Jpn. J. Pharmacol. 69, 391-398 (1995)

Pharmacological Heterogeneity of Both Endothelin ETA- and ETB-Receptors in the Human Saphenous Vein

Mariko Nishiyama (1), Yoshiharu Takahara (2), Tomoh Masaki (3), Nobuyuki Nakajima (2) and Sadao Kimura (1)

(1) Division of Cardiovascular Biology, Center for Biomedical Science, Chiba University School of Medicine, Chiba 260, Japan
(2) The First Department of Surgery, Chiba University School of Medicine, Chiba 260, Japan
(3) Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto 606, Japan

Abstract: 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.

Keywords: Endothelin, Sarafotoxin, Saphenous vein (human), Endothelin receptor, Endothelin receptor antagonist

Copyright© The Japanese Pharmacological Society 1995

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