Endothelin 1 (ET-1) is a potent vasoconstrictor peptide produced by vascular endothelial cells. There are at least four types known, ETA, ETB (ETB1, ETB2) and ETC. Endothelins are synthesized in several tissues, including the vascular endothelium (ET-1 exclusively) and smooth muscle cells. Released endothelin binds to the endothelin receptors ETA and ETB, the ETA receptors on vascular smooth muscle cells mediating vasoconstriction, and the ETB receptors on the endothelium linked to nitric oxide (NO) and prostacyclin release.

The potent vasoconstrictive effects of ET1 are mediated via ETA and ETB (expressed on smooth muscle cells) receptors. Meanwhile, its mild vasodilatory effects are mediated by the activation of ETB (expressed on endothelial cells) receptors, which results in the release of the vasodilators (nitric oxide and prostacyclin) that inhibit proliferation and prevent apoptosis. Besides, ET-1 is pro-inflammatory and may promote fibrosis, cell proliferation, and remodeling, effects that are mediated via one or both of its receptors.

Bosentan is an orally active, competitive and dual endothelin-1 (ET) receptor antagonist that binds the ETA and ETB receptors.

Bosentan competitively and specifically antagonizes binding of ¹²⁵I-labelled ET-1 to ETA receptors on human smooth muscle cells (SMC) and ETB receptors on human placenta cells. Importantly, Bosentan has the potential for pulmonary arterial hypertension (PAH) research.

In addition, the pharmacokinetics of bosentan are dose- and time-dependent; clearance and volume of distribution decrease with increasing intravenous doses. Moreover, Bosentan is metabolized by cytochrome P450 (CYP) 2C9 and CYP3A4 into three metabolites, Ro 48-5033 (major metabolite), Ro 47-8634, and Ro 64-1056. Furthermore, Bosentan reverses the pro-fibrotic phenotype of systemic sclerosis (SSc) fibroblasts and prevents the development of dermal fibrosis in bleomycin-treated mice by blocking this signaling pathway. Specifically, Bosentan reduces the expression of c-Abl and PKC-δ, the nuclear localization of PKC-δ, and Fli1 phosphorylation in SSc fibroblasts.

To sum up, Bosentan is an orally active dual ETA and ETB receptors antagonist, has the potential for PAH research.

References:

[1] Sohita Dhillon, et al. Am J Cardiovasc Drugs. 2009;9(5):331-50.

[2] Marc Iglarz, et al. Life Sci. 2014 Nov 24;118(2):333-9.

[3] Kaname Akamata, et al. Arthritis Res Ther. 2014 Apr 3;16(2):R86.