ATZ1993, an Orally Active and Novel Nonpeptide Antagonist for Endothelin Receptors and Inhibition of Intimal Hyperplasia After Balloon Denudation of the Rabbit Carotid Artery

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The present experiments were designed to investigate the effect of ATZ1993 {3-carboxy-4, 5-dihydro-1-[1-(3-ethoxyphenyl)propyl]-7-(5-pyrimidinyl)methoxy-[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 (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 mg·200 ml-1·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 ETA/ETB-receptor antagonist, and the agent when administered orally inhibits effectively intimal hyperplasia after balloon denudation of the rabbit carotid artery.
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