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首页> 外文期刊>American Journal of Physiology >Role of cGMP-dependent protein kinase in development of tolerance to nitric oxide in pulmonary veins of newborn lambs.
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Role of cGMP-dependent protein kinase in development of tolerance to nitric oxide in pulmonary veins of newborn lambs.

机译：cGMP依赖性蛋白激酶在新生羔羊肺静脉对一氧化氮耐受性发展中的作用。

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Continuous exposure to nitrovasodilators and nitric oxide induces tolerance to their vasodilator effects in vascular smooth muscle. This study was done to determine the role of cGMP-dependent protein kinase (PKG) in the development of tolerance to nitric oxide. Isolated fourth-generation pulmonary veins of newborn lambs were studied. Incubation of veins for 20 h with DETA NONOate (DETA NO; a stable nitric oxide donor) significantly reduced their relaxation response to the nitric oxide donor and to beta-phenyl-1,N2-etheno-8-bromo-cGMP (8-Br-PET-cGMP, a cell-permeable cGMP analog). Incubation with DETA NO significantly reduced PKG activity and protein and mRNA levels in the vessels. These effects were prevented by 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (an inhibitor of soluble guanylyl cyclase) and Rp-8-Br-PET-cGMPS (an inhibitor of PKG). A decrease in PKG protein and mRNA levels was also observed after continuous exposure to cGMP analogs. The PKG inhibitor abrogated these effects. The decrease in cGMP-mediated relaxation and in PKG activity caused by continuous exposure to DETA NO was not affected by KT-5720, an inhibitor of cAMP-dependent protein kinase. Prolonged exposure to 8-Br-cAMP (a cell-permeable cAMP analog) did not affect PKG protein level in the veins. These results suggest that continuous exposure to nitric oxide or cGMP downregulates PKG by a PKG-dependent mechanism. Such a negative feedback mechanism may contribute to the development of tolerance to nitric oxide in pulmonary veins of newborn lambs.
机译：持续暴露于硝基血管舒张剂和一氧化氮可诱导其对血管平滑肌的血管舒张作用的耐受性。进行这项研究是为了确定cGMP依赖性蛋白激酶（PKG）在对一氧化氮耐受性发展中的作用。研究了新生羔羊离体的第四代肺静脉。用DETA NONOate（DETA NO;稳定的一氧化氮供体）孵育静脉20小时，可显着降低其对一氧化氮供体和β-苯基-1，N2-etheno-8-bromo-cGMP（8-Br -PET-cGMP，可渗透细胞的cGMP类似物）。用DETA NO孵育可显着降低血管中的PKG活性以及蛋白质和mRNA水平。通过1H-（1,2,4）恶二唑并（4,3-a）喹喔啉-1-一（可溶性鸟苷酸环化酶抑制剂）和Rp-8-Br-PET-cGMPS（PKG抑制剂）可以预防这些作用）。连续暴露于cGMP类似物后，还观察到PKG蛋白和mRNA水平降低。 PKG抑制剂消除了这些作用。连续暴露于DETA NO引起的cGMP介导的舒张和PKG活性的降低不受cAMP依赖性蛋白激酶抑制剂KT-5720的影响。长时间暴露于8-Br-cAMP（可透过细胞的cAMP类似物）不会影响静脉中的PKG蛋白水平。这些结果表明，持续暴露于一氧化氮或cGMP会通过PKG依赖性机制下调PKG。这种负反馈机制可能有助于发展对新生羔羊肺静脉中一氧化氮的耐受性。

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