Induction of PDE5 and de-sensitization to endogenous NO signaling in a systemic resistance artery under altered blood flow.
Induction of PDE5 and de-sensitization to endogenous NO signaling in a systemic resistance artery under altered blood flow.
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DOI：
10.1016/j.yjmcc.2009.03.025
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发表时间：
2009-07
影响因子：
5
通讯作者：
Fisher, Steven A.
中科院分区：
文献类型：
--
作者：
Zhang, Haiying;Pakeerappa, Praveen;Lee, Hyon Jae;Fisher, Steven A.
在经典途径中，观酰基环化酶（GC）和磷酸二酯酶（PDE）的相反活性，以及cgmp依赖性蛋白激酶（cGK）对其靶点的作用，决定了NO信号的生物学反应。在这里，我们验证了血管功能障碍可能是由于这些NO信号效应物的表达和活性改变引起的假设。结扎各组大鼠二级肠系膜阻力动脉（MA），造成上游MA1动脉慢性低流量（LF），邻近MA1动脉慢性高流量（HF），无组织缺血。在血管重构亚急性期（4 d），心衰MA1和LF MA1中eNOS和iNOS分别上调。第4天HF/LF ma1在NO控制下增加，对血管收缩剂苯肾上腺素的敏感性降低，其与NOS拮抗剂L-NAME的关系正常化。PDE5 mRNA和蛋白在HF/LF MA1中也显著上调，而sGC或PKG1没有变化，这种作用依赖于no合成。PDE5抑制剂西地那非在缓解HF/LF ma1方面的作用强数倍，并且西地那非预处理发现HF/LF ma1对NO供体DEA/NO的反应性增加。我们得出结论，PDE5的诱导使慢性HF/LF下的系统性抵抗动脉对持续的NO信号去敏化。与NO供体相比，PDE5拮抗剂治疗可能更特异性和有效地增加慢性低灌注组织的血流量。
In the classical pathway, the opposing activities of guanylyl cyclases (GC) and phosphodiesterases (PDE), and the effect of the cGMP-dependent protein kinase (cGK) on its targets, determine the biological responses to NO signaling. Here we tested the hypothesis that vascular dysfunction may be due to altered expression and activity of these effectors of NO signaling. Every other set of rat second order mesenteric resistance arteries (MA) were ligated, resulting in chronic low flow (LF) in the upstream MA1 and high flow (HF) in the adjacent MA1 without tissue ischemia. eNOS and iNOS were up-regulated in HF and LF MA1, respectively, in the sub-acute phase (four days) of vascular remodeling. The Day4 HF/LF MA1s were under increased control of NO as indicated by reduced sensitivity to the vasoconstrictor phenylephrine and its normalization with the NOS antagonist L-NAME. PDE5 mRNA and protein were also significantly up-regulated in the HF/LF MA1 with no change in sGC or PKG1, an effect that was dependent upon NO synthesis. The PDE5 inhibitor Sildenafil was several-fold more powerful in relaxing the HF/LF MA1s, and pre-treatment with Sildenafil uncovered an increased responsiveness of HF/LF MA1s to the NO donor DEA/NO. We conclude that induction of PDE5 de-sensitizes this systemic resistance artery to sustained NO signaling under chronic HF/LF. Treatment with PDE5 antagonists, in contrast to NO donors, may more specifically and effectively increase blood flow to chronically hypo-perfused tissues.
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DOI：
10.1038/nrd2030
发表时间：
2006-08
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Ghofrani HA;Osterloh IH;Grimminger F
通讯作者：
Grimminger F
影响因子：
4.6
作者：
Lam, Christopher;Baker, Scott;Eghtesady, Pirooz
通讯作者：
Eghtesady, Pirooz
影响因子：
20.1
作者：
Bakker, Erik N. T. P.;Pistea, Adrian;VanBavel, Ed
通讯作者：
VanBavel, Ed
影响因子：
5.5
作者：
Lu, Yuan;Zhang, Haiying;Fisher, Steven A.
通讯作者：
Fisher, Steven A.
影响因子：
3.1
作者：
Oishi, Peter;Sharma, Shruti;Fineman, Jeffrey R.
通讯作者：
Fineman, Jeffrey R.