Endothelin antagonism

Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selec-tive endothelin antagonism in heart failure Int J Cardiol 2002 85(2-3) 195-7. 

Verma S, Li SH, Badiwala MV, et al. Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation 2002 105 1890-1896. 

Nitric oxide, a vasodilatory hormone released by the endothelium, is found in higher concentrations in HF patients and provides two main benefits in HF vasodilation and neurohormonal antagonism of endothelin.9 Nitric oxide s production is affected by the enzyme inducible nitric oxide synthetase (iNOS), which is up-regulated in the setting of HF, likely due to increased levels of angiotensin II, norepinephrine, and multiple cytokines. In HF, the physiologic response to nitric oxide appears to be blunted, which contributes to the imbalance between vasoconstriction and vasodilation. 

Wang A, Ffolcslaw T Bashore TM, et al. Exacerbation of radio-contrast nephrotoxicity by endothelin receptor antagonism. Kidney Int 2000 57 1675-1680. 

The first compound with published detailed information which supports the claims for a specific ETg antagonist is IRL 1038, (20) [Cys -Cys ] ET-1 (11-21). This compound showed specific antagonist activity both in binding assays and in endothelin-induced contraction models. With ET-3 as agonist, 3 /M IRL 1038 antagonized the ETb receptor-mediated contraction of guinea-pig ileal and tracheal smooth muscle but did not affect the ET receptor-mediated contraction of rat aortic tissue [110]. 

Wang A, HolcsIawT, BashoreTM, Freed Ml, Miller D, RudnickMR, Szerlip H,Thames MD, Davidson CJ, Shusterman N, Schwab SJ Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int 57 1675-80,2000... 

Kon V, Flunley TE, Fogo A. Combined antagonism of endothelin A/B receptors links endothelin to vasoconstriction whereas angiotensin II effects fibrosis. Studies in chronic cyclosporine nephrotoxicity in rats.Transplantation 1995 60 89-95. 

Packer M, McMurray J, Massie BM, et al. Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure results of a pilot study. J Cardiac Fail 2005 1 12-20. 

Fogo A, Flellings SE, Inagami T, Kon V. Endothelin receptor antagonism is protective in in vivo acute cyclosporine toxicity. Kidney Int 1992 42 770-774. 

Bosentan is an endothelin receptor antagonist. It antagonized endothelin (ET) receptor by binding to ET and ETg receptors in the endothelium and vascular smooth muscle. Bosentan is indicated in treatment of pulmonary arterial hypertension in patients with WHO class III and IV symptoms, to improve exercise ability, and decrease the rate of clinical worsening. 

In vitro studies have revealed that a number of mitogens are released by endothelial cells PDGF-A and -B [280,281], bFGF [282,283], endothelin-1 [284], and connective tissue growth factor [285]. On the other hand, endothelial cells can produce factors that antagonize the SMC proliferation such as heparin [286], and TGFp [287,288], the latter showing either proliferative or inhibitory properties for SMC. 

Endothelin is produced by both endothelial and smooth muscle cells and exerts vasodilator and vasoconstrictor effects via ETA and ETB receptor subtypes, respectively (88). The net effect of endothelin infused to the fetus is dependent upon the vascular bed in question and the proportion of ETA and ETB receptors a sustained pulmonary hypertension and modulation of carotid artery responses to hypoxia via action at ETA receptors (64,89,90) and a renal vasodilatation by ETB-receptor mediated NO release (91). As a result, it is likely that the observed lack of effect of specific antagonism of ETA receptors during late gestation on peripheral vascular resistance or arterial pressure reflects the net effect in a number of vascular beds. 

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