Differential effects of phosphodiesterase PDE-3/PDE-4-specific inhibitors on vasoconstriction and cAMP-dependent vasorelaxation following balloon angioplasty.
Differential effects of phosphodiesterase PDE-3/PDE-4-specific inhibitors on vasoconstriction and cAMP-dependent vasorelaxation following balloon angioplasty.
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磷酸二酯酶 PDE-3/PDE-4 特异性抑制剂对球囊血管成形术后血管收缩和 cAMP 依赖性血管舒张的不同影响。
DOI：
10.1152/ajpheart.00419.2006
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Smith,CarolynJ
中科院分区：
文献类型：
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作者：
Zhao,Hong;Quilley,John;Montrose,DavidC;Rajagopalan,Swarna;Guan,Qizhi;Smith,CarolynJ
已知cAMP和cGMP对于血管舒张是重要的，并且环核苷酸磷酸二酯酶（PDE）调节它们的水平。球囊血管成形术（BAL）与cAMP和cGMP水平降低相关，PDE-3的抑制可减少再狭窄。在这项研究中，我们发现，BAL增加PDE-3的活性，影响大鼠主动脉环的血管反应性后24小时BAL，这些与完整的（INT）和离体内皮剥脱环（RUB）从假手术大鼠进行了比较。在BAL和RUB环，ACh的血管舒张反应被取消。苯肾上腺素（PE）的EC_（50）在RUB中比在INT或BAL中小1.8倍，而PE在BAL中的最大收缩作用大于INT或RUB。PDE-3抑制剂使BAL中对PE的最大应答降低>65%，而INT和RUB中降低10-30%; BAL中对U-46619的最大应答降低37%，而INT中降低8%，而RUB中未降低。PDE-4抑制剂以内皮依赖性方式使PE诱导的张力降低<30%。在BAL和RUB环中，对利用cAMP的激动剂的血管舒张反应大大受损，并且PDE-3的抑制增强了BAL或RUB中的血管舒张反应。PDE-4的抑制增加了对异丙肾上腺素（ISO）的血管舒张反应，但程度要小得多。因此，PDE-3和PDE-4抑制剂对PE诱导的张力和对ISO的血管舒张反应表现出不同的作用。PDE-3的抑制也使BAL中cAMP的增加大于INT或RUB环。这些结果表明，BAL后PDE-3活性的增加可能会促进血管痉挛状态，cAMP的减少可能会影响血管重塑。
It is known that cAMP and cGMP are important for vasorelaxation, and cyclic nucleotide phosphodiesterases (PDEs) regulate their levels. Balloon angioplasty (BAL) is associated with reduced cAMP and cGMP levels, and inhibition of PDE-3 reduces restenosis. In this study, we found that BAL increased PDE-3 activity, which affected vasoreactivity of rat aortic rings 24-h post-BAL; these were compared with intact (INT) and ex vivo endothelium-denuded rings (RUB) from sham rats. In BAL and RUB rings, vasorelaxant responses to ACh were abolished. The EC50for phenylephrine (PE) was 1.8-fold less in RUB than in INT or BAL, whereas the maximal contractile effect of PE was greater in BAL than in INT or RUB. PDE-3 inhibitors reduced the maximal response to PE by >65% in BAL compared with 10–30% in INT and RUB; the reduction of the maximal response to U-46619 was 37% in BAL compared with 8% in INT with no reduction in RUB. PDE-4 inhibitors reduced PE-induced tone by <30% in an endothelium-dependent manner. Vasorelaxant responses to agonists that utilize cAMP were greatly impaired in BAL and RUB rings, and inhibition of PDE-3 enhanced the vasorelaxant responses in BAL or RUB. Inhibition of PDE-4 increased vasorelaxant responses to isoproterenol (ISO) to a much lesser degree. Thus PDE-3 and PDE-4 inhibitors exhibited differential effects on PE-induced tone and vasorelaxant responses to ISO. Inhibition of PDE-3 also produced a greater increase in cAMP in BAL than INT or RUB rings. These results suggest that increased PDE-3 activity after BAL may promote a vasospastic state and that the reduction in cAMP may, possibly, influence vessel remodeling.