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[Ala1,3,11,15]-Endothelin (53-63) (TFA) 是一种内皮素 (ET)-1 的线性肽类似物，对内皮素 B (ETB) 受体具有高度选择性。
[Ala1,3,11,15]-Endothelin (53-63) (TFA), a linear peptide analog of endothelin (ET)-1, is a highly selective endothelin B (ETB) receptor[1].

Definition

A peptidergic activity produced in endothelial cells that caused coronary vasoconstriction was described in 1985, and a family of peptides, named the endothelins, was subsequently isolated and identified. The three members of the family — endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3 )— are produced in a variety of tissues, where they act as modulators of vasomotor tone, cell proliferation, and hormone production 1.

Related Peptides

The 21-amino acid peptide ET-1 is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells 2.

Discovery

Endothelin, one of the most potent vasoconstrictors, was first discovered by Yanagisawa and co-workers in 1981. It was first isolated, characterized, and cloned in porcine aortic endothelial cells 3.

Structural Characteristics

First of the three isoforms, the ET-1, is a 21-amino acid peptide; it has a molecular weight of 2,492, free carboxyl and amino termini and has two intramolecular disulfide bonds. It is present in many mammalian species, including humans. Other two human endothelin isopeptides, ET-2 and ET-3 are encoded by separate genes. They contain two intramolecular disulfide bonds. They also contain a cluster of polar charged side chains in the hairpin loop and a hydrophobic COOH terminus, containing the aromatic indole side chain at trp21 3.

Mode of Action

Two endothelin receptors have been characterised in the mammals. They are classified according to the relative binding affinities of the 3-endothelin isopeptides to the receptors. The order of affinity of endothelins for 1st receptor type designated ETA is ET-1 > ET-2 > ET- 3. The second receptor subtype designated ETB shows equipotent affinity for all 3 endothelins 3.

Functions

Endothelins appear to act mainly as local paracrine/autocrine peptides, but circulating levels of endothelins also have great biological significance especially in pathological states of increased serum concentration.

Pathophysiology of Endothelins:

1. Renal haemodynamics: In various studies in dogs and rats it has been seen that endothelin peptides have both contractile and promitogenic actions in renal mesangial cells.
2. Renal disease: In various studies it has been shown that ET-1 plays a role in the pathogenesis of acute renal failure after renal ischaemia, i.e., plasma levels of ET-1 are increased in patients with acute renal failure.
3. Hypertension: ET-1 causes potent vasoconstriction and prolonged elevation of blood pressure in experimental models. But the relationship between the plasma levels of ET-1 and severity of hypertension is inconsistent in humans.
4. Heart failure: Plasma endothelin levels are increased in animal models of CHF (Chronic Heart Failure) and in patients with CHF. In patients, increased plasma endothelin levels correlate closely with the degree of haemodynamic and functional impairment, with higher levels predicting a greater likelihood of death or need for cardiac transplantation.
5. Ischaemic heart disease: In human studies, plasma endothelin levels are increased in unstable angina and acute myocardial infarction.
6. Variant angina: Patients with Prinzmetal’s angina are known to have endothelial dysfunction affecting the L-arginine nitric oxide system, and as a potent vasoconstrictor of coronary arteries, endothelin-1 has been implicated in the pathophysiology of this condition.
7. Primary pulmonary hypertension: In primary pulmonary hypertension there is proliferation of pulmonary arterial smooth muscle and endothelial injury. It has been observed that depending on the state of vasomotor tone, endothelin isopeptides can cause either pulmonary vasodilatation or vasoconstriction.
8. Raynaud’s disease: Raynaud’s disease is seen commonly in cold climates and is associated with vasospastic conditions like migraine and Prinzmetal’s angina. There has been exaggerated increase in endothelin levels in venous blood draining from the cold challenged arm, in cases with Raynaud’s disease as compared with responses in healthy volunteers.
9. Subarachnoid haemorrhage (SAH): Endothelin-1 has a causative role in mediating sub-arachnoid hemorrhage induced vasospasm. Plasma and CSF endothelin levels are significantly increased in patients after SAH and plasma levels of endothelins are highest in those who develop vasospasm.
10. Migraine: In the recent studies it has been found that levels of endothelins are increased during migraine headaches 3.

References

1. Levin ER (1995). Endothelins. NEJM., 333:356-363.
2.  Lüscher TF, Barton M (2000). Endothelins and Endothelin Receptor Antagonists Circulation., 102:2434:2440.
3. Jain SK, Yadava RK, Raikar R (2002). Role of Endothelins in Health and Disease. JIACM,  3(1):59-64.