Pea-derived tripeptide LRW fails to reduce blood pressure in spontaneously hypertensive rats due to its low gastrointestinal stability and transepithelial permeability

Leu-Arg-Trp (LRW), a pea-derived tripeptide, is an isomer of Ile-Arg-Trp (IRW), an egg-derived tripeptide possessing various health benefits including antihypertensive activity. Since LRW and IRW are structural analogs, we hypothesized that LRW can significantly reduce blood pressure in spontaneously hypertensive rats. LRW showed a more potent in vitro ACE-inhibitory activity (IC₅₀ value of 0.45 ± 0.06 μM) than that of IRW (1.65 ± 0.14 μM); molecular docking results also verified that LRW could form a more stable complex with ACE than that of IRW. In addition, LRW could inhibit tumor necrosis factor alpha-induced endothelial inflammation in similar manners to IRW. However, oral administration of LRW at a dose of 15 mg/kg/day body weight over 12 days did not cause any blood pressure reduction (p > 0.05). Subsequent tissue analyses revealed no changes in the vascular renin-angiotensin system components and vascular inflammation, which are the primary targets of IRW, indicating that LRW might not be able to reach the blood circulation and exert in vivo efficacies. Furthermore, LRW demonstrated significantly lower gastrointestinal stability (p < 0.001) and lower permeability (p < 0.001) across human Caco-2 cell monolayers than those of IRW. These findings indicated the low oral bioavailability of LRW which might underlie its failure in reducing blood pressure in vivo.