title: 'Irreversible' endothelin-1 binding does not prohibit ABT-627 from reversing endothelin-1-induced effects.
abstract: Endothelin-1 (ET-1) is thought to play a role in a wide range of pathological conditions. One of the distinct characteristics of ET-1 is its long-lasting vasoconstrictor action, which is presumably caused by the irreversible binding of ET-1 to ET receptors and by the functional effects of internalized ET receptors. ABT-627 is a potent endothelin-A (ET(A))-selective antagonist with a Ki value at 0.034 nM for the human ET(A) receptor, and is currently being used in clinical studies for prostate cancer. Unlike ET-1, the binding of 125I-labeled ABT-627 to human ET(A) receptors expressed in Chinese hamster ovary (CHO) cells is reversible, and the dissociation half-life for the ligand/receptor complex is 2 h. Interestingly, the binding of both ET-1 and ABT-627 to the ET(A)-receptor results in partial receptor internalization but only ET-1 is capable of triggering intracellular functional responses. Although ABT-627 binding to membranes is more reversible than ET-1 binding, ABT-627 is able to reverse an ET-1-induced contraction in rat aortic rings in a dose-dependent manner, and at 1 microM produces nearly complete reversal of the constrictor effects of 10 nM ET-1 within 60 min. Similarly, in vivo studies show that ABT-627 (0.01 and 0.1 mg/kg/min i.v.) reverses the ET-1-induced increase in arterial pressure in anesthetized, ganglionic-blocked rats, and after 60 min, ABT-627 essentially normalizes pressure. Our data show that ABT-627 is capable of reversing an established response induced by ET-1 and is useful in reversing pathological conditions involving ET-1.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Chiou
authors.forename: J L
authors.initials: JL
authors.lastname: Wessale
authors.forename: T
authors.initials: T
authors.lastname: von Geldern
authors.forename: T J
authors.initials: TJ
authors.lastname: Opgenorth
authors.forename: J R
authors.initials: JR
authors.lastname: Wu-Wong
mesh_terms: D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D000077868:Atrasentan