Steudel W, Scherrer-Crosbie M, Bloch K D, Weimann J, Huang P L, Jones R C, Picard M H, Zapol W M
Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
J Clin Invest. 1998 Jun 1;101(11):2468-77. doi: 10.1172/JCI2356.
Chronic hypoxia induces pulmonary hypertension and right ventricular (RV) hypertrophy. Nitric oxide (NO) has been proposed to modulate the pulmonary vascular response to hypoxia. We investigated the effects of congenital deficiency of endothelial NO synthase (NOS3) on the pulmonary vascular responses to breathing 11% oxygen for 3-6 wk. After 3 wk of hypoxia, RV systolic pressure was greater in NOS3-deficient than in wild-type mice (35+/-2 vs 28+/-1 mmHg, x+/-SE, P < 0.001). Pulmonary artery pressure (PPA) and incremental total pulmonary vascular resistance (RPI) were greater in NOS3-deficient than in wild-type mice (PPA 22+/-1 vs 19+/-1 mmHg, P < 0.05 and RPI 92+/-11 vs 55+/-5 mmHg.min.gram.ml-1, P < 0.05). Morphometry revealed that the proportion of muscularized small pulmonary vessels was almost fourfold greater in NOS3-deficient mice than in wild-type mice. After 6 wk of hypoxia, the increase of RV free wall thickness, measured by transesophageal echocardiography, and of RV weight/body weight ratio were more marked in NOS3-deficient mice than in wild-type mice (RV wall thickness 0.67+/-0.05 vs 0.48+/-0.02 mm, P < 0.01 and RV weight/body weight ratio 2.1+/-0.2 vs 1.6+/-0.1 mg. gram-1, P < 0.05). RV hypertrophy produced by chronic hypoxia was prevented by breathing 20 parts per million NO in both genotypes of mice. These results suggest that congenital NOS3 deficiency enhances hypoxic pulmonary vascular remodeling and hypertension, and RV hypertrophy, and that NO production by NOS3 is vital to counterbalance pulmonary vasoconstriction caused by chronic hypoxic stress.
慢性缺氧可导致肺动脉高压和右心室（RV）肥厚。一氧化氮（NO）被认为可调节肺血管对缺氧的反应。我们研究了内皮型一氧化氮合酶（NOS3）先天性缺乏对吸入11%氧气3 - 6周时肺血管反应的影响。缺氧3周后，NOS3缺陷小鼠的右心室收缩压高于野生型小鼠（35±2 vs 28±1 mmHg，x±SE，P < 0.001）。NOS3缺陷小鼠的肺动脉压（PPA）和总肺血管阻力增量（RPI）高于野生型小鼠（PPA 22±1 vs 19±1 mmHg，P < 0.05；RPI 92±11 vs 55±5 mmHg·min·g·ml-1，P < 0.05）。形态学测量显示，NOS3缺陷小鼠中肌化小肺血管的比例几乎是野生型小鼠的四倍。缺氧6周后，经食管超声心动图测量，NOS3缺陷小鼠右心室游离壁厚度增加以及右心室重量/体重比增加比野生型小鼠更明显（右心室壁厚度0.67±0.05 vs 0.48±0.02 mm，P < 0.01；右心室重量/体重比2.1±0.2 vs 1.6±0.1 mg·g-1，P < 0.05）。在两种基因型小鼠中，吸入百万分之20的NO可预防慢性缺氧引起的右心室肥厚。这些结果表明，先天性NOS3缺乏会增强缺氧性肺血管重塑、高血压和右心室肥厚，并且NOS3产生的NO对于抵消慢性缺氧应激引起的肺血管收缩至关重要。
