This Article Full Text Full Text (PDF) All Versions of this Article: 52/3/460    most recent HYPERTENSIONAHA.108.117226v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sica, D. A. Search for Related Content PubMed PubMed Citation Articles by Sica, D. A. Related Collections Pathophysiology Clinical Studies

(Hypertension. 2008;52:460.)
© 2008 American Heart Association, Inc.

Editorial Commentaries

Endothelin Receptor Antagonism

What Does the Future Hold?

From the Division of Nephrology, Virginia Commonwealth University Health System, Richmond.

Correspondence to Domenic A. Sica, Professor of Medicine and Pharmacology, Chairman, Clinical Pharmacology and Hypertension, Virginia Commonwealth University Health System, Richmond, VA 23298-0160. E-mail dsica@mcvh-vcu.edu

An extract of the first 250 words of the full text is provided, because this article has no abstract.

The endothelins are a family (ET-1, ET-2, and ET-3) of naturally occurring polypeptides, with ET-1 being the most clinically pertinent isoform. ET-1 was formally identified in 1988, at which time it was viewed mainly as a potent vasoconstrictor; however, the biological understanding of endothelin has since rapidly evolved, and it is now appreciated that ET-1 is not only a potent vasoconstrictor but also that it has a prominent role in fibrogenesis, inflammatory states, oxidative stress, atherosclerosis, salt and water balance, and pulmonary artery hypertension.^1–3

ET-1 binds to 2 receptors: ET_A and ET_B. In general, stimulation of these receptors has opposing actions. For example, ET_A stimulation is vasoconstricting, as well as being profibrotic and proinflammatory, whereas ET_B stimulation is vasodilatory, antiproliferative, and natriuretic. The ET_B receptor also subserves a clearance role for ET-1. The varying distribution of the endothelin receptors in different tissues is responsible for the mixture of actions attributed to endothelin. For example, the renal medulla contains the highest concentration of endothelin receptors in the body.⁴ The renal cortex is also heavily populated with endothelin receptors (50% of the density of the medulla). The ET_B receptor predominates in the kidney, composing 70% of the receptors in both locations. Thus, the important roles of ET-1 and the ET_B receptor are in regulating renal hemodynamics and tubular transport processes, as well as mesangial and vascular smooth muscle cell proliferation and mitogenesis.³

Likewise, ET_A and ET_B receptors are highly expressed in smooth muscle cells and foamy macrophages in atherosclerotic models. Stimulation . . . [Full Text of this Article]