title: The therapeutic potential of endothelin-1 receptor antagonists and endothelin-converting enzyme inhibitors on the cardiovascular system.
abstract: Clinical trials have established bosentan, an orally active non-selective endothelin (ET) receptor antagonist, as a beneficial treatment in pulmonary hypertension. Trials have also shown short-term benefits of bosentan in systemic hypertension and congestive heart failure. However, bosentan also increased plasma levels of ET-1, probably by inhibiting the clearance of ET-1 by endothelin type B (ET(B)) receptors, and this may mean its effectiveness is reduced with long-term clinical use. Preliminary data suggests that selective endothelin type A (ET(A)) receptor antagonists (BQ-123, sitaxsentan) may be more beneficial than the non-selective ET receptor antagonists in heart failure, especially when the failure is associated with pulmonary hypertension. Experimental evidence in animal disease models suggests that non-selective ET or selective ET(A) receptor antagonism may have a role in the treatment of atherosclerosis, restenosis, myocarditis, shock and portal hypertension. In animal models of myocardial infarction and/or reperfusion injury, non-selective ET or selective ET(A) receptor antagonists have beneficial or detrimental effects depending on the conditions and agents used. Thus clinical trials of the non-selective ET or selective ET(A) receptor antagonists in these conditions are not presently warranted. Several selective endothelin-converting enzyme inhibitors have been synthesised recently, and these are only beginning to be tested in animal models of cardiovascular disease, and thus the clinical potential of these inhibitors is still to be defined.
authors.affiliation: Department of Physiology and Pharmacology, School of Biomedical Sciences, The University of Queensland, QLD 4072, Australia. s_doggrell@yahoo.com
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Doggrell
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000201:enzymology; D002319:Cardiovascular System / Q000187:drug effects* / Q000201:enzymology; D065128:Endothelin Receptor Antagonists; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008666:Metalloendopeptidases; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism
chemical_list: D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes