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The Endothelin System
The endothelin system is composed of endothelin peptides and their receptors that together affect a wide variety of physiological functions and pathological conditions. Endothelin was initially identified in the cells of the endothelium. The endothelium is composed of a layer of cells that line the blood and lymph vessels as well as many body cavities such as the heart. This cell layer may be regarded as a functional organ, with a total weight of approximately 1.5 kg, and a combined surface area equivalent to four tennis courts.
Components of the Endothelin System
Three types of endothelin (ET) peptides have been identified: ET-1, ET-2, and ET-3. ET-1 is composed of 21 amino acid residues1, and ET-2 and ET-3 differ from ET-1 in amino acid residues two and six respectively. As the most powerful vasoconstrictor that has been described to date, ET-1 has great structural homology with sarafotoxin, snake venom that induces myocardial infarction by exaggerated contraction of the cardiac vessels and interruption of the blood supply to the heart. Endothelins are produced by a variety of body tissues such as the lung and kidney as well as the brain, pituitary, peripheral endocrine tissues, and placenta2,3,4. ET-1 is also produced by endothelial cells, and most abundantly by the vascular endothelium1,5.
Endothelin binds to two types of receptors (ETA and ETB). Although structurally highly similar, these receptors have differing affinities to the three types of endothelin they bind. The ETA receptor has a higher affinity to ET-1 and ET-2 than ET-3, and is predominantly found in smooth muscle cells, where it mediates vasoconstriction and proliferative responses. By contrast, the ETB receptor binds all three peptides with equal affinity and is located on the surface of the endothelium, in fibroblasts and smooth muscle cells that are abundant in the brain and kidneys.
Functions of the Endothelin System
Endothelin has a variety of roles in both normal physiology and pathological conditions in a number of compartments of the body6:
- Blood vessels-ET maintains a basal level of vasoconstriction and may be involved in the development of hypertension, atherosclerosis, and vasospasm after subarachnoid hemorrhage
- Heart-ET affects force and rate of contraction and may mediate hypertrophy and remodeling in congestive heart failure
- Lungs-ET regulates the tone of both airways and blood vessels and may be involved in the development of pulmonary hypertension
- Kidney-ET controls water and sodium excretion and acid-base balance and may participate in acute and chronic renal failure
- Brain-ET modulates cardio-respiratory centers and hormone release
Regulation of Vascular Tone by the Endothelin System
Under normal physiological conditions, vascular tone is defined by the interplay of circulating levels of vasodilators and vasoconstrictors. Healthy ET-1 levels are very low, and help to maintain a basal level of vasoconstriction. Elevated levels of ET-1 lead to severe vasoconstriction and pulmonary vascular hypertrophy. This decreases blood flow to the lungs and results in dyspnoea as well as cardiac damage such as right-ventricular hypertrophy. In addition, the numbers of ETA and ETB receptors are up regulated in pathological conditions.
ET-1, which is a particularly strong vasoconstrictor in the pulmonary vasculature, plays a role in the pathophysiology of pulmonary arterial h ypertension (PAH). Plasma and tissue concentrations of ET-1 are elevated in patients with different forms of PAH, and are proportional to the degree of thei r pulmonary arterial h ypertension. This is particularly the case for patients with PPH, where the disease arises sporadically and in isolation.
Treatment of PAH via Endothelin Receptor Antagonism
Antagoni sm of the ETA and ETB receptors, to block the action of ET-1 offers a new approach to treating PAH.
References
1. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332(6163):411-415.
2. Watson S & Arkinstall S. Endothelin in The G-protein Linked Receptor Facts Book 1994.; pp 11. London. Academic Press.
3. Stojilkovic S & Katt KJ. Neuroendocrine actions of endothelins. Trends Pharmacol Sci 1992; 13: 385-391.
4. Hemsen A. Biochemical and functional characterization of endothelin peptides with special reference to vascular effects. Acta Physiol Scand Suppl. 1991;602: 1-61.
5. Yanagisawa M. The endothelin system. A new target for therapeutic intervention. Circulation. 1994; 89: 1320-1322.
6. Kedzierski RM & Yanagisawa M. Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol 2001; 41:851-876.
