Rapakinin, an anti-hypertensive peptide derived from rapeseed protein, dilates mesenteric artery of spontaneously hypertensive rats via the prostaglandin IP receptor followed by CCK sub(1) receptor

The anti-hypertensive peptide Arg-Ile-Tyr, which was isolated based on its inhibitory activity (IC sub(50) = 28 mu M) for angiotensin I-converting enzyme (ACE) from the subtilisin digest of rapeseed protein, exhibited vasorelaxing activity (EC sub(50) = 5.1 mu M) in an endothelium-dependent manner in the mesenteric artery of spontaneously hypertensive rats (SHRs). We named the peptide rapakinin. ACE inhibitors are reported to induce nitric oxide (NO)-dependent vasorelaxation by elevating the endogenous bradykinin level; however, the vasorelaxation induced by 10 mu M of rapakinin was blocked only insignificantly by HOE140 or N super(G)-nitro-l-arginine methyl ester (l-NAME), antagonists of bradykinin B sub(2) receptor and an inhibitor of NO synthase, respectively. On the other hand, the vasorelaxation induced by 10 mu M rapakinin was significantly blocked by indomethacin and CAY10441, a cyclooxygenase (COX) inhibitor and an antagonist of the IP receptor, respectively. The vasorelaxing activity of rapakinin was also blocked by lorglumide, an antagonist of the cholecystokinin (CCK) CCK sub(1) receptor, although rapakinin has no affinity for the IP and CCK sub(1) receptors. The vasorelaxation induced by 10 mu M iloprost, an IP receptor agonist, was also blocked by lorglumide, suggesting that CCK-CCK sub(1) receptor system is activated downstream of the PGI sub(2)-IP receptor system. The anti-hypertensive activity of rapakinin after oral administration in SHRs was also blocked by CAY10441 and lorglumide. These results suggest that the anti-hypertensive activity of rapakinin might be mediated mainly by the PGI sub(2)-IP receptor, followed by CCK-CCK sub(1) receptor-dependent vasorelaxation.