Endothelins and antagonists
Endothelins
Endothelins are polypeptides of 21 amino acid residues with two disulfide bridges connecting cystein residues. Three endothelins, I, II and III, different only by some amino acids, are described. Endotheline I (ET-1) is considered as the most active. They act on at least two types of receptors called ETA and ETB.
Endothelins are found primarily in vascular endothelium (which explains their denomination), but also in brain, kidney, intestine, adrenal gland. Their formation is carried out from prepropeptides, preproendotheline, which is hydrolyzed by endopeptidases into pro-endothelins (39 amino acids) which, under the influence of endothelin converting enzyme, ECE, a zinc enzyme, give endothelins
An increase in plasma endothelins can be observed during arterial hypertension, myocardial infarction, congestive heart failure, Raynaud disease.
Endothelin activates ETA and ETB receptors:
- ETA, located in vascular smooth muscles, their stimulation gives vasoconstriction and a mitogenic effect.
- ETB,
- present in vascular smooth muscles: their activation gives vasoconstriction
- present in endothelial cells: their activation leads to the release of nitric oxide, NO, and of prostacyclin and leads to vasodilation.
The vasoconstrictive effect is widely predominant.
Cardiovascular effects
Endothelins, by activating ETA and ETB receptors, elicit a general vasoconstriction of long duration, including coronary and pulmonary arteries. This long duration of action contrasts with their very short half-life, of about one minute. The vasoconstriction can be preceded by an hypotension of very short duration whose mechanism is not well known.
They increase heart rate (positive chronotropic effect) and contraction forces (positive inotropic effect).
As angiotensin, they could, bya mitogenic effect, induce development of cardiac hypertrophy and atherosclerosis.
Other effects
Endothelins, have a bronchoconstrictive effect but they do not seem to play a determining part in asthma. They constrict intestinal fibers.
Endothelins elicit release of other transmitters such as nitric oxide, NOES, certain prostaglandins (prostacyclin), atrial natriuretic factor.
Endothelins act via the G proteins and phospholipase C and release of intracellular calcium; they also inhibit adenylcyclase activity.
Taking into account the generally harmful effects of endothelins, one currently seeks inhibitors of their synthesis, in particular endothelin converting enzyme inhibitors, and antagonists of their receptors.
Endothelin antagonists
From a pharmacological point of view, to reduce the effects of endothelins, it is possible
- to decrease its formation, by inhibition of endothelin conversion enzyme for example, but there is no drug now available.
- to directly reduce its effects by inhibition of its receptors. The first drug of this group is bosentan.
Bosentan is an antagonist of type A and B receptors, ETA and ETB (ET for endothelins) but it has an affinity approximately 50 times more important for type A receptors than for type B. The international common name of antagonists of endothelins receptors ends by “-sentan”.
The bioformation of endothelin and the mechanism of action of bosentan are summarized below.
Bosentan,
(Tracleer*), antagonist of ETA and ETB endothelin receptors, inhibit vasoconstriction induced by endogenous endothelins. Administered by oral route, bosentan decreases systolic and diastolic arterial pressure which implicates a role of endothelins in regulation of arterial pressure. It decreases pulmonary arterial hypertension which is now, in practice, its only therapeutic use.
Bosentan is metabolized by P450 cytochrome CYP3A4 and CYP2C9 isoenzymes into 3 metabolites, one of them is responsible pharmacological activity. Bosentan is an enzymatic inducer of CYP2C9 and CYP3A4, and many drug interactions have been described.
To detect bosentan dose-dependant hepatic toxicity, serum aminotransferase levels should be measured before and during treatment.
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