Endothelin pharmacology in the setting of pulmonary hypertension

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 – ET_A located on smooth muscle cells in many blood vessels to cause contraction; ET_B located on endothelial cells to mediate the release of the potent vasodilator nitric oxide (NO); and ET_B located on some artery smooth muscle cells to mediate contraction. There is also a protective mechanism in pulmonary arteries mediated by ET_B receptors to bind ET-1 and remove this potent autacoid from the circulation. Our work explores this dynamic relationship between antagonism of ET_A constrictor receptors, ET_B constrictor actions and the site of loss of ET-1. Theoretically then, an antagonist of ET_A receptors may have little direct effect on the pulmonary artery; however, ET_B receptor antagonists could potentiate the ET_A antagonist through block of the removal of ET-1, thus potentiating its action. Our work explores specifically what is the functionally appropriate mix of ET_A and ET_B receptor antagonism profile in a drug for pulmonary hypertension. Work to date suggests that ET_A selective/specific ET-1 antagonists registered today are not appropriate for treating pulmonary hypertension. On the contrary, ET_A/ET_B 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 ET_B receptor-sensitive ET-1 clearance mechanisms are protective of vasoconstriction, but where ET_B 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.