Differential inhibition by TAK-044 of the inotropic effects of endothelin-1 and endothelin-3

The influence of a nonselective antagonist of endothelin receptors, TAK-044 (cyclo-[D-alpha-aspartyl-3-[(4-phenylpiperazin-1-yl)carbonyl]-L-alanyl-L-alpha-aspartyl-D-2-(2-thienyl)glycyl-L-leucyl-D-tryptophyl] disodium), on the positive inotropic effect of endothelin-1 and endothelin-3 was investigated in isolated rabbit myocardium. While TAK-044 produced a concentration-dependent rightward shift of the concentration-response curve for endothelin-1 and endothelin-3, the effect of endothelin-3 was hundred times more sensitive to TAK-044 than that of endothelin-1. The combination of FR139317 ([2-(R)-[2(R)-[2(S)-[[1-(hexahydro-1H-azepinyl)]carbonyl]amino-4-methylpentanoyl]amino-3[3-(1-methyl-1H-indolyl)]propionyl] amino-3-(2-pyridyl)propionic acid]) and BQ-788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methyl-leucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine) mimicked the inhibitory action of TAK-044 on the positive inotropic effect of endothelin-3 but enhanced the effect of endothelin-1. In a receptor-binding assay, TAK-044 was four times more potent in antagonizing the specific binding of endothelin-1 than that of endothelin-3. Endothelin-1 may activate receptor subtypes that trigger both positive and negative inotropic effects, the latter being more susceptible to the antagonistic action of TAK-044, which may explain in part the differential antagonistic action of TAK-044 on the inotropic effect of endothelin-1 and endothelin-3. (C) 2004 Elsevier B.V. All rights reserved.