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首页> 外文期刊>American Journal of Physiology >cAMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogs in hypoxic pulmonary vascular remodeling.
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cAMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogs in hypoxic pulmonary vascular remodeling.

机译：cAMP磷酸二酯酶抑制剂可增强前列环素类似物在低氧性肺血管重构中的作用。

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摘要

We investigated the effects of prostacyclin analogs and isoform-selective phosphodiesterase (PDE) inhibitors, alone and in combination, on pulmonary vascular remodeling in vitro and in vivo. Vascular smooth muscle cells (VSMC) isolated from pulmonary (proximal and distal) and systemic circulations demonstrated subtle variations in expression of PDE isoform mRNA. However, using biochemical assays, we found PDE3 and PDE4 isoforms to be responsible for the majority of cAMP hydrolysis in all VSMC. In growth assays, the prostacyclin analogs cicaprost and iloprost inhibited mitogen-induced proliferation of VSMC in a cAMP-dependent manner. In addition, isoform-selective antagonists of PDEs 1, 3, or 4 inhibited VSMC proliferation, an effect that synergized with the effect of prostacyclin analogs. The inhibitory effects were greater in cells isolated from pulmonary circulation. In an in situ perfused rat lung preparation, administration of prostacyclin analogs or the PDE inhibitors vinpocetine (PDE1), cilostamide (PDE3), or rolipram (PDE4), but not EHNA (PDE2), attenuated acute hypoxic vasoconstriction (HPV). Combinations of agents led to a greater reduction in HPV. Furthermore, during exposure to hypoxia for 13 days, Wistar rats were treated with iloprost, rolipram, cilostamide, or combinations of these agents. Compared with normoxic controls, hypoxic animals developed pulmonary hypertension and distal pulmonary artery muscularization. These parameters were attenuated by iloprost+cilostamide, iloprost+rolipram, and cilostamide+rolipram but were not significantly affected by single agents. Together, these findings provide a greater understanding of the role of cAMP PDEs in VSMC proliferation and provide rationale for combined use of prostacylcin analogs plus PDE3/4 inhibitors in treatment of pulmonary vascular remodeling.
机译：我们研究了前列环素类似物和同工型选择性磷酸二酯酶（PDE）抑制剂单独和组合对体外和体内肺血管重构的影响。从肺部（近端和远端）和全身循环中分离出的血管平滑肌细胞（VSMC）表现出PDE亚型mRNA表达的细微变化。但是，通过生化分析，我们发现在所有VSMC中，PDE3和PDE4同工型都是造成大部分cAMP水解的原因。在生长试验中，前列环素类似物西卡前列素和伊洛前列素以依赖cAMP的方式抑制有丝分裂原诱导的VSMC增殖。另外，PDE 1、3或4的同工型选择性拮抗剂抑制VSMC增殖，该作用与前列环素类似物的作用协同作用。在从肺循环分离的细胞中，抑制作用更大。在原位灌注大鼠肺准备中，给予前列环素类似物或PDE抑制剂长春西汀（PDE1），西洛他酰胺（PDE3）或咯利普兰（PDE4），但不给予EHNA（PDE2）可减轻急性缺氧性血管收缩（HPV）。药剂的组合导致HPV的更大降低。此外，在暴露于缺氧状态下的13天中，用伊洛前列素，咯利普兰，西洛他酰胺或这些药物的组合治疗了Wistar大鼠。与正常氧对照相比，低氧动物出现肺动脉高压和远端肺动脉肌肉化。这些参数被伊洛前列素+西洛他酰胺，伊洛前列素+咯利普兰和西洛酰胺+咯利普兰衰减，但不受单一药物的显着影响。在一起，这些发现提供了对cAMP PDEs在VSMC增殖中作用的更深入的了解，并提供了前列环素类似物加PDE3 / 4抑制剂联合用于治疗肺血管重塑的理论基础。

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