Pharmacological heterogeneity of both endothelin ETA- and ETB-receptors in the human saphenous vein.
To study endothelin receptor subtypes that mediate the smooth muscle contraction of human saphenous vein, effects of some endothelin-receptor agonists and antagonists were examined. Endothelin (ET)-1 and sarafotoxin 6b (S6b) elicited potent concentration-dependent contractions with similar pD2 values and similar maximal responses. Selective ETB-receptor agonists, sarafotoxin 6c (S6c) and IRL1620 (Suc-[Glu9,Ala11,15]-endothelin-1(8-21)), also caused contractions, but their maximal responses were about one third of that of ET-1. ET-3 showed a biphasic concentration-response curve. An ETA-receptor antagonist, BQ-123 (cyclo(-D-Asp-L-Pro-D-Val-L-Leu-D-Trp-)), an ETA/ETB-receptor antagonist, PD142893 (Ac-D-Dip-Leu-Asp-Ile-Ile-Trp), or the combination of these two antagonists hardly affected the contractile effect of ET-1, while each of them markedly antagonized the effects of higher concentrations of ET-3 and S6b. Contractions induced by lower concentrations of ET-3 and S6b were resistant to these antagonists. The concentration-response curves for S6c and IRL1620 were not affected by BQ-123. The effect of IRL1620 was markedly inhibited by PD142893, while S6c-induced contractions were much more resistant to PD142893. These different sensitivities to antagonists suggested heterogeneity of both ETA- and ETB-receptors [ETA1 (sensitive to BQ-123), ETA2 (resistant to BQ-123), ETB1 (sensitive to PD142893) and ETB2 (resistant to PD142893)] in the human saphenous vein, although contractions mediated by ETB-subtypes have smaller maximal responses than those mediated by the ETA-subtypes.
Nishiyama
M
M
Division of Cardiovascular Biology, Center for Biomedical Science, Chiba University School of Medicine, Japan.
Takahara
Y
Y
Masaki
T
T
Nakajima
N
N
Kimura
S
S
D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000187:drug effects*; D012501:Saphenous Vein / Q000187:drug effects*
D016232:Endothelins; D010446:Peptide Fragments; D017466:Receptors, Endothelin; C074308:sovateltide