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Chemical Compound Review

Actelion     N-[6-(2-hydroxyethoxy)-5-(2...

Synonyms: Bosentan, Tracleer, bosentanum, CHEMBL957, SureCN4218, ...
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Disease relevance of Bosentan


High impact information on Bosentan


Chemical compound and disease context of Bosentan


Biological context of Bosentan


Anatomical context of Bosentan

  • Compared with placebo, bosentan on day 1 significantly decreased mean arterial pressure (difference from baseline over 12 hours [95% CIs], -13.9% [-16.0% to -11.7%]), pulmonary artery mean (-12.9% [-17. 4% to -8.3%]) and capillary wedge (-14.5% [-20.5% to -8.5%]) pressures, and right atrial pressure (-20.2% [-29.4% to -11.0%]) [4].
  • METHODS AND RESULTS: Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg x kg(-1) x d(-1)) [17].
  • Chronic bosentan treatment also decreased ET-1 levels (390+/-33 versus 475+/-22 pg/g tissue, P<.05) and density of ET-1 receptors (262+/-24 versus 346+/-31 fmol/mg protein, P<.05) in left ventricular myocardium [5].
  • In contrast, reperfusion in the presence of the endothelinA+B receptor antagonist bosentan (2 x 10(-4) mol/L) restored functional sinusoid density and surface PO2 to baseline values, resulted in a small reduction in the number of propidium iodide-positive hepatocytes, and caused similar increases in enzyme release as compared with vehicle [20].
  • Improved blood flow was not mediated by nitric oxide production, because bosentan had no effect on cerebrospinal fluid or plasma nitrite/nitrate concentrations at 6, 12, or 18 hours [21].

Associations of Bosentan with other chemical compounds

  • BQ-123, an ET-A receptor antagonist, and bosentan, a nonselective ET receptor antagonist, significantly blocked the hypertrophic response of MCs induced by treatment with NMC-conditioned media [22].
  • To assess whether endothelin contributes to the pressor response induced by inhibition of NO synthesis, we tested whether bosentan, a nonpeptide antagonist of ETA and ETB endothelin receptors, affected the hypertensive response induced by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) [23].
  • After 6 months of follow-up, diabetes and galactose feeding induced basement membrane thickening, which was partially prevented by bosentan treatment [24].
  • Oral bosentan, an endothelin A/B receptor antagonist, decreased distal nephron H+ secretion in HiPro rats as a result of reduced Na+/H+ exchange and H+-ATPase activity as shown previously by the authors' laboratory [25].
  • Similarly, pretreatment with the endothelin antagonist bosentan abolished the effects of AP6A on both urine flow and Na+ excretion, whereas suramin had no effects on the AP6A-induced increase in urine flow [26].
  • At steady state, concomitant rifampin significantly decreased exposure to bosentan by 58% [27].

Gene context of Bosentan

  • Hemodynamic and coronary effects of the endothelin antagonist bosentan in patients with coronary artery disease [16].
  • The ETA/ETB receptor antagonist bosentan caused a parallel shift of the concentration-contraction curve to the right at all concentrations of endothelin [28].
  • For determination of whether endothelin-1-mediated effects were crucial in the transition from benign to malignant phase hypertension, an oral nonspecific combined endothelin-A and endothelin-B receptor antagonist (bosentan) was given to hypertensive rats susceptible to malignant hypertension [29].
  • Furthermore, bosentan, a pharmacological inhibitor of Endothelin-1 signaling caused a loss of I56i-lacZ expression in the most distal aspects of the expression domain, corresponding to the area of Dlx-6 expression previously shown to be under the control of Endothelin-1 [30].
  • Acute inhibition of both ETA and ETB receptors with bosentan dramatically prolonged 125I-ET-1 plasma half-life and shifted tissue uptake from lung to liver and kidneys [31].

Analytical, diagnostic and therapeutic context of Bosentan

  • 24 patients with chronic heart failure received randomly and double blind two intravenous infusions of either placebo or bosentan (100 mg followed after 60 min by 200 mg) [32].
  • CONCLUSIONS--Endothelin plays a role in the maintenance of blood pressure in CHF rats, as evidenced by the significant reduction in mean arterial pressure after oral administration of bosentan [33].
  • METHODS AND RESULTS: Three hours after coronary ligation or sham operation, bosentan (100 mg x kg body wt(-1) x d(-1)) or placebo was given by gavage [5].
  • Role of endogenous endothelin in the development of graft arteriosclerosis in rat cardiac allografts: antiproliferative effects of bosentan, a nonselective endothelin receptor antagonist [34].
  • METHODS AND RESULTS: Recipient male Lewis rats were divided into three groups; group 1 received heterotopic heart transplantations from Lewis donors and groups 2 and 3 received transplantations from Brown-Norway donors; group 3 recipients also received bosentan orally at the dose of 20 mg/kg per day for 120 days [34].


  1. Bosentan in essential hypertension. Haynes, W.G., Ferro, C.J., Webb, D.J. N. Engl. J. Med. (1998) [Pubmed]
  2. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Channick, R.N., Simonneau, G., Sitbon, O., Robbins, I.M., Frost, A., Tapson, V.F., Badesch, D.B., Roux, S., Rainisio, M., Bodin, F., Rubin, L.J. Lancet (2001) [Pubmed]
  3. Use of a mixed endothelin receptor antagonist in portopulmonary hypertension: a safe and effective therapy? Kuntzen, C., Gülberg, V., Gerbes, A.L. Gastroenterology (2005) [Pubmed]
  4. Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Sütsch, G., Kiowski, W., Yan, X.W., Hunziker, P., Christen, S., Strobel, W., Kim, J.H., Rickenbacher, P., Bertel, O. Circulation (1998) [Pubmed]
  5. Chronic endothelin receptor blockade attenuates progressive ventricular dilation and improves cardiac function in rats with myocardial infarction: possible involvement of myocardial endothelin system in ventricular remodeling. Fraccarollo, D., Hu, K., Galuppo, P., Gaudron, P., Ertl, G. Circulation (1997) [Pubmed]
  6. Experience with inhaled iloprost and bosentan in portopulmonary hypertension. Hoeper, M.M., Seyfarth, H.J., Hoeffken, G., Wirtz, H., Spiekerkoetter, E., Pletz, M.W., Welte, T., Halank, M. Eur. Respir. J. (2007) [Pubmed]
  7. Safety and tolerability of bosentan in idiopathic pulmonary fibrosis: an open label study. Günther, A., Enke, B., Markart, P., Hammerl, P., Morr, H., Behr, J., Stähler, G., Seeger, W., Grimminger, F., Leconte, I., Roux, S., Ghofrani, H.A. Eur. Respir. J. (2007) [Pubmed]
  8. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan Hypertension Investigators. Krum, H., Viskoper, R.J., Lacourciere, Y., Budde, M., Charlon, V. N. Engl. J. Med. (1998) [Pubmed]
  9. Nitric oxide inhibition induces early activation of type I collagen gene in renal resistance vessels and glomeruli in transgenic mice. Role of endothelin. Chatziantoniou, C., Boffa, J.J., Ardaillou, R., Dussaule, J.C. J. Clin. Invest. (1998) [Pubmed]
  10. Reduction of renal mass is lethal in mice lacking vimentin. Role of endothelin-nitric oxide imbalance. Terzi, F., Henrion, D., Colucci-Guyon, E., Federici, P., Babinet, C., Levy, B.I., Briand, P., Friedlander, G. J. Clin. Invest. (1997) [Pubmed]
  11. Differential effects of endothelin-1 antagonists on erythropoietin-induced hypertension in renal failure. Brochu, E., Lacasse, S., Larivière, R., Kingma, I., Grose, J.H., Lebel, M. J. Am. Soc. Nephrol. (1999) [Pubmed]
  12. Endothelin is an important determinant of renal function in a rat model of acute liver and renal failure. Anand, R., Harry, D., Holt, S., Milner, P., Dashwood, M., Goodier, D., Jarmulowicz, M., Moore, K. Gut (2002) [Pubmed]
  13. Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. Barst, R.J., Ivy, D., Dingemanse, J., Widlitz, A., Schmitt, K., Doran, A., Bingaman, D., Nguyen, N., Gaitonde, M., van Giersbergen, P.L. Clin. Pharmacol. Ther. (2003) [Pubmed]
  14. Prevention of the cardiovascular and renal effects of angiotensin II by endothelin blockade. Herizi, A., Jover, B., Bouriquet, N., Mimran, A. Hypertension (1998) [Pubmed]
  15. Effects of endothelin or angiotensin II receptor blockade on diabetes in the transgenic (mRen-2)27 rat. Kelly, D.J., Skinner, S.L., Gilbert, R.E., Cox, A.J., Cooper, M.E., Wilkinson-Berka, J.L. Kidney Int. (2000) [Pubmed]
  16. Hemodynamic and coronary effects of the endothelin antagonist bosentan in patients with coronary artery disease. Wenzel, R.R., Fleisch, M., Shaw, S., Noll, G., Kaufmann, U., Schmitt, R., Jones, C.R., Clozel, M., Meier, B., Lüscher, T.F. Circulation (1998) [Pubmed]
  17. Role of endogenous endothelin in chronic heart failure: effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling. Mulder, P., Richard, V., Derumeaux, G., Hogie, M., Henry, J.P., Lallemand, F., Compagnon, P., Macé, B., Comoy, E., Letac, B., Thuillez, C. Circulation (1997) [Pubmed]
  18. Beneficial hemodynamic effects of bosentan, a mixed ET(A) and ET(B) receptor antagonist, in portal hypertensive rats. Sogni, P., Moreau, R., Gomola, A., Gadano, A., Cailmail, S., Calmus, Y., Clozel, M., Lebrec, D. Hepatology (1998) [Pubmed]
  19. Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: implications for regulation of portal pressure and resistance. Rockey, D.C., Weisiger, R.A. Hepatology (1996) [Pubmed]
  20. Role of endothelins and nitric oxide in hepatic reperfusion injury in the rat. Pannen, B.H., Al-Adili, F., Bauer, M., Clemens, M.G., Geiger, K.K. Hepatology (1998) [Pubmed]
  21. Endothelin inhibition improves cerebral blood flow and is neuroprotective in pneumococcal meningitis. Pfister, L.A., Tureen, J.H., Shaw, S., Christen, S., Ferriero, D.M., Täuber, M.G., Leib, S.L. Ann. Neurol. (2000) [Pubmed]
  22. Significance of ventricular myocytes and nonmyocytes interaction during cardiocyte hypertrophy: evidence for endothelin-1 as a paracrine hypertrophic factor from cardiac nonmyocytes. Harada, M., Itoh, H., Nakagawa, O., Ogawa, Y., Miyamoto, Y., Kuwahara, K., Ogawa, E., Igaki, T., Yamashita, J., Masuda, I., Yoshimasa, T., Tanaka, I., Saito, Y., Nakao, K. Circulation (1997) [Pubmed]
  23. In vivo evidence of an endothelin-induced vasopressor tone after inhibition of nitric oxide synthesis in rats. Richard, V., Hogie, M., Clozel, M., Löffler, B.M., Thuillez, C. Circulation (1995) [Pubmed]
  24. Endothelin receptor blockade prevents augmented extracellular matrix component mRNA expression and capillary basement membrane thickening in the retina of diabetic and galactose-fed rats. Evans, T., Deng, D.X., Chen, S., Chakrabarti, S. Diabetes (2000) [Pubmed]
  25. Endothelin-induced increased aldosterone activity mediates augmented distal nephron acidification as a result of dietary protein. Khanna, A., Simoni, J., Wesson, D.E. J. Am. Soc. Nephrol. (2005) [Pubmed]
  26. Effects of diadenosine polyphosphates on renal function and blood pressure in anesthetized Wistar rats. Hohage, H., Reinhardt, C., Borucki, U., Enck, G., Schlüter, H., Schlatter, E., Zidek, W. J. Am. Soc. Nephrol. (1996) [Pubmed]
  27. Inhibitory and inductive effects of rifampin on the pharmacokinetics of bosentan in healthy subjects. van Giersbergen, P.L., Treiber, A., Schneiter, R., Dietrich, H., Dingemanse, J. Clin. Pharmacol. Ther. (2007) [Pubmed]
  28. Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Seo, B., Oemar, B.S., Siebenmann, R., von Segesser, L., Lüscher, T.F. Circulation (1994) [Pubmed]
  29. Endothelin in the kidney in malignant phase hypertension. Whitworth, C.E., Veniant, M.M., Firth, J.D., Cumming, A.D., Mullins, J.J. Hypertension (1995) [Pubmed]
  30. Intergenic enhancers with distinct activities regulate Dlx gene expression in the mesenchyme of the branchial arches. Park, B.K., Sperber, S.M., Choudhury, A., Ghanem, N., Hatch, G.T., Sharpe, P.T., Thomas, B.L., Ekker, M. Dev. Biol. (2004) [Pubmed]
  31. Receptor- and non-receptor-mediated clearance of big-endothelin and endothelin-1: differential effects of acute and chronic ETA receptor blockade. Burkhardt, M., Barton, M., Shaw, S.G. J. Hypertens. (2000) [Pubmed]
  32. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Kiowski, W., Sütsch, G., Hunziker, P., Müller, P., Kim, J., Oechslin, E., Schmitt, R., Jones, R., Bertel, O. Lancet (1995) [Pubmed]
  33. Role of endothelin in the maintenance of blood pressure in conscious rats with chronic heart failure. Acute effects of the endothelin receptor antagonist Ro 47-0203 (bosentan). Teerlink, J.R., Löffler, B.M., Hess, P., Maire, J.P., Clozel, M., Clozel, J.P. Circulation (1994) [Pubmed]
  34. Role of endogenous endothelin in the development of graft arteriosclerosis in rat cardiac allografts: antiproliferative effects of bosentan, a nonselective endothelin receptor antagonist. Okada, K., Nishida, Y., Murakami, H., Sugimoto, I., Kosaka, H., Morita, H., Yamashita, C., Okada, M. Circulation (1998) [Pubmed]
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