Endothelin pharmacology in the setting of pulmonary hypertension

Project Details

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Endothelin-1 (ET-1) is an endogenous autacoid that contracts blood vessels and is considered a major target in the treatment of pulmonary hypertension. ET-1 has 2 specific receptors – ETA located on smooth muscle cells in many blood vessels to cause contraction; ETB located on endothelial cells to mediate the release of the potent vasodilator nitric oxide (NO); and ETB located on some artery smooth muscle cells to mediate contraction. There is also a protective mechanism in pulmonary arteries mediated by ETB receptors to bind ET-1 and remove this potent autacoid from the circulation. Our work explores this dynamic relationship between antagonism of ETA constrictor receptors, ETB constrictor actions and the site of loss of ET-1. Theoretically then, an antagonist of ETA receptors may have little direct effect on the pulmonary artery; however, ETB receptor antagonists could potentiate the ETA antagonist through block of the removal of ET-1, thus potentiating its action. Our work explores specifically what is the functionally appropriate mix of ETA and ETB receptor antagonism profile in a drug for pulmonary hypertension. Work to date suggests that ETA selective/specific ET-1 antagonists registered today are not appropriate for treating pulmonary hypertension. On the contrary, ETA/ETB dual antagonists, when modelled, show remarkable antagonism. This hypothesis requires testing in animal models of pulmonary hypertension and focuses the attention on careful analytical pharmacology of unique vascular beds where ETB receptor-sensitive ET-1 clearance mechanisms are protective of vasoconstriction, but where ETB receptors predominate in the vasoconstriction. This project has the potential to rewrite the 20 year old therapy of ET-1 receptor antagonism in pulmonary hypertension.

Researchers

Associate Professor Christine E. Wright, BSc Hons, PhD, Laboratory Head,

Mr Mark Ross-Smith, BSc Hons, Senior Research Assistant

Ms Linda Cornthwaite-Duncan, Technical Officer

Research Publications

  • Angus JA, Soeding PF, Hughes RJA, Wright CE. Functional estimation of endothelin-1 receptor antagonism by bosentan, macitentan and ambrisentan in human pulmonary and radial arteries in vitro. Eur J Pharmacol 2017, 804: 111-116.

Research Group

Wright laboratory: Cardiovascular Therapeutics Unit


School Research Themes

Cardio-Respiratory, Therapeutics & Translation



Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Pharmacology and Therapeutics Research

Unit / Centre

Wright laboratory: Cardiovascular Therapeutics Unit