Pharmacological Profiles of a Novel Non-peptide Angiotensin II Type I Receptor Antagonist HR720 In Vitro and In Vivo

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he pharmacological properties of 2-butyl-4-(methylthio)-1-[[2'' [[[(propylamino)carbonyl] amino] sulfonyl](1, 1'' biphenyl)-4-yl]methyl]-1<I>H</I>-imidazole-5-carboxylate (HR720), a novel non-peptide angiotensin (Ang) II type I (AT<SUB>1</SUB>) receptor antagonist, were characterized in both in vitro and in vivo systems. In vitro autoradiography using <SUP>125</SUP>I-[Sar<SUP>1<SUP>, IIe<SUP>8</SUP>]Ang II as a ligand revealed that HR720 competitively inhibited the specific binding of the ligand to the adrenal cortex. The IC<SUB>50</SUB> value for the adrenal cortex was 1.5 x 10<SUP>-8</SUP> M, and the IC<SUB>50</SUB> for medulla was 1.4 x 10<SUP>-6</SUP> M. Similar results were obtained in the adrenal cortex with CV-11974, a known potent AT<SUB>1</SUB>-receptor antagonist. Since AT1 receptors are known to predominate in the adrenal cortex and AT<SUB>2</SUB>-receptors in the adrenal medulla, it is considered that HR720 is highly selective for AT, receptors. HR720 inhibited the Ang II-induced contraction of isolated rabbit aortic strips and human gastroepiploic arteries in a noncompetitive manner, pD''<SUB>2</SUB>=9.40 and 9.62 for rabbit aorta and human artery, respectively. With CV-11974, pD''<SUB>2</SUB> values of 9.84 in isolated rabbit aorta and 10.00 in human artery were obtained. HR720 did not affect the norepinephrine-, serotonin or KCl-induced contraction even at a concentration of 1 x 10<SUP>-5</SUP> M. In anesthetized hamsters, HR720 induced a dose-dependent inhibition of the pressure response to Ang II. The potency of HR720 to antagonize the Ang II-induced pressure response was similar to that of CV-11974. These results demonstrate that HR720 is a potent and selective AT<SUB>1</SUB> -receptor antagonist.

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  • The Japanese journal of pharmacology

    The Japanese journal of pharmacology 75(3), 259-266, 1997-11-01

    The Japanese Pharmacological Society

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各種コード

  • NII論文ID(NAID)
    10008190015
  • NII書誌ID(NCID)
    AA00691188
  • 本文言語コード
    ENG
  • 資料種別
    ART
  • ISSN
    00215198
  • NDL 記事登録ID
    4346256
  • NDL 雑誌分類
    ZS51(科学技術--薬学)
  • NDL 請求記号
    Z53-D199
  • データ提供元
    CJP書誌  NDL  J-STAGE 
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