Yamada T, Yukioka H, Hayashi M, Asada A, Inoue M
Department of Anesthesiology and Intensive Care Medicine, Osaka City University Medical School, Osaka, Japan.
Acta Anaesthesiol Scand. 1998 Mar;42(3):358-68. doi: 10.1111/j.1399-6576.1998.tb04930.x.
Platelet-activating factor (PAF), a lipid mediator released during endotoxin shock, induces pulmonary hypertension, systemic hypotension and cardiac dysfunction. In this study, we compared the effect of inhaled nitric oxide (NO) on PAF-induced pulmonary hypertension and NO metabolism with that on pulmonary hypertension induced by a stable thromboxane A2 mimetic, U46619. Since PAF-induced hypotension might be mediated by NO, the effect of inhaled NO combined with an intravenously administered NO synthase inhibitor, NG-nitro-L-arginine (L-NNA), on PAF-induced hemodynamic change was also investigated.
In a total of 28 beagles anesthetized with pentobarbital the following substances were intravenously administered: PAF 0.56 +/- 0.30 microgram.kg-1.min-1 (group PAF), L-NNA 10 mg.kg-1 + PAF 0.04 +/- 0.03 microgram.kg-1.min-1 (group L-NNA + PAF), U46619 0.60 +/- 0.11 microgram.kg-1.min-1 (group U46619) or L-NNA 10 mg.kg-1 + U46619 0.61 +/- 0.23 microgram.kg-1.min-1 (group L-NNA + U46619) to obtain a mean pulmonary arterial pressure (MPAP) of 25 mmHg. Nitric oxide was then inhaled at 5, 10, 20 and 40 ppm for 15 min at 15-min intervals in the order of increasing concentration. An additional 7 dogs (control group) inhaled NO at normal MPAP (17 mmHg). Hemodynamic and respiratory parameters, NOHb, NO2- + NO3-, and MetHb levels in blood were measured before and during NO administration.
In the control group, hemodynamic and respiratory values did not change significantly during NO administration. In group PAF, NO significantly reversed the PAF-induced pulmonary hypertension. PAF induced a marked systemic hypotension and cardiac output reduction, but these changes were not affected by inhalation of NO. L-NNA pretreatment markedly decreased the dose of PAF required to maintain a MPAP of 25 mmHg, and abolished the PAF-induced hypotension. In group L-NNA + PAF, the diminishing effect of inhaled NO on pulmonary vascular resistance (PVR) was significantly greater than that in group PAF. U46619 induced pulmonary hypertension and increases in blood pressure, intrapulmonary shunt and peak airway pressure. L-NNA pretreatment did not change the dose of U46619 required to maintain a MPAP of 25 mmHg. The effects of inhaled NO on PVR decrease were similar in groups U46619 and L-NNA + U46619. No NOHb was detected in any group. NO2- + NO3- concentration increased during NO administrations. There were no significant differences in NO2- + NO3- concentration among groups.
Inhaled NO at the dose of 5-40 ppm effectively reversed PAF-induced pulmonary hypertension, especially following pretreatment with L-NNA. Inhaled NO did not affect PAF-induced hypotension or cardiac dysfunction. These findings indicate that low concentrations of inhaled NO may be useful in reversing pulmonary hypertension in the endotoxemia where PAF may be one mediator.
血小板活化因子（PAF）是内毒素休克期间释放的一种脂质介质，可诱导肺动脉高压、全身低血压和心脏功能障碍。在本研究中，我们比较了吸入一氧化氮（NO）对PAF诱导的肺动脉高压和NO代谢的影响，以及对由稳定的血栓素A2类似物U46619诱导的肺动脉高压的影响。由于PAF诱导的低血压可能由NO介导，我们还研究了吸入NO联合静脉注射NO合酶抑制剂NG-硝基-L-精氨酸（L-NNA）对PAF诱导的血流动力学变化的影响。
在总共28只戊巴比妥麻醉的比格犬中，静脉注射以下物质：PAF 0.56±0.30微克·千克⁻¹·分钟⁻¹（PAF组）、L-NNA 10毫克·千克⁻¹+PAF 0.04±0.03微克·千克⁻¹·分钟⁻¹（L-NNA+PAF组）、U46619 0.60±0.11微克·千克⁻¹·分钟⁻¹（U46619组）或L-NNA 10毫克·千克⁻¹+U46619 0.61±0.23微克·千克⁻¹·分钟⁻¹（L-NNA+U46619组），以使平均肺动脉压（MPAP）达到25 mmHg。然后以5、10、20和40 ppm的浓度依次吸入NO，每次吸入15分钟，间隔15分钟。另外7只犬（对照组）在正常MPAP（17 mmHg）下吸入NO。在吸入NO之前和期间测量血流动力学和呼吸参数、血液中的NOHb、NO₂⁻+NO₃⁻以及高铁血红蛋白水平。
在对照组中，吸入NO期间血流动力学和呼吸值无明显变化。在PAF组中，NO显著逆转了PAF诱导的肺动脉高压。PAF诱导了明显的全身低血压和心输出量降低，但这些变化不受吸入NO的影响。L-NNA预处理显著降低了维持MPAP为25 mmHg所需的PAF剂量，并消除了PAF诱导的低血压。在L-NNA+PAF组中，吸入NO对肺血管阻力（PVR）的降低作用明显大于PAF组。U46619诱导了肺动脉高压以及血压、肺内分流和气道峰压升高。L-NNA预处理未改变维持MPAP为25 mmHg所需的U46619剂量。吸入NO对U46619组和L-NNA+U46619组中PVR降低的作用相似。任何组均未检测到NOHb。吸入NO期间NO₂⁻+NO₃⁻浓度升高。各组之间NO₂⁻+NO₃⁻浓度无显著差异。
5 - 40 ppm剂量的吸入NO可有效逆转PAF诱导的肺动脉高压，尤其是在L-NNA预处理后。吸入NO不影响PAF诱导的低血压或心脏功能障碍。这些发现表明，低浓度的吸入NO可能有助于逆转内毒素血症中的肺动脉高压，其中PAF可能是一种介质。
