Dual ET_A/ET_B vs. selective ET_A endothelin receptor antagonism in patients with pulmonary hypertension

Abstract

Since the identification of endothelin as a key mediator in the pathogenesis of several diseases, including pulmonary arterial hypertension (PAH), the pharmacologic control of the activated endothelin system with endothelin receptor antagonists (ETRA) has been a major therapeutic achievement for the treatment of patients with PAH. To date, dual ET(A)/ET(B) and selective ET(A) receptor antagonists have clinically been evaluated. To answer the question of whether selective or dual ETRA is preferable in patients with PAH, experimental and clinical data with relevance to the pulmonary circulation are reviewed in this article. Whereas experimental and clinical data provide unambiguous evidence that ET(A) receptors mediate the detrimental effects of ET-1, such as vasoconstriction and cell proliferation, the elucidation of the role of ET(B) receptors has been more complex. It has been shown that there is a subpopulation of ET(B) receptors on smooth muscle cells and fibroblasts mediating vasoconstriction and proliferation. On the contrary, there is clear evidence that endothelial ET(B) receptors continue to mediate vasodilation, vasoprotection and ET-1 clearance despite the pathology associated with pulmonary hypertension. More difficult to assess is the net effect of these mechanisms in patients to be treated with ETRA. When considering the available data from controlled clinical trials, nonselectivity does not appear to carry a relevant clinical benefit for the treatment of patients with PAH when compared with selective ET(A) receptor antagonism.

In vitroeffect of endothelin-1 and nifedipine on pulmonary vascular contraction of pulmonary hypertensive and non-pulmonary hypertensive chickens

“…These findings may support recent efforts to enlist novel pharmacological alternatives in the treatment of PAH, having therapeutic targets other than the fundamental mechanisms in the development of the disease, such as ET-1 receptor antagonists (Itoh et al 1999;Opitz & Ewert 2006 additional studies of molecules with this activity to specify the precise involvement of Ca 2+ originating from sources different than the L-type channels in hypoxic vasoconstriction will be necessary.…”

“…Such changes include the following: the overexpression of ET A receptors in VSMS (McCulloch et al 1998;Weigand et al 2006); the overexpression of the ET B2 receptor in small peripheral pulmonary arterioles (Channick et al 2004;Opitz & Ewert 2006); and the decreased expression of the ET B1 receptor, which is directly associated with the reduction of endothelium-dependent vasorelaxation due to a reduction in the synthesis of vasodilators, such as NO and PGI 2 (Adnot et al 1991;Inagami et al 1995;Mam et al 2010) In addition to ET-1, serotonin (5-HT), angiotensin II (Ang II), noradrenaline, and histamine are considered to be substances that induce an increase in the reactivity of the pulmonary vasculature under chronic hypoxic conditions . The increase in the vasoreactivity of hypoxic PAH could also be due to abnormalities found in pulmonary VSMC, such as the following: increased [(Ca 2+ ) i ] at resting levels , the inhibition of K + (K v ) channels due to the reduced expression of their alpha units (Wang et al 1997); and the decreased activity of the K + (K Ca ) channels (Peng et al 1997).…”

“…ET A receptors predominate in the proximal arteries and ET B ones in the small peripheral pulmonary arterioles (Michel et al 2003). In certain cardiovascular diseases, ET B2 receptors are overexpressed while the number of ET B1 receptors is reduced, which is directly related to an increase in contraction and subsequent decrease in vasodilatation (Dupuis et al 2000;Channick et al 2004;Opitz & Ewert 2006).…”

Therapies for pulmonary arterial hypertension: where are we today, where do we go tomorrow?

“…Therefore, other features are likely to be of greater relevance when considering treatment, such as the potential for serious drug-drug interactions, convenience of dosing schedules, or rates of limiting side-effects. These characteristics bear more relation to the chemical or pharmacological properties of the drug than to receptor selectivity itself [40].…”

Pharmacologic and Pharmacokinetic Rationale for Combination Therapy in Pulmonary Arterial Hypertension

“…22 Due to the different effects of the 2 ET receptor subtypes, controversy exists regarding the benefit of selective versus dual receptor blockade, although the difference in efficacy has not been demonstrated in clinical trials. 23,24 Bosentan, a dual endothelin receptor antagonist (ETRA), and ambrisentan, a selective receptor antagonist, are currently approved for treatment in patients with PAH. 25,26 Sitaxsentan is a selective ET A receptor antagonist that is currently under review by the FDA but is approved in the European Union, Canada, and Australia.…”