Endothelin receptors as drug targets in chronic cardiovascular diseases: the rationale for dual antagonism

Abstract

Endothelin has been described as the most potent vasoconstrictor known. Recent research shows that it is also a growth factor, a promoter of fibrosis and inflammation, and a key initiator of endothelial dysfunction. Endothelin becomes, therefore, a candidate in the pathogenesis of many chronic cardiovascular and fibrotic diseases, and inhibition of endothelin function is a potential therapeutic approach for those diseases. Endothelin receptor antagonists are now established therapy in the treatment of pulmonary arterial hypertension, and present promising perspectives in diabetic nephropathy, peripheral arterial disease, hypertension, heart failure, and pulmonary diseases. Endothelin binds to two endothelin receptors, ET A and ET B , and their respective roles are actively debated. A major challenge lies in the understanding of what is the preferred profile for new drugs: selective ET A antagonism or dual ET A and ET B receptor antagonism. A number of cardiovascular diseases are characterized by an up-regulation of smooth muscle cell ET B receptors mediating vasoconstriction and proliferation, and a down-regulation of endothelial ET B receptors, as compared to the physiological state, creating a situation where both ET A and ET B receptors contribute to vasoconstriction and remodeling. When these two receptor subtypes co-exist, a cross-talk between them, probably a result of receptor heterodimerization, suggests that dual ET A /ET B receptor antagonism may be necessary to obtain maximal efficacy. Drug Dev. Res. 67:825-834, 2006.

Endothelin Receptor Antagonists

“…In such pathological situations, both ET A and ET B receptors mediate the detrimental actions of ET-1. Because of a "cross talk" between ET A and ET B receptors (Clozel and Flores 2006;Clozel and Gray 1995), selective antagonism of only one receptor subtype may result in compensation by the other receptor subtype and may be insufficient, whereas dual antagonism may be necessary for complete inhibition.…”

EndothelinA–endothelinB receptor cross-talk in rat basilar artery in situ

“…Despite the numerous reports of ET A -ET B receptor cross-talk in various cell types and tissues, which include a relatively large number of studies in systemic vascular and nonvascular smooth muscle (Clozel and Flores 2006;Watts 2010), it remains unclear whether cross-talk is present in the cerebral vasculature. Using an in situ cranial window preparation, we concluded that ET A -ET B receptor cross-talk was present in the rabbit basilar artery based on the combined observations that the ET-1 contraction was (1) partially relaxed by ET A receptor antagonist and (2) relaxed by ET B receptor antagonist only in the presence of ET A receptor antagonist (Zuccarello et al 1998(Zuccarello et al , 1999.…”

“…The rationale for the use of combined ET A and ET B antagonism stems in part from the apparent functional interaction, or "cross-talk," between these receptors (Clozel and Flores 2006;Dhaun et al 2007;Kirkby et al 2008;Trow and Taichman 2009). That is, ET A -ET B receptor cross-talk may limit the efficacy of a selective ET receptor antagonist due to apparent compensation mediated by the other ET receptor subtype (Clozel and Flores 2006).…”

“…Whether antagonism of both endothelin (ET) receptor subtypes, ET A and ET B , as opposed to selective ET A receptor antagonism, yields greater therapeutic efficacy in a number of pathophysiologies associated with ET-1, including several pathophysiologies involving smooth muscle, is a subject of considerable discussion (Clozel and Flores 2006;Dhaun et al 2007;Kirkby et al 2008;Trow and Taichman 2009). The rationale for the use of combined ET A and ET B antagonism stems in part from the apparent functional interaction, or "cross-talk," between these receptors (Clozel and Flores 2006;Dhaun et al 2007;Kirkby et al 2008;Trow and Taichman 2009).…”

Role of endothelin in lung fibrosis

“…ET B receptors act as the major clearance receptor for ET-1 and can participate in the release of nitric oxide. Sometimes alone, but primarily in combination with ET A receptors, ET B receptors can also mediate multiple detrimental effects in disease states, including cellular hypertrophy, inflammation and fibrosis [3]. ET-1 acts in a paracrine and autocrine manner to mediate its broad range of biological activities, which include the control of vasoconstriction and vasodilation via its action on the endothelium and vascular smooth muscle cells, a chemotactic effect on inflammatory cells, such as monocytes and neutrophils, and, as will be discussed further in the present article, a pivotal role in the function and differentiation of fibroblasts and myofibroblasts ( fig.…”