Orally active anti-hypertensive peptides found based on enteroendocrine cell responses to a dipeptide library

Highlights: • Phe-Trp (FW) evoked the strongest enteroendocrine cell response out of 338 dipeptides. • Phe-Trp-Gly-Lys (FWGK) exhibited more potent hypotensive effects than FW in SHRs. • Vasorelaxing and antihypertensive effects of FWGK were associated with the CCK system. We previously reported that an orally administered dipeptide, Arg-Phe (RF), which causes enteroendocrine cell responses, lowered blood pressure in spontaneously hypertensive rats (SHRs). In this study, we found that Phe-Trp (FW), induced the most potent enteroendocrine cell responses out of total 338 dipeptides. An FW analogue, Phe-Trp-Gly-Lys (FWGK), which was effectively produced by tryptic digestion of bovine serum albumin, decreased blood pressure after oral administration. The minimum effective dose of FWGK (50 μg/kg) was 1/300 of that of RF (15 mg/kg). FWGK stimulated cholecystokinin (CCK) secretion in the enteroendocrine cells and exhibited vasorelaxing and antihypertensive effects via the CCK₁ system.