PHARMACOLOGICAL HETEROGENEITY OF BOTH ENDOTHELIN ET(A)-RECEPTOR AND ET(B)-RECEPTOR IN THE HUMAN SAPHENOUS-VEIN

To study endothelin receptor subtypes that mediate the smooth muscle c ontraction of human saphenous vein, effects of some endothelin-recepto r agonists and antagonists were examined. Endothelin (ET)-1 and sarafo toxin 6b (S6b) elicited potent concentration-dependent contractions wi th similar PD2 values and similar maximal responses. Selective ET(B)-r eceptor agonists, sarafotoxin 6c (S6c) and IRL1620 (Suc-[Glu(9), Ala(1 1,15)]-endothelin-1(8-21)), also caused contractions, but their maxima l responses were about one third of that of ET-1. ET-3 showed a biphas ic concentration-response curve. An ET(A)-receptor antagonist, BQ-123 (cyclo(-D-Asp-L-Pro-D-Val-L-Leu-D-Trp-)) an ET(A)/ET(B)-receptor antag onist, 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 concentr ations of ET-3 and S6b. Contractions induced by lower concentrations o f ET-3 and S6b were resistant to these antagonists. The concentration- response curves for S6c and IRL1620 were not affected by BQ-123. The e ffect of IRL1620 was markedly inhibited by PD142893, while S6c-induced contractions were much more resistant to PD142893. These different se nsitivities to antagonists suggested heterogeneity of both ET(A)- and ET(B)-receptors [ET(Al) (sensitive to BQ-123), ET(A2) (resistant to BQ -123), ET(A2) (sensitive to PD142893) and ET(B2) (resistant to PD14289 3)] in the human saphenous vein, although contractions mediated by ET( B)-subtypes have smaller maximal responses than those mediated by the ET(A)-subtypes.