Sorrentino R, Sautebin L, Pinto A
Department of Experimental Pharmacology, University of Naples, Italy.
Life Sci. 1997;61(13):1283-91. doi: 10.1016/s0024-3205(97)00673-5.
The inhibitory activity of methylguanidine, guanidine and their precursors, creatine and creatinine, on both the neuronal constitutive and lung inducible isoforms of nitric oxide synthase were examined in this study. Methylguanidine and guanidine (0.01-3 mM) significantly (P<0.01) inhibited in a concentration-dependent manner both isoforms of the enzyme. Furthermore analysis of the inhibition curves by ANOVA revealed that methylguanidine and guanidine act as non selective inhibitors of both nitric oxide synthases (P>0.4 for both methylguanidine and guanidine). In contrast, creatine and creatinine, although containing guanidine group, were totally ineffective on either enzyme even at concentration up to 3 mM. The results obtained for tested compounds also suggest a role for the lateral chain of guanidine group in the enzyme inhibition. The lack of selectivity of methylguanidine and guanidine in inhibiting both the nitric oxide synthase enzymes could account for some pathological manifestations like neurological disorders, host defense impairment and probably hypertension, that often occur in patients with uremia or chronic renal failure.
本研究检测了甲基胍、胍及其前体肌酸和肌酐对一氧化氮合酶的神经元组成型和肺诱导型同工酶的抑制活性。甲基胍和胍（0.01 - 3 mM）以浓度依赖性方式显著（P<0.01）抑制该酶的两种同工酶。此外，通过方差分析对抑制曲线进行分析表明，甲基胍和胍作为两种一氧化氮合酶的非选择性抑制剂（甲基胍和胍的P均>0.4）。相比之下，肌酸和肌酐虽然含有胍基，但即使在浓度高达3 mM时对两种酶也完全无效。所测化合物的结果还表明胍基侧链在酶抑制中起作用。甲基胍和胍在抑制两种一氧化氮合酶时缺乏选择性，这可能解释了尿毒症或慢性肾衰竭患者中经常出现的一些病理表现，如神经紊乱、宿主防御受损以及可能的高血压。
