+/-0.7 ppb). L-NIL and dexamethasone decreased exhaled nitric oxide in lipopolysaccharide rats by 83 and 79%, respectively, whereas L-NAME had no effect. In control lungs, L-NAME significantly decreased acetylcholine- and bradykinin-induced vasodilation by 75% and increased hypoxic vasoconstrictions, whereas L-NIL and dexamethasone had no effect. In lipopolysaccharide lungs, acetylcholine and bradykinin both transiently increased the pulmonary artery pressure by 8.4+/-2.0 mmHg and 35.3+/-11.7 mmHg, respectively, immediately after vasodilation. L-NIL and dexamethasone both attenuated this vasoconstriction by 70%, whereas L-NAME did not. The acetylcholine vasoconstriction was dose-dependent (0.01-1.0 microg), unaffected by L-NIL added to the perfusate, and abolished by 4-DAMP. CONCLUSIONS: In isolated perfused lungs, acetylcholine and bradykinin caused vasoconstriction in lipopolysaccharide-treated rats. This vasoconstriction was attenuated by administration of the iNOS inhibitor L-NIL but not with L-NAME. Furthermore, L-NIL administered with lipopolysaccharide preserved endothelium nitric oxide-dependent vasodilation, whereas L-NAME did not.
Asunto(s)
Acetilcolina/metabolismo , Bradiquinina/metabolismo , Inhibidores Enzimáticos/farmacología , Lipopolisacáridos/toxicidad , Pulmón/efectos de los fármacos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Circulación Pulmonar/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Acetilcolina/farmacología , Animales , Bradiquinina/farmacología , Dexametasona/farmacología , Hipoxia/metabolismo , Hipoxia/fisiopatología , Técnicas In Vitro , Pulmón/irrigación sanguínea , Lisina/análogos & derivados , Lisina/farmacología , Masculino , Antagonistas Muscarínicos/farmacología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/administración & dosificación , Óxido Nítrico/farmacología , Óxido Nítrico Sintasa de Tipo II , Nitroprusiato/farmacología , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Salmonella typhimuriumRESUMEN
To test the hypotheses that perfluorochemical (PFC) liquid rescue after natural surfactant (SF) treatment would improve pulmonary function and histology and that this profile would be influenced by PFC dose or ventilator strategy, anesthetized preterm lambs (n = 31) with respiratory distress were studied using nonpreoxygenated perflubron. All animals received SF at 1 h and were randomized at 2 h as follows and studied to 4 h postnatal age: 1) conventional mechanical gas ventilation (n = 8), 2) 30 ml/kg perflubron with gas ventilation [partial liquid ventilation (PLV)] at 60 breaths/min (n = 8), 3) 10 ml/kg perflubron with PLV at 60 breaths/min (n = 7), and 4) 10 ml/kg perflubron with PLV at 30 breaths/min (n = 8). All animals tolerated instillation without additional cardiopulmonary instability. All perflubron-rescued groups demonstrated sustained improvement in gas exchange, respiratory compliance, and reduction in pressure requirements relative to animals receiving SF alone. Improvement was directly related to perflubron dose and breathing frequency; peak inspiratory pressure required to achieve physiological gas exchange was lower in the higher-dose and -frequency groups, and mean airway pressure was lower in the lower-frequency group. Lung expansion was greater and evidence of barotrauma was less in the higher-dose and -frequency group; regional differences in expansion were not different as a function of dose but were greater in the lower-frequency group. Regional differences in lung perflubron content were reduced in the higher-dose and -frequency groups and greatest in the lower-dose and -frequency group. The results suggest that, whereas PLV of the SF-treated lung improves gas exchange and lung mechanics, the protective benefits of perflubron in the lung may depend on dose and ventilator strategy to optimize PFC distribution and minimize exposure of the alveolar-capillary membrane to a gas-liquid interface.
Asunto(s)
Fluorocarburos/farmacología , Surfactantes Pulmonares/farmacología , Respiración Artificial , Animales , Animales Recién Nacidos , Bovinos , Relación Dosis-Respuesta a Droga , Fluorocarburos/administración & dosificación , Fluorocarburos/química , Ventilación de Alta Frecuencia , Hidrocarburos Bromados , Instilación de Medicamentos , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/fisiopatología , Intercambio Gaseoso Pulmonar/efectos de los fármacos , Mecánica Respiratoria/efectos de los fármacos , Ovinos , TráqueaRESUMEN
Tidal liquid ventilation (TLV) with perfluorochemical fluid (PFC) has been successfully used experimentally for up to 4 h. However, no studies of prolonged TLV have been reported. We hypothesized that full-term newborn lambs can safely and effectively be liquid-ventilated for up to 24 h. To test this hypothesis, 17 lambs were liquid-ventilated; 7 for 4 h, 5 for 12 h, and 5 for 24 h. Arterial blood samples were obtained for PFC uptake, lipid analysis, and blood gas measurements. Tissues were obtained for histologic and biochemical analysis. Arterial blood gas and mean arterial blood pressure were as follows (mean +/- SEM): pH 7.48 +/- 0.04; PaCO2 30.6 +/- 2.8; PaO2 424 +/- 17; mean arterial pressure 76 +/- 16 mm Hg. PFC blood levels increased rapidly to a mean of 5.2 +/- 3.9 microg/mL. PFC tissue levels increased significantly (p < 0.01) from 260 +/- 45 microg/g at 4 h to 400 +/- 140 microg/g at 12 h. There was no further increase in PFC tissue levels by 24 h (456 +/- 181 microg/g). There was a significant difference in PFC concentration as a function of tissue (p < 0.01). Furthermore, there was a significant correlation (r = 0.88; p < 0.01) between the amount of PFC and lipid in blood and tissue. Microscopic examination of the lungs demonstrated no evidence of barotrauma. These data demonstrate that prolonged TLV can be safe and efficacious for up to 24 h in full-term newborn lambs.
Asunto(s)
Animales Recién Nacidos , Desconexión del Ventilador , Animales , Animales Recién Nacidos/fisiología , Presión Sanguínea , Gases/sangre , Hemodinámica , Ovinos , Volumen de Ventilación PulmonarRESUMEN
We studied the effect of rescue therapy with modified porcine surfactant (Curosurf) or brief perfluorocarbon liquid ventilation on pulmonary gas exchange, mechanics and structure in very immature lambs. Both rescue strategies produced an improvement in arterial oxygenation and were able to support CO2 elimination. Histology showed unevenly inflated lungs in all but tidal-liquid-ventilated lambs. We speculate that due to immature lung architecture and relatively high permeability, previous exposure to gas ventilation impeded full effectiveness of both rescue modalities, perhaps prophylactic surfactant or liquid ventilation could be a better alternative.
Asunto(s)
Animales Recién Nacidos , Productos Biológicos , Fluorocarburos , Fosfolípidos , Surfactantes Pulmonares/uso terapéutico , Respiración Artificial , Animales , Femenino , Edad Gestacional , Pulmón/anatomía & histología , Intercambio Gaseoso Pulmonar , Mecánica Respiratoria , OvinosRESUMEN
The use of neat perfluorochemical liquid (PFC) as an alternative respiratory medium has gained increasing attention for assessment and treatment of the immature or injured lung. In vitro and in vivo plain film and computed tomographic (CT) studies were performed on small and large animals to evaluate the use of perfluorooctylbromide (perflubron) as a bronchographic contrast agent and to quantitate the distribution and elimination of this fluid from the lung following total liquid ventilation or during gas breathing after tracheal instillation of small quantities of this liquid. The results demonstrate the utility of a highly radiopaque PFC liquid in combination with diagnostic imaging techniques to visualize small airways anatomy, identify regional and gravity dependent differences in distribution/elimination of the fluid, ventilation, and track PFC liquid following therapeutic application.