First identified as a powerful vasoconstrictor, endothelin has an extremely diverse set of actions that influence homeostatic mechanisms throughout the body. Two receptor subtypes, ET A and ET B , which usually have opposing actions, mediate the actions of endothelin. ET A receptors function to promote vasoconstriction, growth, and inflammation while ET B receptors produce vasodilation, increases in sodium excretion, and inhibit growth and inflammation. Potent and selective receptor antagonists have been developed and have shown promising results in the treatment of cardiovascular diseases such as pulmonary arterial hypertension, acute and chronic heart failure, hypertension, renal failure and atherosclerosis. However, results are often contradictory and complicated because of the tissue-specific vasoconstrictor actions of ET B receptors and the fact that endothelin is an autocrine and paracrine factor whose activity is difficult to measure in vivo. Considerable questions remain regarding whether ET A selective or non-selective ET A /ET B receptor antagonists would be useful in a range of clinical settings.
Keywordsreceptor localization; pulmonary hypertension; heart failure; chronic kidney disease Shortly after it was discovered that the vascular endothelium releases a peptide capable of profound vasoconstriction, a considerable amount of attention was paid to the potential actions of endothelin in the pathogenesis of cardiovascular disease. We have since learned a great deal about how this paracrine factor influences function in an extremely wide range of areas including neurotransmission, cell growth and epithelial transport, just to name a few. This myriad of activities has allowed the endothelin system to garner a tremendous amount of attention from the pharmaceutical industry with the development of numerous receptor specific and non-specific antagonists as well as efforts to identify drugs that inhibit endothelin synthesis. This work has led to new therapeutic approaches to pulmonary arterial hypertension and most likely other diseases in the not too distant future. In addition to this enormous drug discovery effort, it has also become clear that endothelin plays an important physiological role in maintaining blood pressure homeostasis, for example, by facilitating the excretion of a high salt diet. Because of the almost bewildering range of actions of the endothelin peptides, we limit this review to focus on the receptor-specific cardiovascular actions of endothelin.
ENDOTHELIN PEPTIDESEndothelin-1, a 21-amino-acid long peptide first isolated from the supernatant of cultured endothelial cells, is perhaps the most potent vasoconstrictor substance known (1). The human Address for Correspondence: David M. Pollock, Ph.D., Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA 30912-2500, +1-706-721-8517 office, +1-706-721-9799 fax, dpollock@mcg.edu.
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Author ManuscriptAnnu Rev Pharmacol Toxicol. Author manuscript; available in PMC 2010 February 22.
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