Novel CCK-dependent vasorelaxing dipeptide, Arg-Phe, decreases blood pressure and food intake in rodents

作者：Kagebayashi Tomomi; Kontani Noriyasu; Yamada Yuko; Mizushige Takafumi; Arai Toshinobu; Kino Kuniki; Ohinata Kousaku^*

来源：Molecular Nutrition & Food Research, 2012, 56(9): 1456-1463.

DOI：10.1002/mnfr.201200168

• Blood pressure
• Cholecystokinin
• Dipeptide
• Food intake
• l-amino acid ligase
• Vasorelaxation

Scope We found that a dipeptide, Arg-Phe (RF), had vasorelaxing activity in mesenteric artery isolated from spontaneously hypertensive rats (SHRs) (EC50 = 580 nM). We then investigated its mechanism of action, and elucidated its physiological functions. Methods and results Vasorelaxing activities of RF-related peptides were tested. The retro-sequence dipeptide FR was inactive, suggesting that the RF sequence is important for a potent vasorelaxing effect. RA and AF were also inactive. RF-nh2 had vasorelaxing activity, implying that the C-terminal amidation of RF is tolerated. Nitric oxide (NO) and prostaglandins (PGs) are known to be vasorelaxing factors; however, the vasorelaxing activity of RF was inhibited by neither NG-nitro-l-arginine methyl ester (l-NAME), an NO synthase inhibitor, nor indomethacin, a COX inhibitor. Interestingly, the activity was blocked by lorglumide, an antagonist of the cholecystokinin (CCK)1 receptor; however, RF had no affinity for CCK receptors, suggesting that RF stimulates CCK release. Orally administered RF decreased blood pressure in SHRs, and this antihypertensive activity was also blocked by a CCK1 antagonist. RF had CCK-like suppressive effects on food intake and gastrointestinal transit. RF increased intracellular Ca2+ flux and CCK release in enteroendocrine STC-1 cells. Conclusion A novel CCK-dependent vasorelaxing RF decreases both blood pressure and food intake.

• 出版日期2012-9