Endothelin (ET), a neurohormonal mediator produced by the endothelium, is overproduced in pulmonary arterial hypertension (PAH), a devastating and rapidly progressing disease.2 This excess ET is associated with dramatic structural changes in the pathology of PAH vasculature, including inflammation,3 vasoconstriction,1 cell proliferation,4 and fibrosis.5 Left untreated, PAH patients have an estimated 5-year survival rate of 34%.2
ET is a 21-amino acid peptide produced primarily by vascular endothelial cells1
*Statements are based on observations reported from in vitro or animal trials. The clinical significance in humans is unknown.
Two receptors mediate the effects of ET*
ET has a strong affinity for 2 receptors (ETA and ETB), which are located on the endothelial cells, smooth muscle cells, fibroblasts, and numerous other cell types throughout the body.6-8 The 2 receptors have similar but distinct activity in pathology.
Endothelin Binding to Both ET Receptors
Here we see ET binding to its two receptors on vascular smooth muscle cells. This action causes contraction, cellular proliferation, and vasoconstriction.
*Statements are based on observations reported from in vitro or animal trials. The clinical significance in humans is unknown.
REFERENCES
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Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol. 1999;61:391–415.
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D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343–349. 1999;61:391–415.
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Muller DN, Mervaala EM, Schmidt F, et al. Effect of bosentan on NF-kappaB, inflammation, and tissue factor in angiotensin II-induced end-organ damage. Hypertension. 2000;36:282–290.
4. 
Davie N, Haleen SJ, Upton PD, et al. ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med. 2002;165:398–405.
5. 
Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732–1739.
6. 
Katwa LC, Guarda E, Weber KT. Endothelin receptors in cultured adult rat cardiac fibroblasts. Cardiovasc Res. 1993;27:2125–2129.
7. 
Masaki T, Miwa S, Sawamura T, Ninomiya H, Okamoto Y. Subcellular mechanisms of endothelin action in vascular system. Eur J Pharmacol. 1999;375:133–138.
8. 
Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Ann Rev Pharmacol Toxicol. 2001;41:851–876.
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