Acceleration of intinul hyperplasia by the enhanced arginase activity due to hyperglycemia

四氧嘧啶引起的高血糖加速了兔颈动脉内皮剥脱后的内膜增生。内膜增生加速与(1)内源性NOS抑制剂代谢酶二甲基精氨酸二甲氨基水解酶（DDAH）活性降低有关；(2)再生内皮细胞内源性NOS抑制剂蓄积加速有关；(3)精氨酸酶活性增强；(4)醛糖还原酶活性加速有关。由于l -精氨酸是精氨酸酶和NOS的共同底物，精氨酸酶活性的大幅增加可能导致NO产量下降，尽管NOS活性本身有所增加。此外，内源性NOS抑制剂的积累和l -精氨酸含量的降低可能与NO生成减少有关。同时，增强的醛糖还原酶对NADPH的加速消耗似乎导致了NO的生成受损，因为NADPA是醛糖还原酶和NOS的共同共同作用。NO的产生与内膜增生的大小呈负相关，即随着NO的产生减少，内膜增生的大小越大。此外，随着再生内皮细胞内源性抑制剂浓度的增加，内部增生的程度变得更大，这可能是由DDAH活性降低引起的。N^G羟基- l -精氨酸（NOHA）作为l -精氨酸生成NO的中间体，其对精氨酸酶的抑制作用呈浓度依赖性，IC_<50>值为2.1±0.1 mM，提示NOHA的减少可能导致精氨酸酶活性的增加，从而进一步降低NO的生成。高血糖引起的阿米氨酸脱羧酶（ODC）和阿米氨酸氨基化酶（OAT）活性的增加分别导致腐胺和脯氨酸的产生增加。前者是众所周知的有效的有丝分裂原，后者是胶原蛋白生产的材料。这些变化可能与高血糖状态下内皮剥落后内膜增生加速密切相关。少

Intimal hyperplasia, which is induced following endothelial denudation of the rabbit carotid artery, was accelerated by hyperglycemia caused by alloxan. The accelerated intimal hyperplasia was associated with (1)the decreased activity of dimethylarginine dimethylaminohydrolase (DDAH), which is a metabolizing enzyme of the endogenous NOS inhibitors, (2)accelerated accumulation of endogenous NOS inhibitors in regenerated endothelial cells, (3)enhanced arginase activity and (4)accelerated activity of aldose reductase. Since L-arginine is a common substrate for arginase and NOS, the greatly increased arginase activity may lead to the decreased NO production although NOS activity itself was increased. Furthermore, accumulation of endogenous NOS inhibitors and decreased L-arginine content possibly relate to the decreased NO production. Meanwhile, accelerated consumption of NADPH by the enhanced aldose reductase appeared to result in the impaired NO generation, since NADPA is a common cofacto … More r for aldose reductase and NOS. There was a negative correlationshp between NO production and magnitude of intimal hyperplasia, that is, the magnitude of intimal hyperplasia became greater as NO production was decreased. In addition, the magnitude of internal hyperplasia became greater as concentrations of endogenous inhibitors were increased in regenerated endothelial cells, which had probably been brought about by the decreased DDAH activity. N^G hydroxy-L-arginine (NOHA) as an intermediate of NO production from L-arginine inhibited arginase in a concentration-dependent manner with IC_<50> value of 2.1±0.1 mM, suggesting that the decreased NOHA due to decreased NO production probably brings about the increased arginase activity and further decrease in NO production. The increased activities of omithine decarboxylase (ODC) and omithine amonitrasferase (OAT) due to hyperglycemia resulted in the increased production of putrescine and proline, respectively. The former is well known as a potent mitogen and the latter as a material of collagen production. All these changes may closely relate to acceleration of intimal hyperplasia following endothelial denudation under the hyperglycemia. Less