The effects of KF31327 (3-ethyl-8-[2-(4-hydroxymethylpiperidino)benzylamino]-2,3-dihydro-1H-imidazo[4,5-g]quinazoline-2-thione dihydrochloride) on phosphodiesterase 5 (cyclic GMP-specific phosphodiesterase) activity and platelet aggregation were investigated and compared with those of sildenafil, a well-known phosphodiesterase 5 inhibitor. KF31327 inhibited phosphodiesterase 5 from canine trachea (K(i)=0.16 nM) more potently than sildenafil (K(i)=7.2 nM). The kinetic analysis revealed that KF31327 was a non-competitive inhibitor. In the presence of nitroglycerin (nitric oxide generator), both compounds inhibited the collagen-induced aggregation of rabbit platelets at less than 0.1 microM, augmenting intracellular cyclic GMP level without affecting cyclic AMP. In contrast, in the absence of nitroglycerin, a higher concentration (10 microM) of KF31327 was required to inhibit platelet aggregation and increased both cyclic nucleotide levels. However, 10 microM sildenafil did not affect aggregation despite elevation of cyclic GMP comparable to that in the presence of nitroglycerin. These results indicate that in the presence of nitroglycerin, the inhibition of platelet aggregation by KF31327 is due to the elevation of cyclic GMP, whereas the mechanism underlying the inhibition without nitroglycerin might be related to a rise in intracellular cyclic AMP.

中文翻译：

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KF31327，一种新的有效且选择性的环状核苷酸磷酸二酯酶5抑制剂。

KF31327（3-乙基-8- [2-（4-羟甲基哌啶子基）苄氨基] -2,3-二氢-1H-咪唑并[4,5-g]喹唑啉-2-硫酮二盐酸盐）对磷酸二酯酶5（环的）的影响研究了GMP特异性磷酸二酯酶的活性和血小板聚集情况，并与著名的磷酸二酯酶5抑制剂sildenafil进行了比较。与西地那非（K（i）= 7.2 nM）相比，KF31327更有效地抑制了来自犬气管的磷酸二酯酶5（K（i）= 0.16 nM）。动力学分析表明，KF31327是一种非竞争性抑制剂。在存在硝酸甘油（一氧化氮产生剂）的情况下，两种化合物均以小于0.1 microM的浓度抑制胶原蛋白诱导的兔血小板聚集，从而在不影响环状AMP的情况下增加了细胞内的环状GMP水平。相反，在缺乏硝酸甘油的情况下，需要较高浓度（10 microM）的KF31327抑制血小板聚集并增加两个环核苷酸水平。然而，尽管与在硝酸甘油存在下相比，环GMP升高，但10 microM西地那非不会影响聚集。这些结果表明，在存在硝酸甘油的情况下，KF31327对血小板聚集的抑制作用是由于环状GMP的升高，而没有硝酸甘油的抑制作用的潜在机制可能与细胞内环状AMP的升高有关。