Selective iNOS inhibition attenuates acetylcholine- and bradykinin-induced vasoconstriction in lipopolysaccharide-exposed rat lungs.

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.

Perfluorochemical rescue after surfactant treatment: effect of perflubron dose and ventilatory frequency.

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.