Cyclic nucleotide phosphodiesterase in human cardiovascular tissues

研究了环核苷酸磷酸二酯酶（PDE）同工酶在人心脏、主动脉和血小板中的分布。在人类心脏的细胞质部分中，识别出四种不同的PDE同工酶，即PDE1， PDE2， PDE3和PDE4。在颗粒组分中，鉴定出PDE3、PDE4和PDE4的一个新亚型（pde4α）。罗利普兰和ro20 -1724对PDE4 α的抑制作用约为PDE4的10倍。在人主动脉中，PDE1、PDE2、PDE3、PDE4和PDE5均被分离，颗粒组分中未检测到PDE活性。在人血小板提取物中检测到PDE的三种同工酶，即PDE2、PDE3和PDE5，未检测到PDE1和PDE4的活性。PDE5在人体中表现出器官特异性表达，PDE5在人体组织中的表达水平排序为血小板>>主动脉和肺>肾脏，PDE5在人体心脏中未发现。新的心血管药物，如NSP-805和MS-857，有效和选择性地抑制PDE3相对于cAMP的竞争性活性。吡嗪酮衍生物如NSP-805抑制PDE3的浓度比抑制PDE4所需的浓度低2到4个数量级，而非吡嗪酮衍生物如MS-857的差异约为1个数量级。现在重要的是评估这些药物治疗充血性心力衰竭的短期和长期疗效，并澄清临床数据与它们的收缩效应的分子机制之间的关系。E4021是一种有效的、高选择性的PDE5抑制剂。E4021与SIN-1联合可使前列腺素f2α诱导的人肺动脉收缩松弛，抑制人血小板聚集。这些结果提示PDE5抑制剂可能是一种新型的血管舒张和抗血小板治疗药物。

The distribution of cyclic nucleotide phosphodiesterase (PDE) isoenzymes in human heart, aorta and platelets was investigated. In a cytosolic fraction from human heart, four distinct PDE isoenzymes, namely, PDE1, PDE2, PDE3 and PDE4 were recognized. In the particulate fraction, PDE3, PDE4 and a new isoform of PDE4 (PDE4alpha) were identified. PDE4alpha was inhibited about 10 times more weakly by rolipram and Ro 20-1724 than was PDE4. In human aorta, PDE1, PDE2, PDE3, PDE4 and PDE5 were resolved and no PDE activity was detected in the particulate fraction. Three isoenzymes of PDE,namely, PDE2, PDE3 and PDE5 were identified in extracts of human platelets, and no activities of PDE1 and PDE4 were detected. PDE5 exhibited an organ-specific expression in humans, and the rank order of the levels of PDE5 in human tissues was platelets >> aorta and lung > kidney and PDE5 was not found in the human heart.New carditonic agents, such as NSP-805 and MS-857, potently and selectively inhibited the activity of PDE3 competitive with respect to cAMP.Pyridazinone derivatives such as NSP-805 inhiubited PDE3 at concentration that were two to four orders of magnitude lower than that required for the inhibition of PDE4, though for the nonpyridazinone derivatives, such as MS-857, the difference was about one order of magnitude. It is now important to estimate the short-and long-term efficacies of these drugs for treatment of congestive heart failure and to clarify the relations between clinical data and the molecular mechanisms of their inotopic effects. E4021 was a potent and highly selective inhibitor of PDE5. E4021 relaxd the prostagrandin F2alpha-induced contraction of human pulmonary artery and inhibited the human platelets aggregation in the combination with SIN-1. These results suggest that PDE5 inhibitor might be useful as a new type of treatment for vasorelaxation and anti-platelets.