Biological Role
As the term suggests, endothelins are a family of peptides secreted by endothelial cells. Their action is vasoconstrictor and markedly hypertensive.
Physiology of Endothelium
Overall, endothelial cells form the innermost lining of blood vessels, thus representing the contact element between blood and arterial wall. This interface, once considered a mere covering, is currently described as a real dynamic and complex organ. Among the most famous substances secreted by the approximately 3 kg of endothelium present in a medium organism, we recall:
- Nitric oxide: gas released rapidly in response to various vasodilatory stimuli and then inactivated within a few seconds, exerts a vasodilating action, therefore hypotensive and inhibits the production of ET-1
- Endothelin (ET-1): peptide with a vasoconstrictor action, therefore hypertensive, which occurs slowly and lasts from minutes to hours. Its synthesis also seems to increase that of nitric oxide, which in turn reduces endothelin-induced vasoconstriction with a balancing effect
- Prostacyclins (PGI2): inhibit platelet aggregation and act as vasodilators
Normally there is a balance between vasoconstrictive and vasodilating factors, but when endothelins are synthesized in excessive amounts, they contribute to the onset of hypertension and heart disease.
Currently three endotheline isoforms are known:
Endothelin-1 (ET-1) is a peptide of 21 amino acids: it is the only or in any case the main isoform synthesized by the endothelium, isolated for the first time by Yanagisawa in 1988; it is synthesized to a lesser extent also by the smooth muscle, the intestine and the adrenal glands, and in good quantities also by the kidney and the brain
The ET-2 and ET-3 endothelins are instead peptides, always made up of 21 amino acids, synthesized in other body sites: ET-2 is distributed much less widely and is present above all in the kidney and in the intestine; ET-3 is concentrated in the brain, lungs, intestines and adrenals
The synthesis of ET-1, schematically shown in the figure, is very complex: it starts from a large precursor molecule, the preproendothelin, which then undergoes a series of enzymatic interventions that reduce it first to "grande endothelin" (big ET) and then - by action of the endothelin- converting enzyme (ECE-1 or Endothelin converting enzyme ) - to Endothelin 1 (ET-1).
The synthesis of endothelin-1 is stimulated by numerous factors with vasoconstrictor action, released during trauma or inflammatory states
thrombin, angiotensin II, catecholamines, vasopressin, bradykinin, hypoxia, pro-inflammatory cytokines (interleukin-1, Tumor Necrosis Factor-α)
while it is inhibited by:
nitric oxide, natriuretic peptides, heparin, PGE2, PGI2, high flow stress
Functions
In addition to the powerful vasoconstrictor properties directed mainly to the coronary, renal and cerebral vessels with an intensity 10 times greater than that of angiotensin - endothelin 1 also exerts an action:
- positive inotrope on the heart (increases its contraction strength)
- of stimulation on cell proliferation, with mitogenic effect on smooth vascular muscle cells
- modulator of sympathetic system activity and of the renin angiotensin system
Clinical meaning
Under physiological conditions, the blood concentration of ET-1 is rather low, and in any case lower than that capable of exercising the vasoconstrictor action. Endothelins therefore play a leading role in maintaining basal vascular tone, acting in synergy with other factors.
In addition to increasing blood pressure, entothelin-1 plays an important role in inflammation and atherogenesis. Indeed, a massive plasma increase in the endothelin rate occurs during serious cardio-circulatory events, such as cardiogenic shock, acute myocardial infarction, major surgery, and liver transplantation.
- the plasma concentration of ET is highest in the early stages of acute myocardial infarction and gradually decreases in the following hours
- in the case of complicated acute myocardial infarction, the endothelin values remain high even for several days.
As a laboratory marker, endothelin-1 levels therefore seem inversely proportional to the patient's survival time (the higher and more persistent the patient's condition is):
Endothelin-1 levels are high even in the presence of:
- pulmonary hypertension
- heart failure
- kidney failure
- renal ischemia
- cirrhosis and ascites
while in the presence of arterial hypertension, the experimental data appear somewhat discordant, so that in general the endothelin levels are superimposable to those found in normotensive patients. In general, however, ET-1 levels are higher in hypertensive patients with advanced disease, probably due to vascular complications related to hypertension.
Endothelin receptors
To perform its action, endothelins interact with at least two different receptor subtypes:
- AGE:
- HYPERTENSIVE EFFECT → vasoconstriction, increased strength of the heart's contraction and aldosterone blood concentration, resulting in sodium retention
- high affinity for ET-1 and to a lesser extent for ET-2
- expressed mainly at the level of vascular smooth muscle
- ET-B:
- HYPOTENSIVE EFFECT → the stimulation of these receptors - secondary to the increase in nitric oxide production - induces vasodilation with the aim of modulating (damping) the vasoconstrictive and mitogenic effects of the endothelin
- equal affinity for the three isoforms
- expressed mainly in the endothelial and smooth muscle cells
The existence of a third type of receptor has also been proposed
- ET-C:
- HYPOTENSIVE EFFECT
- high affinity for ET-3
- expressed mainly at the level of the nervous system
Endothelins and antihypertensive drugs
Clarified, at least in broad terms, the biological role of endothelins, the researchers' efforts focused on the synthesis of drugs capable of blocking their binding to the ET-A receptor, or of reducing their synthesis by blocking the activity of the enzyme ECE- 1 ( Endothelin converting enzyme ); in both cases, the purpose of the drug was to annul the vasoconstrictor, and therefore hypertensive, effect of endothelin, thus obtaining drugs that are very useful in the treatment of hypertension and in the prevention of its complications, especially at the renal level.
One drug that has recently entered therapy is bosentan, a double antagonist of ETa and ETB, taken orally and used in the treatment of pulmonary arterial hypertension. Other drugs, such as ambrisentan and sitaxentan, act as selective ETa receptor antagonists.
