Fagan K A, Tyler R C, Sato K, Fouty B W, Morris K G, Huang P L, McMurtry I F, Rodman D M
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Am J Physiol. 1999 Sep;277(3):L472-8. doi: 10.1152/ajplung.1999.277.3.L472.
Nitric oxide plays an important role in modulating pulmonary vascular tone. All three isoforms of nitric oxide synthase (NOS), neuronal (nNOS, NOS I), inducible (iNOS, NOS II), and endothelial (eNOS, NOS III), are expressed in the lung. Recent reports have suggested an important role for eNOS in the modulation of pulmonary vascular tone chronically; however, the relative contribution of the three isoforms to acute modulation of pulmonary vascular tone is uncertain. We therefore tested the effect of targeted disruption of each isoform on pulmonary vascular reactivity in transgenic mice. Isolated perfused mouse lungs were used to evaluate the effect of selective loss of pulmonary nNOS, iNOS, and eNOS with respect to hypoxic pulmonary vasoconstriction (HPV) and endothelium-dependent and -independent vasodilation. eNOS null mice had augmented HPV (225 +/- 65% control, P < 0.02, mean +/- SE) and absent endothelium-dependent vasodilation, whereas endothelium-independent vasodilation was preserved. HPV was minimally elevated in iNOS null mice and normal in nNOS null mice. Both nNOS and iNOS null mice had normal endothelium-dependent vasodilation. In wild-type lungs, nonselective NOS inhibition doubled HPV, whereas selective iNOS inhibition had no detectable effect. In intact, lightly sedated mice, right ventricular systolic pressure was elevated in eNOS-deficient (42.3 +/- 1.2 mmHg, P < 0.001) and, to a lesser extent, in iNOS-deficient (37.2 +/- 0.8 mmHg, P < 0.001) mice, whereas it was normal in nNOS-deficient mice (30.9 +/- 0.7 mmHg, P = not significant) compared with wild-type controls (31.3 +/- 0.7 mmHg). We conclude that in the normal murine pulmonary circulation 1) nNOS does not modulate tone, 2) eNOS-derived nitric oxide is the principle mediator of endothelium-dependent vasodilation in the pulmonary circulation, and 3) both eNOS and iNOS play a role in modulating basal tone chronically.
一氧化氮在调节肺血管张力方面发挥着重要作用。一氧化氮合酶（NOS）的三种同工型，即神经元型（nNOS，NOS I）、诱导型（iNOS，NOS II）和内皮型（eNOS，NOS III），均在肺中表达。最近的报告表明，eNOS在长期调节肺血管张力中起重要作用；然而，这三种同工型对肺血管张力急性调节的相对贡献尚不确定。因此，我们在转基因小鼠中测试了每种同工型的靶向破坏对肺血管反应性的影响。使用离体灌注的小鼠肺来评估肺nNOS、iNOS和eNOS选择性缺失对低氧性肺血管收缩（HPV）以及内皮依赖性和非依赖性血管舒张的影响。eNOS基因敲除小鼠的HPV增强（为对照的225±65%，P<0.02，平均值±标准误），且不存在内皮依赖性血管舒张，而非内皮依赖性血管舒张得以保留。iNOS基因敲除小鼠的HPV轻度升高，nNOS基因敲除小鼠的HPV正常。nNOS和iNOS基因敲除小鼠均具有正常的内皮依赖性血管舒张。在野生型肺中，非选择性NOS抑制使HPV增加一倍，而选择性iNOS抑制未产生可检测到的影响。在完整的、轻度镇静的小鼠中，与野生型对照（31.3±0.7 mmHg）相比，eNOS缺陷小鼠（42.3±1.2 mmHg，P<0.001）以及程度较轻的iNOS缺陷小鼠（37.2±0.8 mmHg，P<0.001）的右心室收缩压升高，而nNOS缺陷小鼠的右心室收缩压正常（30.9±0.7 mmHg，P=无显著性差异）。我们得出结论，在正常小鼠肺循环中：1）nNOS不调节张力；2）eNOS衍生的一氧化氮是肺循环中内皮依赖性血管舒张的主要介质；3）eNOS和iNOS在长期调节基础张力中均起作用。
