J Cardiovasc Pharmacol. 2015 May 16. [Epub ahead of print]

Vascular effects of endothelin receptor antagonists depends on their selectivity for ETA vs. ETB receptors and on the functionality of endothelial ETB receptors.

Iglarz M, Steiner P, Wanner D, Rey M, Hess P, Clozel M.

Drug Discovery Department, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.



INTRODUCTION: The goal of this study was to characterize the role of Endothelin (ET) type B receptors (ETB) on vascular function in healthy and diseased conditions and demonstrate how it affects the pharmacological activity of ET receptor antagonists (ERAs).

METHODS: The contribution of the ETB receptor to vascular relaxation or constriction was characterized in isolated arteries from healthy and diseased rats with systemic (Dahl-S) or pulmonary hypertension (monocrotaline). Because the role of ETB receptors is different in pathological vis-à-vis normal conditions, we compared the efficacy of ETA-selective and dual ETA/ETB ERAs on blood pressure in hypertensive rats equipped with telemetry.

RESULTS: In healthy vessels, ETB receptors stimulation with sarafotoxin S6c induced vasorelaxation and no vasoconstriction. In contrast, in arteries of rats with systemic or pulmonary hypertension, endothelial ETB-mediated relaxation was lost while vasoconstriction upon stimulation by sarafotoxin S6c was observed. In hypertensive rats, administration of the dual ETA/ETB ERA macitentan on top of a maximal effective dose of the ETA-selective ERA ambrisentan further reduced blood pressure, indicating that ETB receptors blockade provides additional benefit.

CONCLUSION: Taken together these data suggest that in pathology, dual ETA/ETB receptor antagonism can provide superior vascular effects compared to ETA-selective receptor blockade.

PMID: 25992919



ET-1 is a 21-amino acid peptide produced by endothelial and other cells, that binds to two G protein-coupled receptors, ETA and ETB. ETA receptors predominate on vascular smooth muscle cells and mediate vasoconstriction. In healthy tissue, ETB receptors are predominantly expressed on endothelial compared to smooth muscle cells (i.e. 80/20 ratio1). Endothelial ETB receptors may mediate vasodilation through nitric oxide (NO) release2, 3 while the ETB located on smooth muscle cells mediate vasoconstriction4. When looking at the literature, it is commonly stated that endothelial ETB should not be blocked as it plays a role in vasodilation via production of NO. However, in pathological situations such as hypertension, diabetes mellitus or hypercholesterolemia, endothelial ETB expression has been shown to be downregulated whereas ETB expression is upregulated in smooth muscle cells where it mediates vasoconstriction5. Therefore, in pathological conditions, a selective ETA receptor antagonist might not benefit from unblocked endothelial ETB receptors as they are either downregulated and/or not functional anymore (i.e. decreased NO availability), and may miss to block the upregulated smooth muscle ETB receptors that mediate deleterious actions.


Key findings from the article:

  • Endothelial ETB receptors do not vasodilate anymore in pathology

We first used isolated vessels from healthy rats and confirmed that ETB-mediated relaxation was endothelium and nitric oxide-dependent. Then we moved to either pulmonary vessels from pulmonary hypertensive monocrotaline rats or aorta from hypertensive Dahl-S rats which both presented severe endothelial dysfunction. We observed that, in these pathological conditions, ETB-dependent relaxation was not present anymore (Figure 1A).

  • Smooth muscle ETB receptors are vasoconstrictive in pathology

We also demonstrated that ETB receptors localized on smooth muscle cells contribute to vasoconstriction in pathological conditions as evidenced here in monocrotaline and Dahl-S rats (Figure 1B). Our data are in line with clinical data: In patients with essential hypertension or insulin-resistance, acute forearm vasodilation achieved by dual ETA/ETB blockade was superior to ETA-selective agents6, 7 suggesting that in these pathologies, vascular ETB receptors contribute to vasoconstriction.

We then confirmed in vivo in Dahl-S rats that blockade of both ETA/ETB receptors was able to achieve a superior effect on blood pressure reduction. To do so, we set up a special study design that compared the effect of the maximal effective doses of each compound administered on top of the maximal effective dose of the other one. Interestingly, dual ETA/ETB blockade with macitentan was able to further decrease blood pressure when administered on top of the maximal ETA-selective receptor blockade while the opposite was not true. Therefore we concluded that the additional effect obtained with the dual ETA/ETB was attributed to a blockade of the ETB receptors that were not antagonized by the ETA-selective compound.



Our data highlight the difference in role of the vascular ETB receptors in physiology vs. pathology and that lessons learned in physiology do not apply systematically in pathology. Beyond contributing to vasoconstriction, one should keep in mind that ETB are also involved in cell proliferation, inflammatory processes and fibrosis. Therefore dual ET receptor blockade could also confer an advantage over ETA-selective blockade on remodeling processes and hence on long term benefit as suggested by improved survival in preclinical models of PH and chronic heart failure8, 9.

figure1Figure 1 Representative traces (X axis: time, Y axis: force in mN) illustrating the response of isolated pulmonary vessels to ETB agonist sarafotoxin S6c mounted under isometric conditions. One can see that in vessels from a healthy animal (left), ETB receptors stimulation leads to vasodilation only while in vessels from a diseased rat (right), ETB receptors stimulation does not dilate anymore but triggers vasoconstriction.



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