Resta T C, Chicoine L G, Omdahl J L, Walker B R
Departments of Cell Biology and Physiology, Pediatrics, and Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA.
Am J Physiol. 1999 Feb;276(2):H699-708. doi: 10.1152/ajpheart.1999.276.2.H699.
We previously demonstrated augmented endothelium-derived nitric oxide (EDNO)-dependent pulmonary arterial dilation and increased arterial endothelial nitric oxide synthase (eNOS) levels in chronic hypoxic (CH) and monocrotaline (nonhypoxic) models of pulmonary arterial hypertension. Therefore, we hypothesized that the long-term elevation of arterial eNOS levels associated with CH is related to pulmonary hypertension or some factor(s) associated with hypertension and not directly to hypoxia. To test this hypothesis, we examined responses to the EDNO-dependent dilator ionomycin in U-46619-constricted, isolated, saline-perfused lungs from control rats, CH (4 wk at 380 mmHg) rats, and rats previously exposed to CH but returned to normoxia for 4 days or 2 wk. Microvascular pressure was assessed by double-occlusion technique, allowing calculation of segmental resistances. In addition, vascular eNOS immunoreactivity was assessed by quantitative immunohistochemistry, and eNOS mRNA abundance was determined by RT-PCR assays. Our findings indicate that 4-day and 2-wk posthypoxic rats exhibit persistent pulmonary hypertension, likely due to maintained arterial remodeling and polycythemia associated with prior exposure to CH. Furthermore, arterial dilation to ionomycin was augmented in lungs from each experimental group compared with controls. Finally, arterial eNOS immunoreactivity and whole lung eNOS mRNA levels remained elevated in posthypoxic animals. These findings suggest that altered vascular mechanical forces or vascular remodeling contributes to enhanced EDNO-dependent arterial dilation and upregulation of arterial eNOS in various models of established pulmonary hypertension.
我们先前在慢性低氧（CH）和野百合碱（非低氧）肺动脉高压模型中证明，内皮源性一氧化氮（EDNO）依赖性肺动脉扩张增强，动脉内皮一氧化氮合酶（eNOS）水平升高。因此，我们假设与CH相关的动脉eNOS水平长期升高与肺动脉高压或与高血压相关的某些因素有关，而不是直接与缺氧有关。为了验证这一假设，我们检测了对照大鼠、CH（380 mmHg下4周）大鼠以及先前暴露于CH但恢复常氧4天或2周的大鼠的U-46619收缩、离体、盐水灌注肺对EDNO依赖性扩张剂离子霉素的反应。通过双闭塞技术评估微血管压力，从而计算节段阻力。此外，通过定量免疫组织化学评估血管eNOS免疫反应性，通过RT-PCR测定法测定eNOS mRNA丰度。我们的研究结果表明，低氧后4天和2周的大鼠表现出持续性肺动脉高压，可能是由于先前暴露于CH导致的动脉重塑和红细胞增多症持续存在。此外，与对照组相比，每个实验组的肺对离子霉素的动脉扩张增强。最后，低氧后动物的动脉eNOS免疫反应性和全肺eNOS mRNA水平仍然升高。这些发现表明，在各种已建立的肺动脉高压模型中，血管机械力改变或血管重塑有助于增强EDNO依赖性动脉扩张和动脉eNOS上调。
