Harvard Medical School, Brigham and Women's Hospital, Division of Vascular Surgery, Boston, MA 02115, USA.
Am J Physiol Lung Cell Mol Physiol. 2012 May 1;302(9):L875-90. doi: 10.1152/ajplung.00293.2011. Epub 2012 Jan 27.
Pulmonary hypertension (PH) is characterized by pulmonary arteriolar remodeling with excessive pulmonary vascular smooth muscle cell (VSMC) proliferation. This results in decreased responsiveness of pulmonary circulation to vasodilator therapies. We have shown that extracellular acidosis inhibits VSMC proliferation and migration in vitro. Here we tested whether induction of nonhypercapnic acidosis in vivo ameliorates PH and the underlying pulmonary vascular remodeling and dysfunction. Adult male Sprague-Dawley rats were exposed to hypoxia (8.5% O(2)) for 2 wk, or injected subcutaneously with monocrotaline (MCT, 60 mg/kg) to develop PH. Acidosis was induced with NH(4)Cl (1.5%) in the drinking water 5 days prior to and during the 2 wk of hypoxic exposure (prevention protocol), or after MCT injection from day 21 to 28 (reversal protocol). Right ventricular systolic pressure (RVSP) and Fulton's index were measured, and pulmonary arteriolar remodeling was analyzed. Pulmonary and mesenteric artery contraction to phenylephrine (Phe) and high KCl, and relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) were examined ex vivo. Hypoxic and MCT-treated rats demonstrated increased RVSP, Fulton's index, and pulmonary arteriolar thickening. In pulmonary arteries of hypoxic and MCT rats there was reduced contraction to Phe and KCl and reduced vasodilation to ACh and SNP. Acidosis prevented hypoxia-induced PH, reversed MCT-induced PH, and resulted in reduction in all indexes of PH including RVSP, Fulton's index, and pulmonary arteriolar remodeling. Pulmonary artery contraction to Phe and KCl was preserved or improved, and relaxation to ACh and SNP was enhanced in NH(4)Cl-treated PH animals. Acidosis alone did not affect the hemodynamics or pulmonary vascular function. Phe and KCl contraction and ACh and SNP relaxation were not different in mesenteric arteries of all groups. Thus nonhypercapnic acidosis ameliorates experimental PH, attenuates pulmonary arteriolar thickening, and enhances pulmonary vascular responsiveness to vasoconstrictor and vasodilator stimuli. Together with our finding that acidosis decreases VSMC proliferation, the results are consistent with the possibility that nonhypercapnic acidosis promotes differentiation of pulmonary VSMCs to a more contractile phenotype, which may enhance the effectiveness of vasodilator therapies in PH.
肺动脉高压（PH）的特征是肺小动脉重构，伴有肺血管平滑肌细胞（VSMC）过度增殖。这导致肺循环对血管扩张剂治疗的反应性降低。我们已经表明，细胞外酸中毒可抑制体外 VSMC 的增殖和迁移。在这里，我们测试了体内非高碳酸酸中毒的诱导是否可以改善 PH 及其潜在的肺血管重构和功能障碍。成年雄性 Sprague-Dawley 大鼠暴露于低氧（8.5% O2）2 周，或皮下注射马兜铃酸（MCT，60mg/kg）以发展 PH。在低氧暴露的 2 周前和期间，用 NH4Cl（1.5%）在饮用水中诱导酸中毒（预防方案），或在 MCT 注射后第 21 天至第 28 天（逆转方案）。测量右心室收缩压（RVSP）和富尔顿指数，并分析肺小动脉重构。离体检测肺和肠系膜动脉对苯肾上腺素（Phe）和高 KCl 的收缩以及对乙酰胆碱（ACh）和硝普钠（SNP）的舒张。低氧和 MCT 处理的大鼠表现出 RVSP、富尔顿指数和肺小动脉增厚增加。在低氧和 MCT 大鼠的肺动脉中，对 Phe 和 KCl 的收缩减少，对 ACh 和 SNP 的血管舒张减少。酸中毒可预防低氧诱导的 PH，逆转 MCT 诱导的 PH，并降低包括 RVSP、富尔顿指数和肺小动脉重构在内的所有 PH 指标。Phe 和 KCl 收缩以及 ACh 和 SNP 舒张在 NH4Cl 处理的 PH 动物中得到保留或改善。单独的酸中毒不会影响血液动力学或肺血管功能。各组肠系膜动脉的 Phe 和 KCl 收缩以及 ACh 和 SNP 舒张均无差异。因此，非高碳酸酸中毒可改善实验性 PH，减轻肺小动脉增厚，并增强肺血管对血管收缩剂和血管扩张剂刺激的反应性。结合我们发现酸中毒可减少 VSMC 增殖的结果，表明非高碳酸酸中毒可促进肺 VSMC 向更收缩表型分化，这可能增强 PH 中血管扩张剂治疗的效果。
