ROLE OF K CHANNELS IN HYPOXIC PULMONARY VASOCONSTRICTION

我们对组织氧传感细胞机制的理解 仍然不完整。 与大多数其他血管床相比， 动脉（PA）床在轻度至中度缺氧时收缩， 这种现象称为缺氧性肺血管收缩（HPV）。 当气道 缺氧是局部的，HPV执行匹配区域的有用功能， 从灌注到通气 然而，在与全身性疾病相关的疾病中， 呼吸道缺氧，如慢性阻塞性肺疾病和新生儿 呼吸窘迫，HPV导致肺动脉压升高 （肺动脉高血压）与显著相关的发病率和 mortality. HPV的发病机制尚不清楚，尽管它似乎 HPV是PA的固有特性， 通过神经系统或循环血液成分进行转导。 广泛的调查未能确定非血管性 氧敏感细胞或HPV的可扩散介质。 我们最近的研究 实验室和其他机构已经证明，PA的分离片段显示， 缺氧收缩类似于HPV，这表明氧敏感是一种 PA的固有特性。 几条线索的调查让我们 提出了一个工作假设，即氧气直接影响 PA平滑肌细胞（SMC）离子通道，导致膜 去极化、钙内流和血管收缩。 这种假设是 基于以下观察结果：1）缺氧导致PA SMC膜 去极化; 2）钾通道的药理学抑制剂 引起肺血管收缩; 3）氧敏感性钾 通道存在于另一个氧传感细胞，颈动脉体I型 cell. 拟议的研究将使用膜片钳和荧光 显微镜下测量氧张力对PA SMC钾和 钙通道、细胞内钙离子浓度和收缩。 待检验的具体假设是：1）缺氧导致PA SMC 通过降低钾电导的膜去极化; 2）氧- 感知是钾通道子集的固有特性; 3） 肺动脉和体动脉对缺氧反应的差异 （血管收缩与血管舒张）是由于内在的差异， 氧对SMC钾通道的影响;和4）遗传转移 氧敏感通道的信息编码可以赋予氧传感 一个不敏感的细胞 虽然主要假设集中在 钾通道作为HPV的传感器，两种替代假设将 还可以测试：1）氧气直接影响钙的功能 通道; 2）氧通过一个离子通道间接影响离子通道功能。 细胞内信号传导过程。

Our understanding of the cellular mechanisms of tissue oxygen sensing remains incomplete. In contrast to most other vascular beds, the pulmonary arterial (PA) bed constricts during mild to moderate hypoxia in a phenomenon known as hypoxic pulmonary vasoconstriction (HPV). When airway hypoxia is localized, HPV performs the useful function of matching regional perfusion to ventilation. However, in diseases associated with generalized airway hypoxia, such as chronic obstructive lung disease and neonatal respiratory distress, HPV causes an increase in pulmonary artery pressure (pulmonary hypertension) with significant associated morbidity and mortality. The mechanism of HPV is poorly understood, although it appears that HPV is an intrinsic property of the PA which does not require transduction by the nervous system or circulating blood components. Extensive investigation has failed to identify either a non-vascular oxygen-sensing cell or a diffusible mediator of HPV. Recent studies in our laboratory and others have demonstrated that isolated segments of PA show hypoxic contraction similar to HPV, suggesting that oxygen-sensing is an intrinsic property of the PA. Several lines of investigation have led us to propose the working hypothesis that oxygen directly affects the function of PA smooth muscle cell (SMC) ion channels, causing membrane depolarization, calcium influx and vasoconstriction. This hypothesis is based on the observations: 1) that hypoxia causes PA SMC membrane depolarization; 2) that pharmacologic inhibitors of potassium channels cause pulmonary vasoconstriction; and 3) that an oxygen-sensitive potassium channel is present on another oxygen sensing cell, the carotid body type I cell. The proposed studies will use patch clamp and fluorescence microscopy to measure the effects of oxygen tension on PA SMC potassium and calcium channels, intracellular calcium ion concentration, and contraction. The specific hypotheses to be tested are: 1) hypoxia causes PA SMC membrane depolarization by decreasing potassium conductance; 2) oxygen- sensing is an intrinsic property of a subset of potassium channels; 3) differences between pulmonary and systemic artery responses to hypoxia (vasoconstriction vs vasodilation) are due to intrinsic differences in the effect of oxygen on SMC potassium channels; and 4) transfer of genetic information coding for oxygen-sensitive channels can confer oxygen-sensing to a non-sensitive cell. While the primary hypotheses focus on the potassium channel as the sensor for HPV, two alternative hypotheses will also be tested: 1) oxygen directly affects the function of a calcium channel; and 2) oxygen indirectly affects ion channel function through an intracellular signalling process.