NITRIC-OXIDE AND CGMP CAUSE VASORELAXATION BY ACTIVATION OF A CHARYBDOTOXIN-SENSITIVE K-CHANNEL BY CGMP-DEPENDENT PROTEIN-KINASE
NITRIC-OXIDE AND CGMP CAUSE VASORELAXATION BY ACTIVATION OF A CHARYBDOTOXIN-SENSITIVE K-CHANNEL BY CGMP-DEPENDENT PROTEIN-KINASE
复制标题
DOI：
10.1073/pnas.91.16.7583
复制
发表时间：
1994-08-02
影响因子：
11.1
通讯作者：
WEIR, EK
中科院分区：
文献类型：
--
作者：
ARCHER, SL;HUANG, JMC;WEIR, EK
一氧化氮(NO)诱导的松弛与血管平滑肌细胞内cGMP水平升高有关。然而，cGMP引起松弛的机制尚不清楚。本研究验证了一种假说，即依赖于cGMP的蛋白激酶介导的钙敏感钾(K-Ca)通道的激活是cGMP引起的松弛的原因。在依赖于cGMP但不依赖于cGMP的大鼠肺动脉环上，钾通道阻滞剂四乙铵和钾-钙通道阻断剂查氏毒素均能抑制其松弛。增加细胞外钾浓度也可抑制cGMP依赖的松弛，但不会降低血管平滑肌cGMP水平。在全细胞膜片钳实验中，NO和cGMP通过激活钾-钙通道增加全细胞钾电流。细胞内给予(Sp)-鸟苷环3‘，5’-硫代磷酸，这是一种优先依赖cGMP的蛋白激酶激活剂，可以模拟这种作用。磷酸酶抑制剂冈田酸增强了全细胞钾电流，这与通道磷酸化在激活NO反应性钾-钙通道中的重要作用是一致的。因此，NO和cGMP通过cGMP依赖的蛋白激酶依赖的K通道激活来松弛血管平滑肌。这表明，NO和硝基血管扩张剂共有的最终共同途径是依赖cGMP的K通道激活。
Nitric oxide (NO)-induced relaxation is associated with increased levels of cGMP in vascular smooth muscle cells. However, the mechanism by which cGMP causes relaxation is unknown. This study tested the hypothesis that activation of Ca-sensitive K (K-Ca) channels, mediated by a cGMP-dependent protein kinase, is responsible for the relaxation occurring in response to cGMP. In rat pulmonary artery rings, cGMP-dependent, but not cGMP-independent, relaxation was inhibited by tetraethylammonium, a classical K-channel blocker, and charybdotoxin, an inhibitor of K-Ca channels. Increasing extracellular K concentration also inhibited cGMP-dependent relaxation, without reducing vascular smooth muscle cGMP levels. In whole-cell patch clamp experiments, NO and cGMP increased whole cell K current by activating K-Ca channels. This effect was mimicked by intracellular administration of (Sp)-guanosine cyclic 3',5'-phosphorothioate, a preferential cGMP-dependent protein kinase activator. Okadaic acid, a phosphatase inhibitor, enhanced whole cell K current, consistent with an important role for channel phosphorylation in the activation of NO-responsive K-Ca channels. Thus NO and cGMP relax vascular smooth muscle by a cGMP-dependent protein kinase-dependent activation of K channels. This suggests that the final common pathway shared by NO and the nitrovasodilators is cGMP-dependent K-channel activation.