INVITRO BIOLOGICAL PROFILE OF A HIGHLY POTENT NOVEL ENDOTHELIN (ET) ANTAGONIST BQ-123 SELECTIVE FOR THE ET(A) RECEPTOR

The novel endothelin (ET) receptor antagonists BE-18257A and BE-18257B were isolated from the fermentation products of Streptomyces misakiensis. The above-mentioned compounds inhibited [I-125]ET-1 binding to ET(A) receptors (selective for ET-1) on porcine aortic vascular smooth muscle cells (VSMCs) with IC50 values of 1.4 and 0.47 muM, respectively. [I-125]ET-1 binding to ET(B) receptors (nonselective to ET isopeptides) in cerebellar membranes was not inhibited by either of these compounds even at 100 muM. The synthesized analogue BQ-123 induced extremely potent inhibition of [I-125]ET-1 binding to ET(A) receptors (IC50 of 7.3 nM), but it barely inhibited [I-125]ET-1 binding to ET(B) receptors (IC50 of 18 muM) and binding of various other peptides to their receptors. BQ-123 shifted the concentration-response curve for ET-1 toward the right in porcine isolated coronary arteries, indicative of competitive antagonism for the ET(A) receptor. However, there was a small amount of BQ-123-insensitive vasocontraction that paralleled the incomplete inhibition of [I-125]ET-1 binding in the membrane of the vascular smooth muscle layer. These data suggest that the artery contracts via both ET(A) and ET(B) receptors and that BQ-123 selectively inhibits ET(A)-mediated contraction. Furthermore, BQ-123 revealed large tissue and species differences in the distribution of ET(A) receptors. Thus, the potent ET(A) antagonist BQ-123 should be useful in clarifying the (patho)physiological roles of ET(A) receptors.