Activation of the nitric oxide-cGMP pathway reduces phasic contractions in neonatal rat bladder strips via protein kinase G
Activation of the nitric oxide-cGMP pathway reduces phasic contractions in neonatal rat bladder strips via protein kinase G
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DOI：
10.1152/ajprenal.00207.2009
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发表时间：
2009-08-01
影响因子：
4.2
通讯作者：
de Groat, William C.
中科院分区：
文献类型：
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作者：
Artim, Debra E.;Kullmann, F. Aura;de Groat, William C.
Artim DE，Kullmann FA，Daughter SL，Wu HY，de Groat WC.一氧化氮-cGMP通路的激活通过蛋白激酶G减少新生大鼠膀胱条的阶段性收缩。美国肾脏生理学杂志297：F333-F340，2009年。首次发表于2009年6月3日; doi：10.1152/ajprenal.00207.2009。一氧化氮（NO）是下尿路中的一种神经递质，其刺激可溶性鸟苷酸环化酶（sGC），进而刺激cGMP依赖性蛋白激酶G（PKG）以调节许多下游靶标。NO供体在某些病理模型中减少膀胱过度活动，但不影响成年大鼠的正常膀胱活动。在这项研究中，NO供体S-亚硝基-N-乙酰基-DL-青霉胺（SNAP; 100 μ M）的幅度和频率降低自发和卡巴胆碱增强收缩新生大鼠膀胱条，这是内在的过度活跃。这种作用被sGC的抑制所阻断，并通过应用膜渗透性cGMP类似物（8-溴-cGMP，100 μ M）来模拟。PKG的抑制阻止或逆转8-溴-cGMP的抑制作用。SNAP介导的抑制的一部分也依赖于PKG;然而，在PKG抑制后，SNAP的短暂的sGC依赖性抑制作用仍然存在。用L-NAME（100 μ M）抑制NO合酶并不改变收缩的幅度或频率。然而，抑制内源性磷酸二酯酶（PDE）-5与扎普司特（25 μ M）减少的幅度和频率的阶段性收缩和增加的幅度由最大浓度的SNAP产生的抑制，这表明内源性PDE是组成性的活性和调节cGMP的生产。结果提示，NO-cGMP-PKG通路可能参与了新生大鼠膀胱的抑制性调控。
Artim DE, Kullmann FA, Daugherty SL, Wu HY, de Groat WC. Activation of the nitric oxide-cGMP pathway reduces phasic contractions in neonatal rat bladder strips via protein kinase G. Am J Physiol Renal Physiol 297: F333-F340, 2009. First published June 3, 2009; doi:10.1152/ajprenal.00207.2009.-Nitric oxide (NO), a neurotransmitter in the lower urinary tract, stimulates soluble guanylyl cyclase (sGC) and in turn cGMP-dependent protein kinase G (PKG) to modulate a number of downstream targets. NO donors reduce bladder hyperactivity in some pathological models but do not affect normal bladder activity in the adult rat. In this study, the NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP; 100 mu M) decreased the amplitude and frequency of spontaneous and carbachol-enhanced contractions in neonatal rat bladder strips, which are intrinsically hyperactive. This effect was blocked by inhibition of sGC and mimicked by application of a membrane-permeable cGMP analog (8-bromo-cGMP, 100 mu M). Inhibition of PKG prevented or reversed the inhibitory effects of 8-bromo-cGMP. A portion of the SNAP-mediated inhibition was also dependent upon PKG; however, a short-lasting, sGC-dependent inhibitory effect of SNAP was still present after PKG inhibition. Inhibition of NO synthase with L-NAME (100 mu M) did not change the amplitude or frequency of contractions. However, inhibition of endogenous phosphodiesterase (PDE)-5 with zaprinast (25 mu M) reduced the amplitude and frequency of phasic contractions and increased the magnitude of inhibition produced by maximal concentrations of SNAP, suggesting that endogenous PDEs are constitutively active and regulate cGMP production. These results suggest that the NO-cGMP-PKG pathway may be involved in inhibitory control of the neonatal rat bladder.