Endothelin l

Mechanism of Action An antihypertensive that blocks endothelin-l, the neurohormone that constricts pulmonary arteries. Therapeutic Effect Improves exercise ability and slows clinical worsening of pulmonary arterial hypertension (PAH). Pharmacokinetics Highlybound to plasma proteins, mainlyalbumin. Metabolized in the liver. Eliminated by biliary excretion. Half-life Approximately 5 hr. 

Fig. (18). Effect of kuwanon H (2) on agonist-induced increases in [Ca2+I, in Swiss 3T3 cells. Cells were stimulated by I O mol/L bombesin (BOM), 10" mol/L endothelin-l (ET) or 10" mol/L bradykinin (BK). Kuwanon H (S, 500 nmol/L at the final concentration) or dimethyl sulfoxide (V) was added I min before stimulation.

The thrombotic disorders include atherothrombosis, endothelial dysfunction, hypercoagulable states, and the thrombophilias. Atherothrombosis or atherosclerosis is a systemic disease of the vessel wall occuring in the aorta, carotid, coronary, and peripheral arteries. The associated inflammatory response is mediated by macrophages and T-lymphocytes with continued smooth muscle cell proliferation, The levels of endothelin-l (ET-I), an extremely potent... 

Known substrates of CatA include endothelin 1, angiotensin I, bradykinin, substance P, and oxytocin, with endothelin 1 being so far the substrate with the highest affinity toward the enzyme [7], Among the substrates depicted in Figure 23.2, the affinity toward CatA decreases in the following fashion endothelin l>substance P (acid form)>oxytocin (acid form) = angiotensin l>bradykinin>oxytocin = substance P. 

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

Stenberg, P., Luthman, K., Ellens, H., Lee, C. P., Smith, Ph. L, Lago, A., Elliott, J. D. Artursson, P. Prediction of the intestinal absorption of endothelin receptor antagonists using three theoretical methods of increasing complexity. Pharm. Res. 1999, 16, 1520-1526. 

Murugesan N, Gu Z, Fadnis L, et al. Dual angiotensin II and endothelin A receptor antagonists synthesis of 2 -substituted N-3-isoxazolyl biphenylsulfonamides with improved potency and pharmacokinetics. J Med Chem 2005 48 171-179. 

B8. Beishuizen, A, Gotz, J. M., Kip, L Haanen, C., and Vermes, I Elevated plasma levels of endothelin are associated with the severity of sepsis and presence of shock in contrast to the levels of atrial natriuretic peptide. Med. Inflam. 1,419-423 (1992). 

Holla, L. L, Vasku, A., Izakovic, V., and Znojil, V. (2001) Variants of endothelin-1 gene in atopic diseases. J. Investig. Allergol. Clin. Immunol. 11, 193-198. 

Kozak, M., Izakovicova, H. L., Krivan, L., et al. (2004) Endothelin-1 gene polymorphism in patients with malignant arrhythmias. J. Cardiovasc. Pharmacol. 44, S92-S95. 

Tiret, L., Poirier, O., HaUet, V., et al. (1999) The Lysl98Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people. Hypertension. 33, 1169-1174. 

Barden, A. E., Herbison, C. E., Beilin, L. J., Michael, C. A., Walters, B. N., and Van Bockxmeer, E. M. (2001) Association between the endotheUn-l gene Lysl98Asn polymorphism blood pressure and plasma endothelin-1 levels in normal and pre-eclamptic pregnancy. J. Hypertens. 19, 1775-1782. 

Eckman, E.A., Watson, M., Marlow, L., Sambamurti, K., Eckman, C.B. (2003) Alzheimer s disease P-amyloid peptide is increased in mice deficient in endothelin-converting enzyme. J. Biol. Chem., 278, 2081-2084. 

P. Johnstrom, F.l. Aigbirhio, J.C. Clark, S.P.M.J. Downey, J.D. Pickard, A.P. Davenport, Syntheses of the first endothelin-A- and -B-selective radioligands for positron emission tomography, J. Cardiovasc. Pharmacol. 36 (2000) S58-S60. 

Pairet L, Wrigley SK, Chetland I, Reynolds EE, Hayes MA, Holloway J, Ainsworth AM, Katzer W, Cheng X-M, Hupe DJ, Charlton P, Doherty AM (1995) Azaphilones with Endothelin Receptor Binding Activity Produced by Penicillium sclerotiorum Taxonomy, Fermentation, Isolation, Structure Elucidation and Biological Activity. J Antibiot 48 913... 

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