Journal
PEPTIDES
Volume 30, Issue 8, Pages 1502-1507Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.peptides.2009.05.012
Keywords
Tri-peptide; Vasodilation; Rat aorta; Hypertension; L-type Ca2+ channel
Funding
- JSPS
- Ministry of Education, Science, Sports and Culture of Japan [19208012]
- Grants-in-Aid for Scientific Research [19208012] Funding Source: KAKEN
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In the present study, we primarily attempted to identify di- and tri-peptides showing potent vasodilation in 1.0 mu M phenylephrine-contracted thoracic aortas of Sprague-Dawley rats. Synthetic 15 Trp-His (WH) skeleton analogues were used for rat aorta ring's force measurements, since WH was found to be a vasoactive di-peptide so far. Among the synthesized peptides consisted of both His and Trp amino acid residues, His-Arg-Trp (HRW) was found to evoke the most potent vasodilation with an EC50 value of 1.2 +/- 0.08 mM in an endothelium-independent manner, while no effect was evoked by a mixture of individual amino acids. In addition to the structure of tri-peptides-activity relationship, chemically modified HRW analogues, i.e., 1- or 3-methyl-His-Arg-Trp and His-citrulline-Trp demonstrated the structural importance of tri-peptide to evoke the vasoactivity as following factors: (1) Neutral imidazole and indole groups from His and Trp residues at N- and C-terminals, respectively and (2) basic amino acids at the middle position. In mitogen (10 mu M angiotensin II or 50 mu M Bay K8644)-stimulated vascular smooth muscle cells, vasoactive HRW (100 mu M) caused significant [Ca2+](i) reduction to an extent of >30%. Thus, our results suggest that HRW caused vasodilation action via an endothelium-independent mechanism which probably involves the suppression of extracellular Ca2+ influx through voltage-gated L-type Ca2+ channel. (C) 2009 Elsevier Inc. All rights reserved.
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