Abstract：
Peptide IRW is the first food-derived angiotensin-converting enzyme 2 (ACE2) upregulator. This study aimed to investigate the pharmacokinetic characteristics of IRW and identify the metabolites contributing to its antihypertensive activity in spontaneously hypertensive rats (SHRs). Rats were administered 100 mg of IRW/kg of the body weight via an intragastric or intravenous route. The bioavailability (F %) was determined to be 11.7%, and the half-lives were 7.9 ± 0.5 and 28.5 ± 6.8 min for gavage and injection, respectively. Interestingly, significant blood pressure reduction was not observed until 1.5 h post oral administration, or 2 h post injection, indicating that the peptide\'s metabolites are likely responsible for the blood pressure-lowering activity. Time-course metabolomics revealed a significant increase in the level of kynurenine, a tryptophan metabolite, in blood after IRW administration. Kynurenine increased the level of ACE2 in cells. Oral administration of tryptophan (W), but not dipeptide IR, lowered the blood pressure and upregulated aortic ACE2 in SHRs. Our study supports the key role of tryptophan and its metabolite, kynurenine, in IRW\'s blood pressure-lowering effects.
摘要：
肽IRW是第一个食物来源的血管紧张素转换酶2（ACE2）上调剂。本研究旨在研究IRW的药代动力学特征，并确定其在自发性高血压大鼠（SHR）中的代谢产物。通过胃内或静脉内途径给大鼠施用100mgIRW/kg体重。生物利用度（F%）确定为11.7%，灌胃和注射的半衰期分别为7.9±0.5和28.5±6.8分钟，分别。有趣的是,直到口服后1.5h才观察到明显的血压下降，或注射后2小时，这表明该肽的代谢物可能是降低血压的原因。时程代谢组学显示犬尿氨酸水平显着增加，色氨酸代谢产物,在IRW给药后的血液中。犬尿氨酸增加细胞中ACE2的水平。口服色氨酸（W），但不是二肽IR，在SHR中降低血压并上调主动脉ACE2。我们的研究支持色氨酸及其代谢物的关键作用，犬尿氨酸,在IRW的降血压作用中。
