Endothelin (ET) stimulates potent ET_A/ET_B receptors important in the pathogenesis of pulmonary arterial hypertension (PAH) and fibrosis. Though therapy with ET-receptor antagonists is well established uncertainty exists whether selective ET_A or dual ET_A/ET_B-receptor antagonism is superior in PAH. The objective of this study was to further elucidate the pro-inflammatory effects of ET-1 on ET_B receptors in cultured human monocytes (10⁵/20h) compared with non-specific stimulation with LPS in vitro and to define the antagonizing effects of bosentan, a dual ET_A/ET_B-receptor antagonist, on inflammatory mediator production. We further hypothesized that ET_B-receptor antagonism reduces the requirement of PGE₂ to control inflammatory mediator production. Activation of the monocyte ET_B subtype by ET (1ng/ml) concentration-dependently stimulated TNF-⍺ (744%) >PGE₂ (570%) > IL-1β (112%) and had no effect on 5-lipoxygenase metabolism. Compared with ET a different profile of IL-1β >TNF-⍺ >PGE₂ was induced by LPS. ET_B-receptor antagonism attenuated ET- and LPS-responses in monocytes, in particular of TNF-⍺ and PGE₂ to a similar extend (40%) that were only demonstrable following LPS at therapeutic plasma concentrations of bosentan and had no effect on IL-1β. Inhibition of ET_B receptors in LPS-stimulated monocytes by bosentan was responded with suppression of PGE₂ and increased production of leukotrienes indicating strong effects in the cyclooxygenase pathway that is known to control cellular ET transcription.

These data suggest an important signaling pathway between ET-induced cytokine production following ET_B-receptor activation with no further control of ET transcription by PGE₂ required following ET_B receptor antagonism. Therefore, in states of inflammation increased ET_B-receptor expression and activation mediated by elevated ET concentrations may be an underestimated mechanism, which warrants the application of combined ET_A/ET_B-receptor antagonists.