Endothelin activity

Rivera A, Rotter MA, Brugnara C. Endothelins activate Ca(2+)-gated K(+) channels via endothelin B receptors in CD-I mouse erythrocytes. Am J Physiol 1999 277 C746-754. 

Endothelin. The endothelin (ET) peptide family (50) comprises thiee peptides ET-1 (133), ET-2 (134), and ET-3 (135). ET-1, the most abundant, is a 21-amino acid peptide. A 203-amino acid peptide piecuisoi, piepioET, is cleaved after translation by endopeptidases to form a 38-amino acid proET which is converted to active ET by a putative endothelin-converting enzyme (ECE). ET-3 differs from ET-1 and ET-2 by sis amino acids. 

Ro 46-2005 (140) and SB 209670 (141) are the first synthetic orally active endothelin receptor antagonists. The ET receptor is a third ET receptor. 

Endothelin Concerting Enzymes (ECEs) belong to the family of metalloproteases that catalyze the proteolytic activation of big endothelins. 

ET-1 also stimulates anti-apoptotic signal cascades in fibroblasts, vascular smooth muscles and endothelial cells (via phosphatidylinositol-3-kinase and Akt/pro-tein kinase B). In prostate and ovarian cancer, upregulation of endothelin synthesis and ETA receptors has been associated with a progression of the disease. The inhibiton of ETA receptors results in a reduced tumour growth. In malignant melanoma, ETB receptors are associated with tumour progression. Endothelins can also stimulate apoptosis in stretch-activated vessels via the ETB receptor, which contrasts the above-mentioned effects. The molecular basis for these differential anti- and pro-apoptotic reactions mediated by endothelins remains elusive. 

As endothelins mediate potent vasoconstrictor effects, ECE inhibitors and endothelin receptor antagonists were developed for the treatment of cardiovascular diseases, such as acute and chronic heart failure, pulmonary hypertension and subarachnoid haemorrhage. As ETa recqrtors have potent mitogenic responses and may promote progression of ovarian and prostate cancer and bone metastases ETA receptors are also considered as a potential targets for anti-tumour activity. 

Khodorova A, Navarro B, Jouaville LS et al (2003) Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury. Nat Med 9 1055-1061... 

Most GPCRs interact with and activate more than one G-protein subfamily, e.g., with Gs plus Gq/n (histamine H2, parathyroid hormone and calcitonin recqrtors), Gs plus G (luteinising hormone receptor, 32-adrenoceptor) or Gq/11 plus G12/13 (thromboxane A2, angiotensin ATb endothelin ETA receptors). Some receptors show even broader G-protein coupling, e.g., to Gi, Gq/n plus Gi n ( protease-activated receptors, lysophosphatidate and sphingosine-1-phosphate receptors) or even to all four G-protein subfamilies (thyrotropin receptor). This multiple coupling results in multiple signaling via different pathways and in a concerted reaction of the cell to the stimulus. 

Recent evidence from our laboratory shows that the supernatants of HHMC activated by anti-IgE can convert a synthetic substrate of big endothelin to endothelin 1. The latter observation is particularly important because endothelin 1 is a potent bronchoconstrictor in allergic subjects [30]. 

Advenier C, Sarria B, Naline E. Bybasset L. Lagente 42 V Contractile activity of three endothelins (ET-1,... 

Astles PC, Brown TJ, Handscombe CM, Harper MF, Harris NV, Lewis RA, Lockey PM, McCarthy C, McLay IM, Porter B, Roach AG, Smith C, Walsh RJA. Selective endothelin A receptor antagonists. 1. Discovery and structure-activity of 2,4-disubstituted benzoic acid derivatives. Eur J Med Ghent 1997 32 409-23. 

Sanders et al. [133] found that although quercetin treatment of streptozotocin diabetic rats diminished oxidized glutathione in brain and hepatic glutathione peroxidase activity, this flavonoid enhanced hepatic lipid peroxidation, decreased hepatic glutathione level, and increased renal and cardiac glutathione peroxidase activity. In authors opinion the partial prooxidant effect of quercetin questions the efficacy of quercetin therapy in diabetic patients. (Antioxidant and prooxidant activities of flavonoids are discussed in Chapter 29.) Administration of endothelin antagonist J-104132 to streptozotocin-induced diabetic rats inhibited the enhanced endothelin-1-stimulated superoxide production [134]. Interleukin-10 preserved endothelium-dependent vasorelaxation in streptozotocin-induced diabetic mice probably by reducing superoxide production by xanthine oxidase [135]. 

The pathogenesis of hypertension in patients with CKD is multifactorial and includes fluid retention, increased sympathetic activity, an endogenous digitalis-like substance, elevated levels of endothelin-1, erythropoietin use, hyperparathyroidism, and structural arterial changes. 

M. V. Hoang, A. J. Turner, Novel Activity of Endothelin-Converting Enzyme Hydrolysis of Bradikinin , Biochem. J. 1997, 327, 23-26. 

Figure 22.4 Injury to endothelial cells can lead to vasospasm. Normal endothelial cells release nitric oxide (NO) which relaxes smooth muscle this is achieved by nitric oxide increasing the concentration of cyclic GMP within smooth muscle fibres and cyclic GMP relaxing the smooth muscle. Injured endothelial cells secrete very little nitric oxide but secrete more endothelin. The latter increases the formation of inositol trisphosphate (IP3), which binds to the sarcoplasmic reticulum (SR) where it stimulates the Ca ion channel. The Ca ion channel in the plasma membrane is also activated. Both effects result in an increase in cytosolic Ca ion concentration, which then stimulates contraction (vasospasm). This reduces the diameter of the lumen of the artery.

R.A.F. Discovery ofTBC11251, a potent, long acting, orally active endothelin receptor-A selective antagonist./. Med. Chem. 1997, 40, 1690-1697. 

B., Okun, I., and Castillo, R.S. Structure-activity relationships of N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides as selective endothelin receptor-A antagonists. 

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