Endothelin-1-induced potentiation of adrenergic responses in the rabbit pulmonary artery: role of thromboxane A(2)

To examine whether low concentrations of endothelin-1 potentiate the vasoco ntrictor response to adrenergic stimulation, we recorded the isometric resp onse of rings of rabbit pulmonary artery to electrical stimulation and nora drenaline. Endothelin-1 (10(-10) M) potentiated the contractions induced by electrical stimulation and noradrenaline. The endothelin ETB receptor anta gonist (2,6-dimethylpiperidinecarbonyl-gamma -methyl-Leu-N-in-[Methoxycarbo nyl]-D-Trp-D-Nle) (BQ-788, 10(-6) M), but not the endothelin ETA receptor antagonist cyclo(D-Asp-Pro-D-Val-Leu-D-TRP) (BQ-123, 10(-6) M), inhibited t he potentiating effects of endothelin-1. Pretreatment with the cyclooxygena se inhibitor indomethacin, the thromboxane synthase inhibitor furegrelate a nd the thromboxane receptor antagonist [1S-[1 alpha ,2 alpha (Z),3 alpha ,4 alpha]]-7-[3-[[[[(1-oxoheptyl)amino]acetyl]amino] methyl]-7-oxabicyclo-[2. 2.1]hept-2-yl]-5-heptenoic acid (SQ-30741) (all at 10(-5) M) prevented the potentiation induced by endothelin-1 on adrenergic stimulation. The Ca2+ ch annel antagonist nifedipine (10(-6) M) did not affect the potentiation indu ced by endothelin-1. The results indicate that endothelin-1 potentiates the responses to electrical stimulation and noradrenaline by activating endoth elin ETB receptors. This potentiation depends on the production of cyclooxy genase-generated factors, probably thromboxane A(2). (C) 2001 Elsevier Scie nce B.V. All rights reserved.