title: ATZ1993, an orally active and novel nonpeptide antagonist for endothelin receptors and inhibition of intimal hyperplasia after balloon denudation of the rabbit carotid artery.
abstract: The present experiments were designed to investigate the effect of ATZ1993 [3-carboxy-4,5-dihydro-1-[1-(3-ethoxyphenyl)propyl]-7-(5-pyrimidinyl)met hoxy-[1H]-benz[g]indazole] on the intimal hyperplasia after balloon endothelial denudation of the rabbit carotid artery. ATZ1993 inhibited the specific [125I]endothelin (ET)-1 binding not only to ET-receptor subtype A (ET(A)) with a pKi value of 8.69+/-0.02, but also to ET-receptor subtype B (ET(B)) with a pKi value of 7.20+/-0.03. Counterscreening in the binding assay (30 different receptors) confirmed that ATZ1993 had a high selectivity for ET receptors. Increases in intima:media ratio and DNA content in the vessel wall were significantly (P < 0.005) inhibited by ATZ1993 in a daily dose of 30 mg x 200 ml(-1) x kg(-1) for 1 week before and 6 weeks after balloon denudation. Inhibition of the intimal hyperplasia with ATZ1993 was determined as approximately 77% for increases in intima:media ratio and DNA content. Plasma concentrations of ATZ1993 ranged between 121.6+/-26.6 and 131.7+/-20.9 nM throughout experimental periods. Mean arterial blood pressure, heart rate and body weight gain remained unaffected by administering ATZ1993. These results demonstrate that ATZ1993 is a novel nonpeptide and nonselective ET(A)/ET(B)-receptor antagonist, and the agent when administered orally inhibits effectively intimal hyperplasia after balloon denudation of the rabbit carotid artery.
authors.affiliation: Department of Molecular Design, Institute of Biomedicals & Bioengineering, Tokyo Medical & Dental University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Azuma
authors.forename: J
authors.initials: J
authors.lastname: Sato
authors.forename: H
authors.initials: H
authors.lastname: Masuda
authors.forename: M
authors.initials: M
authors.lastname: Goto
authors.forename: S
authors.initials: S
authors.lastname: Tamaoki
authors.forename: A
authors.initials: A
authors.lastname: Sugimoto
authors.forename: H
authors.initials: H
authors.lastname: Hamasaki
authors.forename: H
authors.initials: H
authors.lastname: Yamashita
mesh_terms: D000284:Administration, Oral; D000800:Angioplasty, Balloon; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D020212:Carotid Artery Injuries / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D017536:Carotid Artery, Common / Q000187:drug effects / Q000473:pathology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006965:Hyperplasia; D007191:Indazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011817:Rabbits; D017466:Receptors, Endothelin / Q000378:metabolism / Q000502:physiology; D013552:Swine; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology*
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007191:Indazoles; D017466:Receptors, Endothelin; C402783:ATZ1993