Relative contributions of endothelial, inducible, and neuronal NOS to tone in the murine pulmonary circulation
Relative contributions of endothelial, inducible, and neuronal NOS to tone in the murine pulmonary circulation
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DOI：
10.1152/ajplung.1999.277.3.l472
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发表时间：
1999-09-01
影响因子：
4.9
通讯作者：
Rodman, DR
中科院分区：
文献类型：
--
作者：
Fagan, KA;Tyler, RC;Rodman, DR
一氧化氮在调节肺血管张力中起重要作用。一氧化氮合酶(NOS)、神经型(nNOS，NOS I)、诱导型(iNOS，NOS II)和内皮(eNOS，NOS III)三种亚型均在肺中表达。最近的报道表明eNOS在慢性肺血管张力调节中起重要作用；然而，这三种异构体在急性肺血管张力调节中的相对作用尚不确定。因此，我们在转基因小鼠中测试了靶向破坏每种异构体对肺血管反应性的影响。采用小鼠离体肺灌流模型，观察选择性去除肺组织中nNOS、iNOS和eNOS对缺氧性肺血管收缩(HPV)和内皮依赖性和非依赖性血管扩张的影响。ENOS基因敲除小鼠HPV增强(225+/-65%对照组，P<；0.02，均值+/-SE)，内皮依赖性血管扩张消失，而非内皮依赖性血管扩张得以保留。INOS缺失组HPV轻度升高，nNOS缺失组HPV正常。NNOS和iNOS基因缺失的小鼠均有正常的内皮依赖性血管扩张。在野生型肺中，非选择性一氧化氮合酶抑制使HPV倍增，而选择性诱导型一氧化氮合酶抑制没有检测到的效果。在完整的、轻度镇静的小鼠中，eNOS缺乏的小鼠右室收缩压(42.3+/-1.2 mm Hg，P<；0.001)和iNOS缺乏的小鼠(37.2+/-0.8 mm Hg，P<；0.001)的右室收缩压较小程度升高，而nNOS缺乏的小鼠的右室收缩压(30.9+/-0.7 mm Hg，P=不显著)与野生型对照组(31.3+/-0.7 mm Hg)相比正常。我们认为，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内皮依赖性血管扩张的主要介质，3)eNOS和iNOS都在慢性调节基础张力中起作用。
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.