His-Arg-Trp potently attenuates contracted tension of thoracic aorta of Sprague-Dawley rats through the suppression of extracellular Ca2+ influx.
In the present study, we primarily attempted to identify di- and tri-peptides showing potent vasodilation in 1.0 microM 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 microM angiotensin II or 50 microM Bay K8644)-stimulated vascular smooth muscle cells, vasoactive HRW (100 microM) caused significant [Ca(2+)](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.
Tanaka
Mitsuru
M
Faculty of Agriculture, Graduate School of Kyushu University, Fukuoka, 812-8581, Japan. mitsurut@agr.kyushu-u.ac.jp
Watanabe
Shimpei
S
Wang
Zhengquan
Z
Matsumoto
Kiyoshi
K
Matsui
Toshiro
T
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects
D020746:Calcium Channels, L-Type; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009842:Oligopeptides; C029899:imidazole; D002118:Calcium