Hiroshi Azuma1, Jun Sato1, Hiroshi Masuda1,
Moritaka Goto1, Satoru Tamaoki1, Akiko Sugimoto1,
Hidehisa Hamasaki2 and Haruo Yamashita2
1Department of Molecular Design, Institute of Biomedicals & Bioengineering, Tokyo Medical & Dental University, 2 - 3 - 10 Surugadai, Kanda, Chiyoda-ku, Tokyo 101 - 0062, Japan
2Pharmacology and Organic Chemistry Research Departments, Teikoku Hormone MFG., 1604 Shimo-Sakunobe, Takatsu-ku, Kawasaki 213 - 8522, Japan
Abstract: The present experiments were designed to investigate the effect of ATZ1993 o3-carboxy-4,5-dihydro-1-[1-(3-ethoxyphenyl)propyl]-7-(5-pyrimidinyl)methoxy-[1H]-benz[g]indazolep 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 (ETA) with a pKi value of 8.69}0.02, but also to ET-receptor subtype B (ETB) 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 mgE200 ml-1Ekg-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 ETA/ETB-receptor antagonist, and the agent when administered orally inhibits effectively intimal hyperplasia after balloon denudation of the rabbit carotid artery.
Keywords: ATZ1993, Novel endothelin receptor antagonist, Inhibition of intimal hyperplasia, Balloon endothelial denudation, Rabbit carotid artery