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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >Noncompetitive inhibition of glycylsarcosine transport by quinapril in rabbit renal brush border membrane vesicles: effect on high-affinity peptide transporter.
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Noncompetitive inhibition of glycylsarcosine transport by quinapril in rabbit renal brush border membrane vesicles: effect on high-affinity peptide transporter.

机译:奎那普利在兔肾刷状缘膜囊泡中非竞争性抑制奎尼普利转运糖基肌氨酸:对高亲和力肽转运蛋白的影响。

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摘要

Angiotensin converting enzyme (ACE) inhibitors are important therapeutic agents for treating patients with hypertension and cardiovascular diseases. Although most ACE inhibitors are cleared by the kidney via glomerular filtration and tubular secretion, little is known about their reabsorption potential. In particular, it is believed that while certain ACE inhibitors are transported by the intestinal peptide transporter (PepT1), these same compounds do not interact with the renal peptide transporter (PepT2). In the present study, we examined the interaction of quinapril with the high-affinity peptide transporter, PepT2. Studies were performed in rabbit renal brush border membrane vesicles in which the uptake of [14C]glycylsarcosine (GlySar), at low substrate concentrations, was examined in the absence and presence of quinapril (and other ACE inhibitors). We found that quinapril was capable of cis-inhibiting the uptake of GlySar and in a concentration-dependent manner. While the Ki for quinapril ( approximately 1 mM) was several-fold higher than the Km for GlySar ( approximately 160 microM), the interaction was unique in that inhibition of PepT2 was of a noncompetitive type. Overall, the data suggest that quinapril is a low-affinity inhibitor of the renal peptide transporter and that it binds to a site distinct from that of the GlySar binding site.
机译:血管紧张素转换酶(ACE)抑制剂是治疗高血压和心血管疾病患者的重要治疗剂。尽管大多数ACEI抑制剂可通过肾小球滤过和肾小管分泌物被肾脏清除,但对其重吸收潜力了解甚少。特别地,据信尽管某些ACE抑制剂通过肠肽转运蛋白(PepT1)转运,但这些相同的化合物不会与肾肽转运蛋白(PepT2)相互作用。在本研究中,我们研究了奎那普利与高亲和力肽转运蛋白PepT2的相互作用。在兔肾刷缘膜囊泡中进行了研究,其中在不存在和存在喹诺普利(和其他ACE抑制剂)的情况下,检查了低底物浓度下[14C]甘氨酰肌氨酸(GlySar)的摄取。我们发现奎那普利能够以顺应性的方式抑制GlySar的摄取,并且呈浓度依赖性。尽管奎纳普利的Ki(约1 mM)比GlySar的Km(约160 microM)高出几倍,但相互作用的独特之处在于对PepT2的抑制是非竞争性的。总体而言,数据表明奎纳普利是肾肽转运蛋白的低亲和力抑制剂,并且它与不同于GlySar结合位点的位点结合。

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