Blood Pressure–Independent Effects in Rats With Human Renin and Angiotensinogen Genes

DOI Web Site 被引用文献2件
  • Eero Mervaala
    From the Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin (Germany) (E.M., D.N.M., F.S., J-K.P., V.G., H.H., F.C.L.); Institute of Biomedicine, University of Helsinki (Finland) (E.M); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B., D.G., H.H., F.C.L.); dF. Hoffmann–La Roche, Basel, Switzerland (V.B.); and Institute for Clinical Pharmacology, Universitätsklinikum-Benjamin Franklin, Free University of Berlin (Germany) (D.G.).
  • Dominik N. Müller
    From the Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin (Germany) (E.M., D.N.M., F.S., J-K.P., V.G., H.H., F.C.L.); Institute of Biomedicine, University of Helsinki (Finland) (E.M); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B., D.G., H.H., F.C.L.); dF. Hoffmann–La Roche, Basel, Switzerland (V.B.); and Institute for Clinical Pharmacology, Universitätsklinikum-Benjamin Franklin, Free University of Berlin (Germany) (D.G.).
  • Folke Schmidt
    From the Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin (Germany) (E.M., D.N.M., F.S., J-K.P., V.G., H.H., F.C.L.); Institute of Biomedicine, University of Helsinki (Finland) (E.M); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B., D.G., H.H., F.C.L.); dF. Hoffmann–La Roche, Basel, Switzerland (V.B.); and Institute for Clinical Pharmacology, Universitätsklinikum-Benjamin Franklin, Free University of Berlin (Germany) (D.G.).
  • Joon-Keun Park
    From the Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin (Germany) (E.M., D.N.M., F.S., J-K.P., V.G., H.H., F.C.L.); Institute of Biomedicine, University of Helsinki (Finland) (E.M); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B., D.G., H.H., F.C.L.); dF. Hoffmann–La Roche, Basel, Switzerland (V.B.); and Institute for Clinical Pharmacology, Universitätsklinikum-Benjamin Franklin, Free University of Berlin (Germany) (D.G.).
  • Volkmar Gross
    From the Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin (Germany) (E.M., D.N.M., F.S., J-K.P., V.G., H.H., F.C.L.); Institute of Biomedicine, University of Helsinki (Finland) (E.M); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B., D.G., H.H., F.C.L.); dF. Hoffmann–La Roche, Basel, Switzerland (V.B.); and Institute for Clinical Pharmacology, Universitätsklinikum-Benjamin Franklin, Free University of Berlin (Germany) (D.G.).
  • Michael Bader
    From the Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin (Germany) (E.M., D.N.M., F.S., J-K.P., V.G., H.H., F.C.L.); Institute of Biomedicine, University of Helsinki (Finland) (E.M); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B., D.G., H.H., F.C.L.); dF. Hoffmann–La Roche, Basel, Switzerland (V.B.); and Institute for Clinical Pharmacology, Universitätsklinikum-Benjamin Franklin, Free University of Berlin (Germany) (D.G.).
  • Volker Breu
    From the Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin (Germany) (E.M., D.N.M., F.S., J-K.P., V.G., H.H., F.C.L.); Institute of Biomedicine, University of Helsinki (Finland) (E.M); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B., D.G., H.H., F.C.L.); dF. Hoffmann–La Roche, Basel, Switzerland (V.B.); and Institute for Clinical Pharmacology, Universitätsklinikum-Benjamin Franklin, Free University of Berlin (Germany) (D.G.).
  • Detlev Ganten
    From the Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin (Germany) (E.M., D.N.M., F.S., J-K.P., V.G., H.H., F.C.L.); Institute of Biomedicine, University of Helsinki (Finland) (E.M); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B., D.G., H.H., F.C.L.); dF. Hoffmann–La Roche, Basel, Switzerland (V.B.); and Institute for Clinical Pharmacology, Universitätsklinikum-Benjamin Franklin, Free University of Berlin (Germany) (D.G.).
  • Hermann Haller
    From the Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin (Germany) (E.M., D.N.M., F.S., J-K.P., V.G., H.H., F.C.L.); Institute of Biomedicine, University of Helsinki (Finland) (E.M); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B., D.G., H.H., F.C.L.); dF. Hoffmann–La Roche, Basel, Switzerland (V.B.); and Institute for Clinical Pharmacology, Universitätsklinikum-Benjamin Franklin, Free University of Berlin (Germany) (D.G.).
  • Friedrich C. Luft
    From the Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin (Germany) (E.M., D.N.M., F.S., J-K.P., V.G., H.H., F.C.L.); Institute of Biomedicine, University of Helsinki (Finland) (E.M); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B., D.G., H.H., F.C.L.); dF. Hoffmann–La Roche, Basel, Switzerland (V.B.); and Institute for Clinical Pharmacology, Universitätsklinikum-Benjamin Franklin, Free University of Berlin (Germany) (D.G.).

説明

<jats:p> <jats:italic>Abstract</jats:italic> —The blood pressure–independent effects of angiotensin II (Ang II) were examined in double transgenic rats (dTGR) harboring human renin and human angiotensinogen genes, in which the end-organ damage is due to the human components of the renin angiotensin system. Triple-drug therapy (hydralazine 80 mg/L, reserpine 5 mg/L, and hydrochlorothiazide 25 mg/L in drinking water) was started immediately after weaning. Triple-drug therapy normalized blood pressure and coronary resistance, only partially prevented cardiac hypertrophy, and had no effect on ratio of renal weight to body weight. Although triple-drug therapy delayed the onset of renal damage, severe albuminuria nevertheless occurred. Semiquantitative scoring of ED-1–positive and MIB-5–positive (nuclear cell proliferation–associated antigen Ki-67) cells showed profound perivascular monocyte/macrophage infiltration and cell proliferation in kidneys and hearts of untreated dTGR. Triple-drug therapy had only a minimal effect on local inflammatory response or vascular cell proliferation. In contrast, a novel orally active human renin inhibitor (HRI), 30 mg/kg by gavage for 4 weeks, normalized blood pressure and coronary resistance and also prevented cardiac hypertrophy and albuminuria. ED-1–positive cells and MIB-5–positive cells were decreased by HRI in hearts and kidneys almost to levels observed in normotensive Sprague-Dawley rats. The renoprotective effects of HRI were at least in part due to improved renal hemodynamics and distal tubular function, since HRI shifted renal pressure-diuresis/natriuresis curves leftward by ≈35 mm Hg, increased glomerular filtration rate and renal blood flow, and shifted the fractional water and sodium excretion curves leftward. In untreated dTGR, plasma Ang II was increased by 400% and renal Ang II level was increased by 300% compared with Sprague-Dawley rats. HRI decreased plasma human renin activity by 95% and normalized Ang II levels in both plasma and kidney compared with triple-drug therapy. Our findings indicate that in dTGR harboring human renin and angiotensinogen genes, Ang II causes end-organ damage and promotes inflammatory response and cellular growth largely independent of blood pressure. </jats:p>

収録刊行物

  • Hypertension

    Hypertension 35 (2), 587-594, 2000-02

    Ovid Technologies (Wolters Kluwer Health)

被引用文献 (2)*注記

もっと見る

詳細情報 詳細情報について

問題の指摘

ページトップへ