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Endothelin-1: The Yin and Yang on Vascular Function

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Abstract:

Endothelin-1 (ET-1) is a vasoconstrictor secreted by endothelial cells, which acts as the natural counterpart of the vasodilator nitric oxide (NO). ET-1 contributes to vascular tone and regulates cell proliferation through activation of ETA and ETB receptors. Physical factors such as shear stress, or stimuli including thrombin, epinephrine, angiotensin II, growth factors, cytokines and free radicals enhance secretion of ET-1. By contrast, mediators like nitric oxide (NO), cyclic GMP, atrial natriuretic peptide, and prostacyclin reduce the release of endogenous ET-1. Thus, under normal conditions, the effects of the ET-1 are carefully regulated through inhibition or stimulation of ET-1 release from endothelium.

Endothelial dysfunction is one of the earliest landmarks of vascular abnormalities. Altered function of endothelium may result from absolute decrease in bioavailability of NO as well as from relative augment in ET- 1 synthesis, release or activity. Imbalance in the production of vasodilator and vasoconstrictor agents may contribute to the onset of hemodynamic disorders.

Since dysregulation of the endothelin system is important in the pathogenesis of several cardiovascular diseases, the ETA and ETB receptors are attractive therapeutic targets for disorders associated with elevated ET- 1 levels. ET receptor antagonists may be regarded as disease-modifying agents thanks to their ability to preserve endothelial integrity when the endothelin system is overactive.

This review summarizes the current knowledge on the role of ET-1 in experimental hypertension and describes recent findings on the involvement of MAPK signalling pathways in ET-1 release in hypertension associated with insulin resistance. Moreover, therapeutic applications of ET-1 receptor blockers are also discussed.

Keywords: ET receptor antagonists; ET-1; Hypertension; Insulin resistance

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986706777441968

Affiliations: Department of Pharmacology and Human Physiology, Medical School, University of Bari, Policlinico - P.zza G. Cesare, 1, 70124 Bari - Italy.

Publication date: June 1, 2006

More about this publication?
  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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