Rapakinin, an anti-hypertensive peptide derived from rapeseed protein, dilates mesenteric artery of spontaneously hypertensive rats via the prostaglandin IP receptor followed by CCK(1) receptor.
The anti-hypertensive peptide Arg-Ile-Tyr, which was isolated based on its inhibitory activity (IC(50)=28microM) for angiotensin I-converting enzyme (ACE) from the subtilisin digest of rapeseed protein, exhibited vasorelaxing activity (EC(50)=5.1microM) 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 10microM of rapakinin was blocked only insignificantly by HOE140 or N(G)-nitro-l-arginine methyl ester (l-NAME), antagonists of bradykinin B(2) receptor and an inhibitor of NO synthase, respectively. On the other hand, the vasorelaxation induced by 10microM 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(1) receptor, although rapakinin has no affinity for the IP and CCK(1) receptors. The vasorelaxation induced by 10microM iloprost, an IP receptor agonist, was also blocked by lorglumide, suggesting that CCK-CCK(1) receptor system is activated downstream of the PGI(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(2)-IP receptor, followed by CCK-CCK(1) receptor-dependent vasorelaxation.
Yamada
Yuko
Y
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan. yyamada@kais.kyoto-u.ac.jp
Iwasaki
Masashi
M
Usui
Hachiro
H
Ohinata
Kousaku
K
Marczak
Ewa D
ED
Lipkowski
Andrzej W
AW
Yoshikawa
Masaaki
M
D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065169:Bradykinin B1 Receptor Antagonists; D029741:Brassica rapa / Q000378:metabolism*; D007022:Hypotension / Q000188:drug therapy / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*; D010940:Plant Proteins / Q000737:chemistry*; D011377:Proglumide / Q000031:analogs & derivatives / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D043783:Receptor, Bradykinin B1 / Q000378:metabolism; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects
C435663:2-(2-(5-bromo-1H-indol-3-yl)ethyl)-3-(1-methylethoxyphenyl)-4-(3H)-quinazolinone; D000959:Antihypertensive Agents; D065169:Bradykinin B1 Receptor Antagonists; D010455:Peptides; D010940:Plant Proteins; D052999:Quinazolinones; D043783:Receptor, Bradykinin B1; D043886:Receptor, Cholecystokinin A; D011982:Receptors, Prostaglandin; C065679:icatibant; D019001:Nitric Oxide Synthase; D011377:Proglumide; C048181:lorglumide; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin