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Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling
1Department of International Strategic Marketing Cardiovascular, Knoll AG, D-67008 Ludwigshafen, Germany. michael.kirchengast@knoll-ag.de
Insights
Endothelin-1, a potent vasoconstrictor, contributes to cardiovascular diseases. Endothelin receptor antagonists, particularly ETA-selective ones, show promise for treating these conditions.
Area of Science:
- Cardiovascular Pharmacology
- Endocrinology
Background:
- Endothelins are peptide hormones with three isoforms, including endothelin-1 (ET-1).
- ET-1 is a potent endogenous vasoconstrictor and mitogen with significant cardiovascular effects.
- ET-1 plays a role in sustained vasoconstriction and cardiovascular remodeling.
Purpose of the Study:
- To review the cardiovascular actions of endothelin-1.
- To discuss the role of endothelin receptor antagonists in treating cardiovascular diseases associated with remodeling.
Main Methods:
- Review of experimental evidence on endothelin-1.
- Analysis of studies utilizing endothelin receptor antagonists, specifically ETA-selective agents.
Main Results:
- Endothelin-1 contributes to vasoconstriction and cardiovascular remodeling.
- Endothelin receptor antagonists have demonstrated involvement of ETA receptors in diseases like heart failure, pulmonary hypertension, and atherosclerosis.
- ETA-selective antagonists are effective in treating structural cardiovascular diseases.
Conclusions:
- Endothelin receptor antagonists, especially ETA-selective ones, are promising therapeutic agents.
- These agents are valuable for treating chronic cardiovascular diseases characterized by remodeling.
- Several orally available endothelin receptor antagonists are currently in clinical trials.
Abstract:
Endothelins build a peptide family composed of three isoforms, each of them containing 21 amino acids. Endothelin-1 is the isoform mainly responsible for any cardiovascular action and therefore the sole scope of this review. Endothelin-1 is the most potent endogenous vasoconstrictor known; in addition it acts as a potent (co)mitogen. There is a substantial body of experimental evidence that endothelin-1 may contribute not only to sustained vasoconstriction, but also to remodeling within the cardiovascular system. Thus, with the help of endothelin receptor antagonists (available for a few years) the involvement of mainly ETA receptors in structural diseases such as heart failure, pulmonary hypertension, atherosclerosis, restenosis, systemic hypertension, and chronic renal failure has been shown. These data make endothelin receptor antagonists, and especially those selective for the ETA receptor, promising agents for the treatment of chronic cardiovascular diseases associated with remodeling. Currently several chemically distinct, orally available members of this novel class of therapeutic agents are under clinical investigation.