Endothelin peptide receptors

Sarafotoxin is a 21-amino acid peptide which has some structural similarity with endothelins and was isolated from the venom of the burrowing asp. Sarafotoxin is a selective agonist of the endothelin ETB-receptor. 

Endothelins are a family of vasoactive peptides secreted by endothelial cells. The three major endothelin peptides are all composed of 21 amino acids. Endothelins are the most potent vasoconstrictors known. Contraction of vascular smooth muscle in response to endothelin is associated with an increase in intracellular calcium. Increases in endothelin levels have been reported in patients with vasospastic, hypoxic, and ischemic diseases. The two identified isoforms of endothelin receptors have differing affinity for the three endothelin peptides. Selective and nonselective endothelin receptor antagonists are in development for potential use in the treatment of hypertension and other disorders associated with increased vascular resistance. 

Kling A, Muller S, Raschack M, Unger L, Walker N, Wemet W. Discovery and optimization of a novel class of orally active non-peptidic endothelin-A receptor antagonists./. Med. Chem., 1996, 39, 2123-2128. 

Endothelins are peptide vasoconstrictors formed in and released by endothelial cells in blood vessels. Endothelins are believed to function as autocrine and paracrine hormones in the vasculature. Three different endothelin peptides (ET-1, ET-2, and ET-3) with minor variations in amino acid sequence have been identified in humans. Two receptors have been identified, both of which are G protein-coupled. 

An example of the general approach is provided by a study of post-translational modification of the receptor for the peptide hormone, endothelin (Roos et al., 1998). Endothelin, a 21-amino acid peptide, is the strongest vasoconstrictor known it elicits physiological effects on cellular... 

The vascular endothelium produces a number of substances that are released basally into the blood vessel wall to alter vascular smooth muscle tone. One such substance is endothelin (ET-1). Endothelin exerts its effects throughout the body, causing vasoconstriction as well as positive inotropic and chronotropic effects on the heart. The resulting increases in TPR and CO contribute to an increase in MAP. Synthesis of endothelin appears to be enhanced by many stimuli, including Ag II, vasopressin, and the mechanical stress of blood flow on the endothelium. Synthesis is inhibited by vasodilator substances such as prostacyclin, nitric oxide, and atrial natriuretic peptide. There is evidence that endothelin is involved with the pathophysiology of many cardiovascular diseases, including hypertension, heart failure, and myocardial infarction. Endothelin receptor antagonists are currently available for research use only. 

Endothelin 1 (ETl) is a 21-amino acid peptide released from bronchial cells. It has potent vasoconstrictive agonist properties mediated by two receptor types (A and B). The involvement of the endothelin 1 type A (EDNRA) gene (Afill SNP) in atopy, however, is marginal at best and as yet not widely replicated (181). For... 

Non-peptide antagonists of endothelin were discovered by random screening approaches. A comparison of compounds 119 and 120 demonstrates that it is possible to obtain selective and non-selective compounds in the same series by chemical modifications. Carboxyindoline derivative 119 was about 100-fold more selective ETa receptor antagonist and compound 120 was a non-selective antagonist. Another series of... 

E. H. Ohistein, 1,3-Diarylindan-2-carboxylic acids potent and selective non-peptide endothelin receptor antagonists, J. Med. Chem. 37 (1994) 1553-1557. 

Ogawa T, Ando K, Aotani Y, Shinoda K, Tanaka T, Tsukuda E, Yoshida M, Matsuda Y (1995) RES-1214-1 and -2, Novel Non-Peptidic Endothelin Type A Receptor Antagonists Produced by Pestalotiopsis sp. J Antibiot 48 1401... 

In vitro, urotensin II is a potent constrictor of vascular smooth muscle its activity depends on the type of blood vessel and the species from which it was obtained. Vasoconstriction occurs primarily in arterial vessels, where urotensin II can be more potent than endothelin 1, making it the most potent known vasoconstrictor. In vivo, urotensin II has complex hemodynamic effects, the most prominent being regional vasoconstriction and cardiac depression. The extent to which the peptide is involved in the regulation of vascular tone and blood pressure in humans is not clear recent studies have produced conflicting results. The actions of urotensin II are mediated by G protein-coupled receptors that are widely distributed in the brain, spinal cord, heart, vascular smooth muscle, skeletal muscle, and pancreas. Some effects of the peptide including vasoconstriction are mediated by the phospholipase C/IP3/DAG signal transduction pathway. 

Sadowski J, Gasteiger J, Klebe G (1994) Comparison of automatic three-dimensional model builders using 639 X-ray structures. J Chem Inf Comp Sci 34 1000-1008 Stenberg P, Luthman K, Artursson P (1999) Prediction of membrane permeability to peptides from calculated dynamic molecular surface properties. Pharm Res 16 205-212 Stenberg P, Luthman K, Ellens H et al. (1999) Prediction of the intestinal absorption of endothelin receptor antagonists using three theoretical methods of increasing complexity. Pharm Res 16 1520-1526... 

Two different mechanisms have been proposed to explain the cellular events involved in the Ox-LDL-induced endothelin secretion in endothelial cells. Boulanger et al. [126-127] demonstrated that the peptide secretion is mediated by the stimulation of the scavenger receptors by Ox-LDL and that protein kinase C interferes in this process, while Martin-Nizard et al. [128] have reported that lysophosphatidylcholine (LPC) in Ox-LDL exerts a major role in the induction of the secretion of immunoreactive endothelin in endothelial cells. However, M. Jougasaki et al. [133] recently published opposing results. They showed that Ox-LDL suppresses the endothelin secretion by LPC in cultured vascular endothelial cells. 

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