Reversal of established responses to endothelin-1 in vivo and in vitro by the endothelin receptor antagonists, BQ-123 and PD 145065

The saphenous vein is the most commonly used bypass graft in patients with coronary artery disease. During routine coronary artery bypass, grafting the vascular damage inflicted on the vein is likely to stimulate the release of endothelin-1, a potent endothelium-derived vasoconstrictor that also possesses cell proliferation and inflammatory properties, conditions associated with vein graft failure. In both in vitro and in vivo studies, endothelin receptor antagonists reduce neointimal thickening. The mechanisms underlying these observations are multifactorial and include an effect on cell proliferation and cell/tissue damage. Much of the data supporting the beneficial action of endothelin-1 receptor antagonism at reducing intimal thickening and occlusion in experimental vein grafts were published over 20 years ago. The theme of the recent ET-16 conference in Kobe was “Visiting Old and Learning New”. This short review article provides an overview of studies showing the potential of endothelin receptor antagonists to offer an adjuvant therapeutic approach for reducing saphenous vein graft failure and poses the question why this important area of research has not been translated from bench to bedside given the potential benefit for coronary artery bypass patients.

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The Role of Endothelin-1 and Endothelin Receptor Antagonists in Inflammatory Response and Sepsis

Archivum Immunologiae et Therapiae Experimentalis ◽

10.1007/s00005-014-0310-1 ◽

2014 ◽

Vol 63 (1) ◽

pp. 41-52 ◽

Cited By ~ 71

Author(s):

Agata Kowalczyk ◽

Paulina Kleniewska ◽

Michal Kolodziejczyk ◽

Beata Skibska ◽

Anna Goraca

Keyword(s):

Inflammatory Response ◽

Endothelin Receptor Antagonists ◽

Endothelin Receptor ◽

Receptor Antagonists ◽

Endothelin 1

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Pharmacology of endothelin receptor antagonists ABT-627, ABT-546, A-182086 and A-192621: in vitro studies

Clinical Science ◽

10.1042/cs103s107s ◽

2002 ◽

Vol 103 (s2002) ◽

pp. 107S-111S ◽

Cited By ~ 25

Author(s):

J. Ruth WU-WONG ◽

Douglas B. DIXON ◽

William J. CHIOU ◽

Brian K. SORENSEN ◽

Gang LIU ◽

...

Keyword(s):

Arachidonic Acid ◽

Amino Acid ◽

Small Molecule ◽

Endothelin Receptor Antagonists ◽

Endothelin Receptor ◽

Arachidonic Acid Release ◽

Functional Responses ◽

Receptor Antagonists ◽

Acid Release

Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ETA and ETB receptors to initiate their effects. Based on the same core structure, we have developed four small-molecule ET receptor antagonists, ABT-627, ABT-546, A-182086 and A-192621, which exhibit difference in selectivity for ETA and ETB receptors. In this report, we compare the potency and selectivity of these four antagonists in inhibiting 125I-labelled ET-1 binding to cloned human ETA and ETB receptors, and in blocking ET-1-induced functional responses (arachidonic acid release and phosphatidylinositol hydrolysis).

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