ISOZYME-SELECTIVE INHIBITION OF CGMP-STIMULATED CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES BY ERYTHRO-9-(2-HYDROXY-3-NONYL) ADENINE
ISOZYME-SELECTIVE INHIBITION OF CGMP-STIMULATED CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES BY ERYTHRO-9-(2-HYDROXY-3-NONYL) ADENINE
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DOI：
10.1016/0898-6568(95)00042-n
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发表时间：
1995-09-01
影响因子：
4.8
通讯作者：
MULLER, A
中科院分区：
文献类型：
--
作者：
PODZUWEIT, T;NENNSTIEL, P;MULLER, A
赤式-9-（2-羟基-3-壬基）腺嘌呤（EHNA）是腺苷脱氨酶（ADA）的有效抑制剂，对猪和人心肌可溶性环核苷酸磷酸二酯酶（PDE）同工酶进行了抑制试验。用阴离子交换层析（DEAESepharoseCL-6 B）从人乳头肌提取物中分离出四种可溶性PDE活性。根据Beavo的命名法，这些活动被命名为PDE I-IV。PDE I由Ca 2 +-钙调蛋白刺激，PDE II由cGMP（1 μ M）刺激。PDE III被cGMP（1 μ M）以及SK&F 94120抑制，PDE IV被咯利普兰和Ro 20-1724抑制。酶动力学和抑制常数与猪心PDE同工酶相似。然而，猪心肌缺乏Ca 2 +-钙调素刺激的可溶性PDE I活性。目前的数据显示，EHNA对cGMP刺激的PDE II（cGs-PDE）产生浓度依赖性抑制（IC 50：0.8 μ M（人），2 μ M（猪）），但不抑制其他PDE同工酶（IC 50> 100 μ M）。这些发现表明，EHNA是一种有效的，并且就胞质PDE而言，是cGMP刺激PDE的选择性抑制剂。该化合物可用于其他同工酶选择性PDE II抑制剂的合理设计，并用于检查cGs-PDE的特定生物学功能。EHNA可用于ADA抑制无关紧要的系统。相反，EHNA对ADA和cGs-PDE的双重抑制可能导致两种抑制性代谢产物腺苷和cGMP的蓄积，这两种代谢产物可能协同作用，介导多种药理学反应，包括抗病毒、抗肿瘤和抗肿瘤作用。
Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), a potent inhibitor of adenosine deaminase (ADA), was tested as an inhibitor of the soluble cyclic nucleotide phosphodiesterase (PDE) isoenzymes from pig and human myocardium. Four soluble PDE activities were resolved from human papillary muscle extracts using anion exchange chromatography (DEAE Sepharose CL-6B). These activities were designated PDE I-IV according to the nomenclature of Beavo. PDE I was stimulated by Ca2+-calmodulin and PDE II by cGMP (1 mu M). PDE III was inhibited by cGMP (1 mu M) as well as SK&F 94120, and PDE IV by both rolipram and Ro 20-1724. Enzyme kinetics and inhibition constants were similar with the PDE isoenzymes from pig heart. However, porcine myocardium lacked Ca2+-calmodulin-stimulated soluble PDE I activity. The present data reveal that EHNA exerted a concentration-dependent inhibition of the cGMP-stimulated PDE II (cGs-PDE) (IC50: 0.8 mu M (human), 2 mu M (pig)) but did not inhibit the other PDE isoenzymes (IC50 > 100 mu M). These findings indicate that EHNA is a potent and, as far as cytosolic PDEs are concerned, selective inhibitor of cGMP-stimulated PDEs. The compound may lend itself for the rational design of other isozyme selective PDE II inhibitors and for examining the specific biological functions of cGs-PDEs. EHNA may be used in systems in which inhibition of ADA is of no concern. Conversely, dual inhibition of both ADA and cGs-PDE by EHNA may cause accumulation of two inhibitory metabolites, adenosine and cGMP, which may act in synergy to mediate diverse pharmacological responses, including antiviral, antitumour and antiarrhythmic effects.