Carbon monoxide-mediated activation of large-conductance calcium-activated potassium channels contributes to mesenteric vasodilatation in cirrhotic rats
Carbon monoxide-mediated activation of large-conductance calcium-activated potassium channels contributes to mesenteric vasodilatation in cirrhotic rats
复制标题
DOI：
10.1124/jpet.106.116665
复制
发表时间：
2007-04-01
影响因子：
3.5
通讯作者：
Gatta, Angelo
中科院分区：
文献类型：
--
作者：
Bolognesi, Massimo;Sacerdoti, David;Gatta, Angelo
大电导钙激活钾通道（BK(Ca)）是动脉张力的重要调节因子，并且是内源性血管舒张剂一氧化碳（CO）的一种介质。由于血红素加氧酶（HO）/CO系统的上调与肝硬化的肠系膜血管舒张有关，我们分析了BKCa以及HO/CO在腹水肝硬化大鼠肠系膜动脉内皮依赖性舒张中的相互作用。在腹水肝硬化大鼠的加压肠系膜动脉（直径170 - 350μm）中，我们评估了抑制BKCa、HO和鸟苷酸环化酶对乙酰胆碱和外源性CO诱导的舒张的影响，以及HO - 1和BKCa亚基蛋白的表达。在肝硬化大鼠中，抑制HO和BKCa比在对照大鼠中更能降低乙酰胆碱诱导的血管舒张，而抑制鸟苷酸环化酶在两组中有相似的作用。CO在肝硬化大鼠中比在对照大鼠中更有效，并且这种作用被BKCa抑制所阻碍。与对照动物相比，肝硬化大鼠肠系膜动脉中HO - 1和BKCaα亚基的表达更高，而BKCaα1亚基的表达更低。总之，BKCaα亚基的过表达（可能是由于HO上调以及CO产生增加）参与了腹水肝硬化大鼠内皮依赖性改变和肠系膜动脉血管舒张。
Large-conductance calcium-activated potassium channels (BK(Ca)s) are important regulators of arterial tone and represent a mediator of the endogenous vasodilator carbon monoxide (CO). Because an up-regulation of the heme oxygenase (HO)/CO system has been associated with mesenteric vasodilatation of cirrhosis, we analyzed the interactions of BKCa and of HO/CO in the endothelium-dependent dilatation of mesenteric arteries in ascitic cirrhotic rats. In pressurized mesenteric arteries (diameter, 170-350 mu m) of ascitic cirrhotic rats, we evaluated the effect of inhibition of BKCa, HO, and guanylylcyclase on dilatation induced by acetylcholine and by exogenous CO; and HO-1 and BKCa subunit protein expression. Inhibition of HO and of BKCa reduced acetylcholine-induced vasodilatation more in cirrhotic rats than in control rats, whereas inhibition of guanylyl-cyclase had a similar effect in the two groups. CO was more effective in cirrhotic rats than in control rats, and the effect was hindered by BKCa inhibition. The expression of HO-1 and of BKCa alpha-subunit was higher in mesenteric arteries of cirrhotic rats compared with that of control animals, whereas the expression of the BKCa alpha 1-subunit was lower. In conclusion, an overexpression of BKCa alpha-subunits, possibly due to HO up-regulation with increased CO production, participates in the endothelium-dependent alterations and mesenteric arterial vasodilatation of ascitic cirrhotic rats.