INHIBITION OF CREATINE AND PHOSPHOCREATINE ACCUMULATION IN SKELETAL-MUSCLE AND HEART
INHIBITION OF CREATINE AND PHOSPHOCREATINE ACCUMULATION IN SKELETAL-MUSCLE AND HEART
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DOI：
10.1016/0026-0495(80)90115-8
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发表时间：
1980-01-01
影响因子：
9.8
通讯作者：
CHEVLI, R
中科院分区：
文献类型：
--
作者：
FITCH, CD;CHEVLI, R
测试了一系列肌酸类似物在体内抑制14 C-肌酸蓄积的能力和在体外作为肌酸激酶底物的能力。最有效的积累抑制剂是1-羧甲基-2-亚氨基-六氢嘧啶、N-甲基脒基-N-甲基甘氨酸、β-氨基-N-甲基嘧啶、β-氨基-N-甲基嘧啶和β-氨基-N-甲基嘧啶。胍基丙酸酯和DL-β-胍基丁酸盐。前2种化合物作为肌酸激酶的底物是无活性的，而DL-β-胍基丁酸盐在本实验中是无活性的，产生的Vmax小于肌酸产生的Vmax的0.01%。后者化合物和β-胍基丙酸酯在体外作为肌酸激酶抑制剂也是无效的。肌酸激酶的最佳底物是N-乙基-N-脒基甘氨酸和胍基乙酸;这2种化合物作为14 C-肌酸积累的抑制剂是无效的。将甲基添加到β-胍基丙酸酯形成N-甲基-N-脒基-β-丙氨酸消除了化合物抑制14 C-肌酸积累的能力，但对其作为肌酸激酶底物的能力几乎没有影响。没有发现肌酸激酶介导肌酸转运的证据。胍基丁酸作为其饮食的2%或6%持续1个月，该化合物在骨骼肌中累积至14 μ mol/g湿重的浓度，在心脏中累积至4 μ mol/g湿重的浓度。同时，在骨骼肌中，磷酸肌酸消耗到对照值的50%，ATP消耗到对照值的80%。心脏的总肌酸含量（肌酸+磷酸肌酸）从12.8 μ mol/g湿重降低到2.8 μ mol/g湿重。喂食DL-β-胍基丁酸应适用于骨骼肌和心脏中肌酸和磷酸肌酸消耗的长期影响的研究。
A series of creatine analogues was tested for ability to inhibit 14C-creatine accumulation in vivo and for ability to serve as substrates for creatine kinase in vitro. The most potent inhibitors of accumulation were 1-carboxymethyl-2-imino-hexahydropyrimidine, N-methylamidino-N-methylglycine, .beta.-guanidinopropionate and DL-.beta.-guanidinobutyrate. The first 2 compounds are inactive as substrates for creatine kinase, and DL-.beta.-guanidinobutyrate was inactive in the present experiments, producing a Vmax less than 0.01% of that produced by creatine. The latter compound and .beta.-guanidinopropionate were also ineffective as inhibitors of creatine kinase in vitro. The best substrates for creatine kinase were N-ethyl-N-amidinoglycine and guanidinoacetate; these 2 compounds were inefficient as inhibitors of 14C-creatine accumulation. Adding a methyl group to .beta.-guanidinopropionate to form N-methyl-N-amidino-.beta.-alanine eliminated the compound''s ability to inhibit 14C-creatine accumulation but had little effect on its ability to serve as a substrate for creatine kinase. No evidence that creatine kinase mediates creatine transport was found. In feeding trials with rats given DL-.beta.-guanidinobutyric acid as 2 or 6% of their diet for 1 mo, this compound accumulated to concentrations of 14 .mu.mol/g wet weight in skeletal muscle and of 4 .mu.mol/g wet weight in heart. Simultaneously, in skeletal muscle there was a depletion of phosphocreatine to 50%, and of ATP to 80%, of control values. Total creatine content (creatine + phosphocreatine) of the heart decreased from 12.8 to 2.8 .mu.mol/g wet weight. Animals fed DL-.beta.-guanidinobutyric acid should be suitable for studies of the long-term effects of creatine and phosphocreatine depletion in skeletal muscle and heart.