In Vitro Biological Profile of a Highly Potent Novel Endothelin (ET) Antagonist BQ-123 Selective for the ETA 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]ET-1 binding to ETA receptors (selective for ET-1) on porcine aortic vascular smooth muscle cells (VSMCs) with I...

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Veröffentlicht in:Journal of cardiovascular pharmacology 1992-04, Vol.20 Suppl 12, p.S11-S14
Hauptverfasser: Ihara, Masaki, Ishikawa, Kiyofumi, Fukuroda, Takahiro, Saeki, Toshihiko, Funabashi, Kaoru, Fukami, Takehiro, Suda, Hiroyuki, Yano, Mitsuo
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Sprache:eng
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Zusammenfassung: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]ET-1 binding to ETA receptors (selective for ET-1) on porcine aortic vascular smooth muscle cells (VSMCs) with IC50 values of 1.4 and 0.47 μM, respectively. [I]ET-1 binding to ETB receptors (nonselective to ET isopeptides) in cerebellar membranes was not inhibited by either of these compounds even at 100 μM. The synthesized analogue BQ-123 induced extremely potent inhibition of [I]ET-1 binding to ETA receptors (IC50 of 7.3 nM), but it barely inhibited [I]ET-1 binding to ETB receptors (IC50 of 18 μM) 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 ETA receptor. However, there was a small amount of BQ-123-insensitive vasocontraction that paralleled the incomplete inhibition of [I]ET-1 binding in the membrane of the vascular smooth muscle layer. These data suggest that the artery contracts via both ETA and ETB receptors and that BQ-123 selectively inhibits ETA-mediated contraction. Furthermore, BQ-123 revealed large tissue and species differences in the distribution of ETA receptors. Thus, the potent ETA antagonist BQ-123 should be useful in clarifying the (patho)physiological roles of ETA receptors.
ISSN:0160-2446
1533-4023
DOI:10.1097/00005344-199204002-00005