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American Journal of Cardiovascular Drugs

Published in:

01-07-2001 | Review Article

Therapeutic Potential for Endothelin Receptor Antagonists in Cardiovascular Disorders

Authors: Lukas E. Spieker, Georg Noll, Dr Thomas F. Lüscher

Published in: American Journal of Cardiovascular Drugs | Issue 4/2001

Abstract

The endothelins are synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonal, and inflammatory cells. These peptides are converted by endothelin-converting enzymes (ECE-1 and -2) from ‘big endothelins’ originating from large preproendothelin peptides cleaved by endopeptidases. Endothelin (ET)-1 has major influence on the function and structure of the vasculature as it favors vasoconstriction and cell proliferation through activation of specific ET_A and ET_B receptors on vascular smooth muscle cells. In contrast, ET_B receptors on endothelial cells cause vasodilation via release of nitric oxide (NO) and prostacyclin.

Additionally, ET_B receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Indeed, ET-1 contributes to the pathogenesis of important disorders as arterial hypertension, atherosclerosis, and heart failure. In patients with atherosclerotic vascular disease (as well as in many other disease states), ET-1 levels are elevated and correlate with the number of involved sites. In patients with acute myocardial infarction, they correlate with 1-year prognosis. ET receptor antagonists have been widely studied in experimental models of cardiovascular disease. In arterial hypertension, they prevent vascular and myocardial hypertrophy. Experimentally, ET receptor blockade also prevents endothelial dysfunction and structural vascular changes in atherosclerosis due to hypercholesterolemia. In experimental myocardial ischemia, treatment with an ET receptor antagonist reduced infarct size and prevented left ventricular remodeling after myocardial infarction. Most impressively, treatment with the selective ET_A receptor antagonist BQ123 significantly improved survival in an experimental model of heart failure. In many clinical conditions, such as congestive heart failure, both mixed ET_A/B as well as selective ET_A receptor antagonism ameliorates the clinical status of patients, i. e. symptoms and hemodynamics. A randomized clinical trial showed that a mixed ET_A/B receptor antagonist effectively lowered arterial blood pressure in patients with arterial hypertension. In patients with primary pulmonary hypertension or pulmonary hypertension related to scleroderma, treatment with a mixed ET_A/B receptor antagonist resulted in an improvement in exercise capacity. ET receptor blockers thus hold the potential to improve the outcome in patients with various cardiovascular disorders. Randomized clinical trials are under way to evaluate the effects of ET receptor antagonism on morbidity and mortality.

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Title: Therapeutic Potential for Endothelin Receptor Antagonists in Cardiovascular Disorders
Authors: Lukas E. Spieker
Georg Noll
Dr Thomas F. Lüscher
Publication date: 01-07-2001
Publisher: Springer International Publishing
Published in: American Journal of Cardiovascular Drugs / Issue 4/2001
Print ISSN: 1175-3277
Electronic ISSN: 1179-187X
DOI: https://doi.org/10.2165/00129784-200101040-00007

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Therapeutic Potential for Endothelin Receptor Antagonists in Cardiovascular Disorders

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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