Bioavailability and metabolism of bioactive peptide IRW with angiotensin-converting enzyme 2 (ACE2) up-regulatory activity in spontaneously hypertensive rats

Peptide IRW is the first food-derived angiotensin-converting enzyme 2 (ACE2) up-regulator. 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 IRW/kg body weight via 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 kynurenine, a tryptophan metabolite, in blood after IRW administration. Kynurenine increased ACE2 in cells. Oral administration of tryptophan (W), but not dipeptide IR, lowered blood pressure and upregulated ACE2 in SHRs. Our study supports the key role of tryptophan and its metabolite, kynurenine, in IRW’s blood pressure-lowering effects.