'Irreversible' endothelin-1 binding does not prohibit ABT-627 from reversing endothelin-1-induced effects

Endothelin-1 (ET-1) is thought to play a role in a wide range of pathologic al conditions. One of the distinct characteristics of ET-1 is its long-last ing vasoconstrictor action, which is presumably caused by the irreversible binding of ET-1 to ET receptors and by the functional effects of internaliz ed ET receptors. ABT-627 is a potent endothelin-A (ETA)-selective antagonis t with a K-i value at 0.034 nM for the human ETA receptor, and is currently being used in clinical studies for prostate cancer. Unlike ET-1, the bindi ng of I-125-labeled ABT-627 to human ETA receptors expressed in Chinese ham ster ovary (CHO) cells is reversible, and the dissociation half-life for th e ligand/receptor complex is 2 h. Interestingly, the binding of both ET-1 a nd ABT-627 to the ETA-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 muM 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 r ats, and after 60 min, ABT-627 essentially normalizes pressure. Our data sh ow that ABT-627 is capable of reversing an established response induced by ET-1 and is useful in reversing pathological conditions involving ET-1.