Pharmacological characterization of cardiovascular responses induced by endothelin-1 in the perfused rat heart

Abstract

The effects of the endothelin receptor antagonist TAK-044 ( cyclo[ d-α-aspartyl-3-[(4-phenylpiperazin-1-yl)carbonyl]- l-alanyl- l-α-aspartyl- d-2-(2-thienyl)glycyl- l-leucyl- d-tryptop ( cyclo[ d-Asp-Pro- d-Val-Leu- d-Trp]) were studied in the rat heart to characterize the receptor subtypes responsible for the cardiovascular actions of endothelin-1. Endothelin-1 induced a transient decrease and subsequent increase in perfusion pressure in perfused rat hearts, and increased left ventricular developed pressure. TAK-044 diminished these endothelin-1-induced responses (100 pmol/heart) with IC 50 values of 140, 57 and 1.3 nM, respectively. BQ-123 (1–30 μM) partially inhibited the endothelin-1-induced hypertension (30–40%) in the rat heart, and failed to inhibit the hypotension. The positive inotropic effect of endothelin-1 was abolished by BQ-123. Neither indomethacin (10 μM) nor N ω-nitro- l-arginine methyl ester (100 μM) attenuated the endothelin-1-induced hypotension. TAK-044 and BQ-123 attenuated the positive inotropic effect of endothelin-1 in rat papillary muscles. In rat cardiac membrane fractions, TAK-044 and BQ-123 inhibited [ 125I]endothelin-1 binding to endothelin ET A receptors with IC 50 values of 0.39 ± 0.6 and 36 ± 9 nM, respectively, whereas only TAK-044 potently blocked the endothelin ET B receptor subtype (IC 50 value: 370 ± 180 nM). These results suggest that endothelin-1 modulates cardiovascular functions in the rat heart by activating both endothelin ET A and endothelin ET B receptors, all of which are sensitive to TAK-044.