Relevance of receptor selectivity for endothelin antagonists

Dr. Pittrow, David. Technical University Carl Gustav Carus Inst. for Clinical Pharmacology, Fiedlerstr. 27, 01307 Dresden, Germany.

Pulmonary arterial hypertension (PAH) is a group of diseases characterized by progressive increases in pulmonary vascular resistance and pulmonary artery pressure, resulting in right ventricular heart failure and ultimately in premature death. Since the identification of endothelin (ET-1) as one of the key mediators in the pathogenesis of PAH, the pharmacologic control of the activated endothelin system with endothelin receptor antagonists (ETRAs) has represented a major therapeutic achievement for the treatment of patients with PAH. To date, ETA-selective (sitaxentan, to a lesser extent ambrisentan) and non-selective ETA/ETB receptor antagonists (bosentan) have clinically evaluated and approved for the treatment of PAH. However, whether selective or non-selective ETRAs are preferable in patients with PAH remains a matter of debate. Whereas experimental and clinical data provide unambiguous evidence that ETA receptors mediate the detrimental effects of ET-1, such as vasoconstriction and proliferation, the elucidation of the role of ETB receptors has been more complex. Although there is evidence that endothelial ETB receptors continue to be functional in patients with PAH, ETB receptors on smooth muscle cells and fibroblasts may mediate vasoconstriction and proliferation. In placebo-controlled clinical trials in patients with PAH, selective as well as non-selective ETRAs have been shown to improve clinically important endpoints such as exercise capacity, functional class, haemodynamic parameters, time to clinical worsening. In addition, survival appears to be improved when compared with historical controls. Although there might be differences within certain PAH subgroups, such as in patients with PAH associated with connective tissue disease, a significant and clinically meaningful effect attributable to ETA receptor selectivity, has not been proven thus far. According to present knowledge, in clinical practice other features are likely to be of greater relevance when considering treatment, such as the potential for serious drug-drug interactions, convenience of dosing schedule, 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.

Opitz CF, Ewert R, Kirch W, Pittrow D. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur Heart J. 2008:10.1093/eurheartj/ ehn1234.