Lipsitz E C, Weinstein S, Smerling A J, Stolar C J
Division of Pediatric Surgery, Columbia University, New York, NY, USA.
J Pediatr Surg. 1996 Jan;31(1):137-40. doi: 10.1016/s0022-3468(96)90336-x.
In newborns, inhaled nitric oxide (NO) has been shown to ameliorate increased pulmonary vascular resistance (PVR) precipitated by hypoxia. The role of endogenous NO production in this response is not clear. The contribution of endogenous NO to resting PVR in normoxic newborns also has not been well studied. The authors used an isolated, in situ, neonatal piglet lung-perfusion model, devoid of systemic detractors in which endogenous NO could be selectively inhibited, to determine whether (1) endogenous NO plays a role in the maintenance of PVR with normoxia, (2) endogenous NO plays a role in the response to hypoxia, and (c) inhaled NO can reverse changes induced by inhibition of endogenous NO.
Sixteen neonatal piglets underwent occlusive tracheostomy and pressure-cycled ventilation. After heparinization and ligation of the ductus arteriosus, left atrial and pulmonary arterial cannulation were performed, without ischemia, via a median sternotomy. The aorta was ligated, and lung perfusion was set at 80 mL/kg/min via an extracorporeal membrane oxygenation circuit. Hematocrit (40% to 45%), pH (7.37 to 7.44), Pco2 (35 to 40 mm Hg), and peak inspiratory pressures (20 mm Hg) were constant. Pulmonary artery pressure (PPA), left atrial pressure (PLA), and circuit flow (QPA) were recorded continuously. PVR calculated as follows: PVR[(dynes x seconds x cm(-5)) x 1,000] = [(PPA-PLA/(QPA x 1,000/60)] x 1,332. The experimental animals were ventilated with normoxic gas (FIO2, 0.21), followed by hypoxic gas (FIO2, 0.07), returned to normoxia, and then divided into two groups of eight animals each. One group remained normoxemic (FIO2, 0.21; SPA02, 100%) while the other group was made hypoxemic by ventilation with hypoxic gas (FIO2, 0.07; SPA02, 50%). Endogenous NO was suppressed with L-arginine-N-omega methyl ester (L-NAME) at 40 mg/kg in both groups. Inhaled NO was given at 40 ppm in both groups. Analysis of variance for repeated measures was used to test for statistical significance.
Baseline normoxic PVR (3,403 +/- 1,169) was increased significantly by hypoxia (6,524 +/- 1,018, P < .01) and was fully resorted to baseline by normoxia (3,497 +/- 1,079; P = NS). In normoxic animals, inhibition of endogenous NO production by L-NAME increased PVR to levels similar to those seen during hypoxic stress (6,345 +/- 1,441, P < .01). Replacement of endogenous NO by inhaled NO reversed PVR to normoxic baseline values (3,986 +/- 1,363, P = NS). In hypoxic animals, inhibition of endogenous NO production by L-NAME also increased PVR from hypoxic baseline (9,655 +/- 1,642, P < .01). Replacement of endogenous NO by inhaled NO reversed PVR to hypoxic baseline (6,450 +/- 1,796, P = NS).
In this piglet model, endogenous NO is important in the regulation of pulmonary vascular tone during both normoxia and hypoxia. Inhaled NO completely reversed the elevations in PVR caused by inhibition of endogenous NO and may normalize PVR in diseases in which the production of endogenous NO is compromised.
在新生儿中，吸入一氧化氮（NO）已被证明可改善因缺氧导致的肺血管阻力（PVR）升高。内源性NO产生在这种反应中的作用尚不清楚。内源性NO对正常氧合新生儿静息PVR的贡献也未得到充分研究。作者使用了一种孤立的、原位的新生仔猪肺灌注模型，该模型没有全身干扰因素，内源性NO可在其中被选择性抑制，以确定（1）内源性NO在正常氧合时对维持PVR是否起作用，（2）内源性NO在对缺氧的反应中是否起作用，以及（3）吸入NO能否逆转因抑制内源性NO而引起的变化。
16只新生仔猪接受了闭塞性气管切开术和压力控制通气。在肝素化和动脉导管结扎后，通过正中胸骨切开术在无缺血的情况下进行左心房和肺动脉插管。结扎主动脉，通过体外膜肺氧合回路将肺灌注设置为80 mL/kg/min。血细胞比容（40%至45%）、pH（7.37至7.44）、Pco2（35至40 mmHg）和吸气峰压（20 mmHg）保持恒定。连续记录肺动脉压（PPA）、左心房压（PLA）和回路流量（QPA）。PVR计算如下：PVR[（达因×秒×厘米⁻⁵）×1,000] = [（PPA - PLA）/（QPA×1,000/60）]×1,332。实验动物先使用正常氧合气体（FIO2，0.21）通气，然后使用低氧气体（FIO2，0.07）通气，再恢复到正常氧合，然后分为两组，每组8只动物。一组保持正常氧合（FIO2，0.21；SPAO2，100%），而另一组通过使用低氧气体通气使其处于低氧状态（FIO2，0.07；SPAO2，50%）。两组均使用L - 精氨酸 - N - ω甲酯（L - NAME）以40 mg/kg抑制内源性NO。两组均给予40 ppm的吸入NO。使用重复测量方差分析来检验统计学意义。
基线正常氧合PVR（3,403±1,169）在缺氧时显著升高（6,524±1,018，P <.01），在恢复正常氧合时完全恢复到基线水平（3,497±1,079；P =无显著性差异）。在正常氧合动物中，L - NAME抑制内源性NO产生使PVR升高至与缺氧应激时相似的水平（6,345±1,441，P <.01）。吸入NO替代内源性NO使PVR恢复到正常氧合基线值（3,986±1,363，P =无显著性差异）。在缺氧动物中，L - NAME抑制内源性NO产生也使PVR从缺氧基线升高（9,655±1,642，P <.01）。吸入NO替代内源性NO使PVR恢复到缺氧基线（6,450±1,796，P =无显著性差异）。
在该仔猪模型中，内源性NO在正常氧合和缺氧期间对肺血管张力的调节中起重要作用。吸入NO完全逆转了因抑制内源性NO而导致的PVR升高，并可能使内源性NO产生受损的疾病中的PVR恢复正常。
