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

Access this Article

Author(s)

    • Sato Jun SATO Jun
    • Department of Molecular Design, Institute of Biomedicals & Bioengineering, Tokyo Medical & Dental University
    • GOTO Moritaka
    • Department of Molecular Design, Institute of Biomedicals & Bioengineering, Tokyo Medical & Dental University
    • TAMAOKI Satoru
    • Department of Molecular Design, Institute of Biomedicals & Bioengineering, Tokyo Medical & Dental University
    • SUGIMOTO Akiko
    • Department of Molecular Design, Institute of Biomedicals & Bioengineering, Tokyo Medical & Dental University
    • HAMASAKI Hidehisa
    • Pharmacology and Organic Chemistry Research Departments, Teikoku Hormone MFG.
    • YAMASHITA Haruo
    • Pharmacology and Organic Chemistry Research Departments, Teikoku Hormone MFG.

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)methoxy-[1<I>H</I>]-benz[<I>g</I>]indazole} on the intimal hyperplasia after balloon endothelial denudation of the rabbit carotid artery. ATZ1993 inhibited the specific [<SUP>125</SUP>I]endothelin (ET)-1 binding not only to ET-receptor subtype A (ET<SUB>A</SUB>) with a pK<SUB>i</SUB> value of 8.69±0.02, but also to ET-receptor subtype B (ET<SUB>B</SUB>) with a pK<SUB>i</SUB> 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<SUP>-1</SUP>·kg<SUP>-1</SUP> 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<SUB>A</SUB>/ET<SUB>B</SUB>-receptor antagonist, and the agent when administered orally inhibits effectively intimal hyperplasia after balloon denudation of the rabbit carotid artery.

Journal

  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 81(1), 21-28, 1999-09

    The Japanese Pharmacological Society

References:  30

Codes

  • NII Article ID (NAID)
    10008196045
  • NII NACSIS-CAT ID (NCID)
    AA00691188
  • Text Lang
    ENG
  • Article Type
    ART
  • ISSN
    00215198
  • NDL Article ID
    4867767
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z53-D199
  • Data Source
    CJP  NDL  J-STAGE 
Page Top