PSEUDO-NONCOMPETITIVE ANTAGONISM BY BQ123 OF INTRACELLULAR CALCIUM TRANSIENTS MEDIATED BY HUMAN ET(A) ENDOTHELIN RECEPTOR

The family of endothelins, endothelin-1 (ET-1), ET-2 and ET-3, act on two subtypes of receptors called ET(A) and ET(B) receptors. BQ123 is an ET(A)-selective competitive antagonist. In this study, however, BQ123 inhibited ET-1-induced transients of cytosolic Ca2+ concentrations ([Ca2+]i) in an apparently noncompetitive manner in mouse L cell stably expressing cloned human ET(A) receptor. BQ123 (3 - 30 nM) did not change the EC50 of ET-1 (6.6 nM), but reduced the maximum responses down to 15.0 %. In an non-equilibrium binding assay which mimicks the conditions of [Ca2(+)]i transient assay (cells were incubated with [I-125]ET-1 only for 30 s), BQ123 (30 nM) constantly decreased the specific [I-125]ET-1 binding to approximate to 13% of that without the antagonist. Thus, the apparent noncompetitive antagonism by BQ123 of ET(A) receptor-mediated [Ca2+](i) transient is due to the assay condition where the interactions of the agonist, antagonist and receptor remained non-equilibrium state. (C) 1994 Academic Press, Inc.