Am J Physiol Regul Integr Comp Physiol. 2014 Jul 15;307(2):R138-48. doi: 10.1152/ajpregu.00117.2014.
We determined the contribution of vascular large conductance Ca2+-activated K+ (BK) and L-type Ca2+ channel dysregulation to exaggerated mortality in cecal ligation/puncture (CLP)-induced septic BK channel β1-subunit knockout (BK β1-KO, smooth muscle specific) mice. CLP-induced hemodynamic changes and mortality were assessed over 7 days in wild-type (WT) and BK β1-KO mice that were either untreated, given volume resuscitation (saline), or saline + calcium channel blocker nicardipine. Some mice were euthanized 24 h post-CLP to measure tissue injury and vascular and immune responses. CLP-induced hypotension was similar in untreated WT and BK β1-KO mice, but BK β1-KO mice died sooner. At 24 h post-CLP (mortality latency in BK β1-KO mice), untreated CLP-BK β1-KO mice showed more severe hypothermia, lower tissue perfusion, polymorphonuclear neutrophil infiltration-independent severe intestinal necrosis, and higher serum cytokine levels than CLP-WT mice. Saline resuscitation improved survival in CLP-WT but not CLP-BK β1-KO mice. Saline + nicardipine-treated CLP-BK β1-KO mice exhibited longer survival times, higher tissue perfusion, less intestinal injury, and lower cytokines versus untreated CLP-BK β1-KO mice. These improvements were absent in treated CLP-WT mice, although saline + nicardipine improved blood pressure similarly in both septic mice. At 24 h post-CLP, BK and L-type Ca2+ channel functions in vitro were maintained in mesenteric arteries from WT mice. Mesenteric arteries from BK β1-KO mice had blunted BK/enhanced L-type Ca2+ channel function. We conclude that vascular BK channel deficiency exaggerates mortality in septic BK β1-KO mice by activating L-type Ca2+ channels leading to blood pressure-independent tissue ischemia.
我们确定了血管大电导钙激活钾 (BK) 和 L 型钙通道失调对结扎盲肠/穿刺 (CLP) 诱导的败血症 BK 通道β1 亚基敲除 (BK β1-KO，平滑肌特异性) 小鼠过度死亡率的贡献。在未治疗、给予容量复苏 (盐水) 或盐水+钙通道阻滞剂尼卡地平的野生型 (WT) 和 BK β1-KO 小鼠中，评估 CLP 诱导的血流动力学变化和 7 天死亡率。一些小鼠在 CLP 后 24 小时处死，以测量组织损伤和血管及免疫反应。未经治疗的 WT 和 BK β1-KO 小鼠的 CLP 诱导性低血压相似，但 BK β1-KO 小鼠死亡更早。在 CLP 后 24 小时 (BK β1-KO 小鼠的死亡率潜伏期)，未经治疗的 CLP-BK β1-KO 小鼠表现出更严重的体温过低、组织灌注降低、中性粒细胞浸润-independent 严重的小肠坏死和更高的血清细胞因子水平，比 CLP-WT 小鼠严重。盐水复苏可提高 CLP-WT 但不能提高 CLP-BK β1-KO 小鼠的存活率。用盐水+尼卡地平治疗的 CLP-BK β1-KO 小鼠与未经治疗的 CLP-BK β1-KO 小鼠相比，存活时间更长、组织灌注更高、肠损伤更少、细胞因子水平更低。在治疗的 CLP-WT 小鼠中未观察到这些改善，尽管盐水+尼卡地平对两种败血症小鼠的血压改善相似。CLP 后 24 小时，WT 小鼠肠系膜动脉中保持 BK 和 L 型钙通道的功能。BK β1-KO 小鼠的肠系膜动脉中 BK 功能减弱/L 型钙通道功能增强。我们得出结论，血管 BK 通道缺失通过激活 L 型钙通道导致血压-independent 组织缺血，从而使败血症 BK β1-KO 小鼠的死亡率增加。
