**5. Antagonists of endothelin receptors**

Endothelins are a group of peptides discovered in 1988, produced by endothelial cells (ET-1, ET-2 and ET-3). They are one of the most potent vasoconstrictors known. The actions of endothelin ET-1 in humans are mediated through ETA receptors (present in smooth muscle cells of the vessels) and ETB (present on endothelial cells). Endothelins have been implicated in various cardiovascular diseases such as hypertension and HF. (Dhaun et al., 2008)

ET-1 acts on two receptor subtypes: the ETA, located in vascular smooth muscle cells, the myocardium, the fibroblasts, the kidney and the platelets, and the ETB, located on endothelial and vascular smooth muscle cells and in the macrophages. The ETA receptor stimulation produces vasoconstriction, fluid retention, proliferative effects, cardiac hypertrophy and releases norepinephrine and Ang II, and the ETB produces vasodilatation by releasing NO and eicosanoidsfrom endothelial cells and vasoconstriction by stimulating receptors on vascular smooth muscle cells. The ET-1, via ETA receptor stimulation also stimulates the release of cytokines and growth factors (vascular endothelial, of fibroblastic growth, platelet TGF-β) and facilitates platelet aggregation.

Several are the antagonists of endothelin receptors known so far as: ETA (darusentan sitasentan, LU135252); ETB (BQ788) and ETA/ETB (bosentan enrasertan, tezosentan). All these drugs produce beneficial hemodynamic effects in short term treatment, which raised great expectations in its use in hypertension treatment. There are numerous preclinical studies carried out in animals with antagonists of ETA receptors and ETA/ETB mixed antagonists, showing a decrease in BP in them.

Bosentan, a ETA/ETB mixed antagonist, has been used in clinical trials for the treatment of hypertension and HF, being effective in both situations and with tolerance generally acceptable in short term studies. Treatment with bosentan for 4 weeks reduced BP in hypertension as much as 20 mg of enalapril. It is important to notice that, this reduction was achieved without the activation of the sympathetic nervous system or RAAS.

In another study with darusentan, an ETA selective antagonist; in reducing systolic and diastolic BP compared with placebo was also effective. Its most common side effects are headache, facial redness and edema in lower extremities, and liver chemistry changes. Due

of 14-19 h, allowing the administration of the drugs once a day. It is biotransformed into

The OCTAVE study (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) conducted in 25 267 hypertensive patients, confirmed the appearance of pictures of angioedema in omapatrilat treated patients, showing that the incidence of angioedema was 3 times higher than in patients treated with an ACE inhibitor, while in the OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events) performed in 5770 patients with HF, functional class II-IV, ejection fraction ≤ 30% was 0.8% in patients treated with omapatrilat and 0.5% in those treated with enalapril. This dangerous side effect has stopped marketing the product. The simultaneous inhibition of ACE and NEP, both involved in the degradation of bradykinin, could lead to an accumulation of bradykinin and

Endothelins are a group of peptides discovered in 1988, produced by endothelial cells (ET-1, ET-2 and ET-3). They are one of the most potent vasoconstrictors known. The actions of endothelin ET-1 in humans are mediated through ETA receptors (present in smooth muscle cells of the vessels) and ETB (present on endothelial cells). Endothelins have been implicated

ET-1 acts on two receptor subtypes: the ETA, located in vascular smooth muscle cells, the myocardium, the fibroblasts, the kidney and the platelets, and the ETB, located on endothelial and vascular smooth muscle cells and in the macrophages. The ETA receptor stimulation produces vasoconstriction, fluid retention, proliferative effects, cardiac hypertrophy and releases norepinephrine and Ang II, and the ETB produces vasodilatation by releasing NO and eicosanoidsfrom endothelial cells and vasoconstriction by stimulating receptors on vascular smooth muscle cells. The ET-1, via ETA receptor stimulation also stimulates the release of cytokines and growth factors (vascular endothelial, of fibroblastic

Several are the antagonists of endothelin receptors known so far as: ETA (darusentan sitasentan, LU135252); ETB (BQ788) and ETA/ETB (bosentan enrasertan, tezosentan). All these drugs produce beneficial hemodynamic effects in short term treatment, which raised great expectations in its use in hypertension treatment. There are numerous preclinical studies carried out in animals with antagonists of ETA receptors and ETA/ETB mixed

Bosentan, a ETA/ETB mixed antagonist, has been used in clinical trials for the treatment of hypertension and HF, being effective in both situations and with tolerance generally acceptable in short term studies. Treatment with bosentan for 4 weeks reduced BP in hypertension as much as 20 mg of enalapril. It is important to notice that, this reduction was

In another study with darusentan, an ETA selective antagonist; in reducing systolic and diastolic BP compared with placebo was also effective. Its most common side effects are headache, facial redness and edema in lower extremities, and liver chemistry changes. Due

achieved without the activation of the sympathetic nervous system or RAAS.

in various cardiovascular diseases such as hypertension and HF. (Dhaun et al., 2008)

several inactive metabolites which are eliminated by the kidneys.

be responsible, at least in part, of the angioneurotic edema. (Sagnella, 2002)

**5. Antagonists of endothelin receptors** 

growth, platelet TGF-β) and facilitates platelet aggregation.

antagonists, showing a decrease in BP in them.

to the limits of these studies, the role of these drugs is yet to be determined, because they have found significant adverse effects such as teratogenicity, hypertransaminemia and so its use has been limited by the FDA. (Krum et al., 1998)

The future of these drugs is uncertain. The results of human trials with these drugs have not reached the results from animal models. To date, these compounds have only been approved for use in patients with pulmonary arterial hypertension. Although they may reduce BP, there are antihypertensive drugs, safer and better tolerated available. However, the biological understanding of endothelin is rapidly evolving and its role in endothelial dysfunction of cardiovascular diseases is still a promising via in the pathogenesis and treatment of hypertension.
