Endothelin inhibition

Elastase, inhibition, 31 (1994) 59 Electron spin resonance, 12 (1975) 191 Electrophysiological (Class III) agents for arrhythmia, 29 (1992) 65 Endorphins, 17 (1980) 1 Endothelin inhibition, 31 (1994) 371 Enkephalin-degrading enzymes, 30 (1993)... 

Angiotensin II, vasopressin, and endothelin inhibit K tp channels in cultured coronary artery smooth muscle cells (e.g., Miyoshi et al, 1992). Muscarinic receptor stimulation inhibited K jp channels in smooth muscle cells in urinary bladder through stimulation of protein kinase C (Bonev and Nelson, 1993b). Serotonin, phenylephrine, histamine, and neuropeptide Y also inhibit K jp currents in smooth muscle cells from mesenteric arteries through stimulation of protein kinase C (Bonev and Nelson, 1995). 

Endothelin inhibited the evoked H-norepi-nephrine overflow in guinea-pig pulmonary artery (WiKLUND et al. 1989). 

A great number of ECE-inhibitors and mixed and selective ETA and ETB receptor antagonists have been developed in the past. For specific inhibitors of ECE, however, only very limited effects on the endothelin system were found. The limited potency of ECE inhibition might be due to the generation of mature... 

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. 

Fattinger, K., Funk, C., Pantze, M., Weber, C., Reichen, J., Stieger, B., Meier, P. J., The endothelin antagonist bosentan inhibits the canalicular bile salt export pump a potential mechanism for hepatic... 

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 formation of endothelins can be blocked by inhibiting endothelin-converting enzyme with phosphoramidon. Phosphoramidon is not specific for endothelin-converting enzyme, but several more selective inhibitors are now available for research. Although the therapeutic potential of these drugs appeared similar to that of the endothelin receptor antagonists (see below), their use has been eclipsed by endothelin antagonists. 

Opitz CF et al Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension Does selectivity matter Eur Heart J 2008 29 1936. [PMID 18562303]... 

Ohkita M, Takaoka M, Shiota Y, Nojiri R, Matsumura Y. 2002. Nitric oxide inhibits endothelin-1 production through the suppression of nuclear factor kappa B. Clin Sci 103 68S-71S. 

Romero M, Jimenez R, Sanchez M, Lopez-Sepulveda R, Zarzuelo MJ, O Valle F, Zarzuelo A, Perez-Vizcaino F, Duarte J. 2008. Quercetin inhibits vascular superoxide production induced by endothelin-1 Role of NADPH oxidase, uncoupled eNOS and PKC. Atherosclerosis. 

Spinella F, Rosano L, Di Castro V, Decandia S, Albini A, Nicotra MR, Natali PG, Bagnato A. 2006. Green tea polyphenol epigallocatechin-3-gallate inhibits the endothelin axis and downstream signaling pathways in ovarian carcinoma. Mol Cancer Ther 5 1483-1492. 

Rivaroxaban (BAY 59-7939) <2005JME5900> is an oral anticoagulant currently under development. It acts by inhibiting the active form of coagulation factor Xa. Sitaxentan <2004JME1969, 2005MI985> is an orally active sulfonamide class endothelin-A receptor antagonist. 

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