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

Abstract

To examine whether low concentrations of endothelin-1 potentiate the vasocontrictor response to adrenergic stimulation, we recorded the isometric response of rings of rabbit pulmonary artery to electrical stimulation and noradrenaline. Endothelin-1 (10 −10 M) potentiated the contractions induced by electrical stimulation and noradrenaline. The endothelin ET B receptor antagonist (2,6-dimethylpiperidinecarbonyl-γ-methyl-Leu- N in-[Methoxycarbonyl]- d-Trp- d-Nle) (BQ-788, 10 −6 M), but not the endothelin ET A receptor antagonist cyclo( d-Asp-Pro- d-Val-Leu- d-TRP) (BQ-123, 10 −6 M), inhibited the potentiating effects of endothelin-1. Pretreatment with the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor furegrelate and the thromboxane receptor antagonist [1 S-[1α,2α( Z),3α,4α]]-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 Ca 2+ channel antagonist nifedipine (10 −6 M) did not affect the potentiation induced by endothelin-1. The results indicate that endothelin-1 potentiates the responses to electrical stimulation and noradrenaline by activating endothelin ET B receptors. This potentiation depends on the production of cyclooxygenase-generated factors, probably thromboxane A 2.