Research Paper Volume 11, Issue 21 pp 9492—9499

Ser-Tyr and Asn-Ala, vasorelaxing dipeptides found by comprehensive screening, reduce blood pressure via different age-dependent mechanisms

Daiki Koyama 1, , Xinghui Sun 1, , Masaki Sasai 1, , Shigenobu Matsumura 1, , Kazuo Inoue 1, , Kousaku Ohinata 1, ,

  • 1 Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan

received: May 16, 2019 ; accepted: October 26, 2019 ; published: November 4, 2019 ;

https://doi.org/10.18632/aging.102400
How to Cite

Copyright © 2019 Koyama et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

To understand the changes in physiological responses due to aging, a number of bioactive probes based on different signal transduction pathways are necessary. In this study, we comprehensively and systematically investigated changes in blood vessel function with age using a 336-dipeptide library. In the early stage of hypertension, the most potent vasorelaxant dipeptide was Ser-Tyr (SY) in the mesenteric artery isolated from spontaneously hypertensive rats (SHR). SY-induced vasorelaxation and anti-hypertensive effects were blocked by L-NAME, an inhibitor of nitric oxide synthase (NOS), suggesting that SY activates the NO system. On the other hand, the patterns of dipeptides with vasorelaxation activity in early and advanced stages of hypertension were different. In the advanced stage, the most potent vasorelaxing dipeptide was Asn-Ala (NA). Orally administered NA (1.5 mg/kg) reduced the blood pressure in the advanced stage, at which drugs were sometimes less effective, and the anti-hypertensive effects lasted for 6 hr. The NA-induced vasorelaxation and anti-hypertensive activity was blocked by lorglumide, an antagonist of the cholecystokinin CCK1 receptor, suggesting that NA activated the CCK system. Taken together, in the early and advanced stages of hypertension, SY and NA exhibited vasorelaxing and anti-hypertensive effects via the NO and CCK systems, respectively.

Abbreviations

CCK: cholecystokinin; eNOS: endothelial nitric oxide synthase; L-NAME: N(ω)-nitro-L-arginine methyl ester; NA: Asn-Ala; NO: nitric oxide; ODQ: soluble guanylate cyclase inhibitor; SBP: systolic blood pressure; SHR: spontaneously hypertensive rats; SY: Ser-Tyr.