Significance of vascular dipeptidyl peptidase-4 inhibition on vascular protection in Zucker diabetic fatty rats.
Significance of vascular dipeptidyl peptidase-4 inhibition on vascular protection in Zucker diabetic fatty rats.
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DOI：
10.1254/jphs.14052fp
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发表时间：
2014-08
影响因子：
3.5
通讯作者：
S. Takai;H. Sakonjo;D. Jin
中科院分区：
文献类型：
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作者：
S. Takai;H. Sakonjo;D. Jin
为了阐明二肽基肽酶-4(DPP-4)抑制在血管组织中的作用，我们比较了组织穿透性差的DPP-4抑制剂Sitagliptin和组织穿透性高的DPP-4抑制剂linagliptin对Zucker糖尿病脂肪(ZDF)大鼠的影响。6周龄ZDF大鼠分别给予安慰剂、西格列汀(10 mg/kg)或利格列汀(3 mg/kg)灌胃4周。西格列汀和利那格列汀在第一次和最后一次治疗后的口服葡萄糖耐量试验中，血糖浓度下降和血浆胰岛素浓度上升。在分离的动脉中，西格列汀和利那格列汀显著增强乙酰胆碱引起的血管松弛，其中利格列汀的松弛作用明显强于西格列汀。血管DPP-4活性被这些药物减弱，其中利那格列汀的抑制作用明显大于西格列汀。与西格列汀相比，服用利格列汀的患者血管丙二醛水平显著降低。与西格列汀相比，linagliptin对血管内皮细胞p22(Phox)和单核细胞趋化蛋白-1基因表达的抑制作用也显著增强。结论：与西格列汀相比，利格列汀对血管的保护作用优于西格列汀，这与其对循环血糖和胰岛素水平的调节无关，而利格列汀对血管DPP-4的抑制作用可能是其血管保护机制之一。
To clarify the role of dipeptidyl peptidase-4 (DPP-4) inhibition in vascular tissues, we compared the effects of the poorly tissue-penetrative DPP-4 inhibitor sitagliptin to the highly tissue-penetrative DPP-4 inhibitor linagliptin in Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats were orally treated with placebo, sitagliptin (10 mg/kg), or linagliptin (3 mg/kg) for 4 weeks. Sitagliptin and linagliptin produced equivalent decreases in blood glucose concentrations and increased plasma insulin concentrations during oral glucose tolerance tests after the first and the last treatments. In isolated arteries, acetylcholine-induced vascular relaxation was significantly augmented by sitagliptin and linagliptin, with significantly stronger relaxation observed with linagliptin compared to sitagliptin. Vascular DPP-4 activity was attenuated by these drugs, with linagliptin producing significant greater attenuation than sitagliptin. Vascular malondialdehide levels were significantly lower with linagliptin compared to sitagliptin. Significantly greater attenuation of vascular gene expressions of p22(phox) and monocyte chemoattractant protein-1 by linagliptin, compared with sitagliptin, was also observed. In conclusion, the superior vascular protection by linagliptin compared with sitagliptin was unrelated to the regulation of circulating glucose and insulin levels, and the stronger vascular DPP-4 inhibition by linagliptin may contribute to the mechanism of vascular protection.