Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center,Albuquerque, New Mexico 87131-0001, USA.
Am J Physiol Heart Circ Physiol. 2010 Nov;299(5):H1439-50. doi: 10.1152/ajpheart.00124.2010. Epub 2010 Sep 3.
The systemic vasculature exhibits attenuated vasoconstriction following hypobaric chronic hypoxia (CH) that is associated with endothelium-dependent vascular smooth muscle (VSM) cell hyperpolarization. We hypothesized that increased activity of endothelial cell (EC) large-conductance, calcium-activated potassium (BK(Ca)) channels contributes to this response. Gracilis resistance arteries from hypobaric CH (barometric pressure = 380 mmHg for 48 h) rats demonstrated reduced myogenic reactivity and hyperpolarized VSM membrane potential (E(m)) compared with controls under normoxic ex vivo conditions. These differences were eliminated by endothelial disruption. In the presence of cyclooxygenase and nitric oxide synthase inhibition, combined intraluminal administration of the intermediate and small-conductance, calcium-activated K(+) channel blockers TRAM-34 and apamin was without effect on myogenic responsiveness and VSM E(m) in both groups; however, these variables were normalized in CH arteries by intraluminal administration of the BK(Ca) inhibitor iberiotoxin (IBTX). Basal EC E(m) was hyperpolarized in arteries from CH rats compared with controls and was restored by IBTX, but not by TRAM-34/apamin. K(+) channel blockers were without effect on EC basal E(m) in controls. Similarly, IBTX blocked acetylcholine-induced dilation in arteries from CH rats, but was without effect in controls, whereas TRAM-34/apamin eliminated dilation in controls. Acetylcholine-induced EC hyperpolarization and calcium responses were inhibited by IBTX in CH arteries and by TRAM-34/apamin in controls. Patch-clamp experiments on freshly isolated ECs demonstrated greater K(+) current in cells from CH rats that was normalized by IBTX. IBTX was without effect on K(+) current in controls. We conclude that hypobaric CH induces increased endothelial BK(Ca) channel activity that contributes to reduced myogenic responsiveness and EC and VSM cell hyperpolarization.
全身血管系统在低压慢性缺氧（CH）后表现出血管收缩减弱，这与内皮依赖性血管平滑肌（VSM）细胞超极化有关。我们假设内皮细胞（EC）大电导、钙激活钾（BK（Ca））通道活性增加有助于这种反应。与正常氧条件下的对照组相比，来自低压 CH（气压为 380mmHg 持续 48 小时）大鼠的骼肌阻力动脉表现出血管平滑肌反应性降低和 VSM 膜电位（E（m））超极化。这些差异在去除内皮细胞后消除。在环氧化酶和一氧化氮合酶抑制的情况下，中等和小电导、钙激活的 K（+）通道阻滞剂 TRAM-34 和 apamin 的联合腔内给药对两组的血管平滑肌反应性和 VSM E（m）均无影响；然而，在 CH 动脉中，腔内给予 BK（Ca）抑制剂 Iberiotoxin（IBTX）可使这些变量正常化。与对照组相比，CH 大鼠动脉中的 EC E（m）在基础状态下超极化，并用 IBTX 恢复，但不能用 TRAM-34/apamin 恢复。K（+）通道阻滞剂对对照组 EC 的基础 E（m）没有影响。同样，IBTX 阻断了 CH 大鼠动脉中乙酰胆碱诱导的扩张，但对对照组没有影响，而 TRAM-34/apamin 消除了对照组的扩张。IBTX 抑制了 CH 动脉中乙酰胆碱诱导的 EC 超极化和钙反应，而 TRAM-34/apamin 抑制了对照组中的扩张。在新鲜分离的 EC 上进行的膜片钳实验表明，CH 大鼠细胞中的 K（+）电流更大，用 IBTX 归一化。IBTX 对对照组的 K（+）电流没有影响。我们的结论是，低压 CH 诱导内皮 BK（Ca）通道活性增加，导致血管平滑肌反应性降低和 EC 和 VSM 细胞超极化。
