BLOCKADE BY INTRAVENOUS LOSARTAN OF AT1 ANGIOTENSIN II RECEPTORS IN RAT BRAIN, KIDNEY AND ADRENALS DEMONSTRATED BY IN VITRO AUTORADIOGRAPHY

Jialong Zhuo, Keifu Song, Aly Abdelrahman, Frederick A.O. Mendelsohn

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

1. The in vivo inhibition of angiotensin II (AII) receptor binding in the rat brain, kidney and adrenal was investigated after intravenous administration of the AT1‐selective AII receptor antagonist losartan. 2. Male Sprague‐Dawley rats were administered intravenously either vehicle, or losartan at doses of 1, 3 or 10 mg/kg. Plasma samples were collected and tissues removed at 1,2, 8 or 24 h after administration of the antagonist, The effects of losartan on AII receptor binding were assessed by quantitative in vitro autoradiography. 3. Losartan significantly increased plasma renin activity (PRA) by six‐fold and nine‐fold at doses of 1 and 10 mg/kg, respectively (P<0.05). Plasma losartan concentrations rose from 0.83 μg/mL at 1 mg/kg to 46.5 μg/mL at 10 mg/kg 1 h after administration of the drug. Plasma renin activity returned to control, whilst losartan was undetectable 24 h after injection of the antagonist. 4. In the brain, losartan produced a dose‐dependent inhibition of AII receptor binding to the brain structures which express exclusively, or predominantly, AT1 receptors both outside and within the blood brain barrier. By contrast, losartan did not affect binding to the nuclei which contain exclusively, or predominantly, AT2 receptors. 5. In the kidney, losartan blocked AII receptor binding to all anatomical sites in a dose‐dependent manner. The inhibition peaked at 1 h and persisted beyond 24 h despite the fact that PRA had returned to control, and losartan was not detectable in the circulation. In the adrenal gland, where AT1 and AT2 receptors occur in both the cortex and medulla, losartan caused partial inhibition at both regions. 6. These results indicate that losartan, administered intravenously at these doses, and/or its active metabolites, partially penetrate the blood brain barrier to selectively inhibit central AT1 receptors, and exert selective and prolonged blockade of AT1 receptors in peripheral target tissues.

Original languageEnglish
Pages (from-to)557-567
Number of pages11
JournalClinical and Experimental Pharmacology and Physiology
Volume21
Issue number7
DOIs
Publication statusPublished - 1994

Fingerprint

Angiotensin Receptors
Losartan
Autoradiography
Kidney
Brain
Renin
Blood-Brain Barrier
In Vitro Techniques
Angiotensin Receptor Antagonists
Adrenal Glands
Intravenous Administration

Keywords

  • adrenal
  • angiotensin II receptor
  • autoradiography
  • blood brain barrier
  • brain
  • kidney
  • losartan
  • pharmacology.

ASJC Scopus subject areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

Cite this

BLOCKADE BY INTRAVENOUS LOSARTAN OF AT1 ANGIOTENSIN II RECEPTORS IN RAT BRAIN, KIDNEY AND ADRENALS DEMONSTRATED BY IN VITRO AUTORADIOGRAPHY. / Zhuo, Jialong; Song, Keifu; Abdelrahman, Aly; Mendelsohn, Frederick A.O.

In: Clinical and Experimental Pharmacology and Physiology, Vol. 21, No. 7, 1994, p. 557-567.

Research output: Contribution to journalArticle

@article{feec0e5083bc4df6af7621a13b4567e0,
title = "BLOCKADE BY INTRAVENOUS LOSARTAN OF AT1 ANGIOTENSIN II RECEPTORS IN RAT BRAIN, KIDNEY AND ADRENALS DEMONSTRATED BY IN VITRO AUTORADIOGRAPHY",
abstract = "1. The in vivo inhibition of angiotensin II (AII) receptor binding in the rat brain, kidney and adrenal was investigated after intravenous administration of the AT1‐selective AII receptor antagonist losartan. 2. Male Sprague‐Dawley rats were administered intravenously either vehicle, or losartan at doses of 1, 3 or 10 mg/kg. Plasma samples were collected and tissues removed at 1,2, 8 or 24 h after administration of the antagonist, The effects of losartan on AII receptor binding were assessed by quantitative in vitro autoradiography. 3. Losartan significantly increased plasma renin activity (PRA) by six‐fold and nine‐fold at doses of 1 and 10 mg/kg, respectively (P<0.05). Plasma losartan concentrations rose from 0.83 μg/mL at 1 mg/kg to 46.5 μg/mL at 10 mg/kg 1 h after administration of the drug. Plasma renin activity returned to control, whilst losartan was undetectable 24 h after injection of the antagonist. 4. In the brain, losartan produced a dose‐dependent inhibition of AII receptor binding to the brain structures which express exclusively, or predominantly, AT1 receptors both outside and within the blood brain barrier. By contrast, losartan did not affect binding to the nuclei which contain exclusively, or predominantly, AT2 receptors. 5. In the kidney, losartan blocked AII receptor binding to all anatomical sites in a dose‐dependent manner. The inhibition peaked at 1 h and persisted beyond 24 h despite the fact that PRA had returned to control, and losartan was not detectable in the circulation. In the adrenal gland, where AT1 and AT2 receptors occur in both the cortex and medulla, losartan caused partial inhibition at both regions. 6. These results indicate that losartan, administered intravenously at these doses, and/or its active metabolites, partially penetrate the blood brain barrier to selectively inhibit central AT1 receptors, and exert selective and prolonged blockade of AT1 receptors in peripheral target tissues.",
keywords = "adrenal, angiotensin II receptor, autoradiography, blood brain barrier, brain, kidney, losartan, pharmacology.",
author = "Jialong Zhuo and Keifu Song and Aly Abdelrahman and Mendelsohn, {Frederick A.O.}",
year = "1994",
doi = "10.1111/j.1440-1681.1994.tb02555.x",
language = "English",
volume = "21",
pages = "557--567",
journal = "Clinical and Experimental Pharmacology and Physiology",
issn = "0305-1870",
publisher = "Wiley-Blackwell",
number = "7",

}

TY - JOUR

T1 - BLOCKADE BY INTRAVENOUS LOSARTAN OF AT1 ANGIOTENSIN II RECEPTORS IN RAT BRAIN, KIDNEY AND ADRENALS DEMONSTRATED BY IN VITRO AUTORADIOGRAPHY

AU - Zhuo, Jialong

AU - Song, Keifu

AU - Abdelrahman, Aly

AU - Mendelsohn, Frederick A.O.

PY - 1994

Y1 - 1994

N2 - 1. The in vivo inhibition of angiotensin II (AII) receptor binding in the rat brain, kidney and adrenal was investigated after intravenous administration of the AT1‐selective AII receptor antagonist losartan. 2. Male Sprague‐Dawley rats were administered intravenously either vehicle, or losartan at doses of 1, 3 or 10 mg/kg. Plasma samples were collected and tissues removed at 1,2, 8 or 24 h after administration of the antagonist, The effects of losartan on AII receptor binding were assessed by quantitative in vitro autoradiography. 3. Losartan significantly increased plasma renin activity (PRA) by six‐fold and nine‐fold at doses of 1 and 10 mg/kg, respectively (P<0.05). Plasma losartan concentrations rose from 0.83 μg/mL at 1 mg/kg to 46.5 μg/mL at 10 mg/kg 1 h after administration of the drug. Plasma renin activity returned to control, whilst losartan was undetectable 24 h after injection of the antagonist. 4. In the brain, losartan produced a dose‐dependent inhibition of AII receptor binding to the brain structures which express exclusively, or predominantly, AT1 receptors both outside and within the blood brain barrier. By contrast, losartan did not affect binding to the nuclei which contain exclusively, or predominantly, AT2 receptors. 5. In the kidney, losartan blocked AII receptor binding to all anatomical sites in a dose‐dependent manner. The inhibition peaked at 1 h and persisted beyond 24 h despite the fact that PRA had returned to control, and losartan was not detectable in the circulation. In the adrenal gland, where AT1 and AT2 receptors occur in both the cortex and medulla, losartan caused partial inhibition at both regions. 6. These results indicate that losartan, administered intravenously at these doses, and/or its active metabolites, partially penetrate the blood brain barrier to selectively inhibit central AT1 receptors, and exert selective and prolonged blockade of AT1 receptors in peripheral target tissues.

AB - 1. The in vivo inhibition of angiotensin II (AII) receptor binding in the rat brain, kidney and adrenal was investigated after intravenous administration of the AT1‐selective AII receptor antagonist losartan. 2. Male Sprague‐Dawley rats were administered intravenously either vehicle, or losartan at doses of 1, 3 or 10 mg/kg. Plasma samples were collected and tissues removed at 1,2, 8 or 24 h after administration of the antagonist, The effects of losartan on AII receptor binding were assessed by quantitative in vitro autoradiography. 3. Losartan significantly increased plasma renin activity (PRA) by six‐fold and nine‐fold at doses of 1 and 10 mg/kg, respectively (P<0.05). Plasma losartan concentrations rose from 0.83 μg/mL at 1 mg/kg to 46.5 μg/mL at 10 mg/kg 1 h after administration of the drug. Plasma renin activity returned to control, whilst losartan was undetectable 24 h after injection of the antagonist. 4. In the brain, losartan produced a dose‐dependent inhibition of AII receptor binding to the brain structures which express exclusively, or predominantly, AT1 receptors both outside and within the blood brain barrier. By contrast, losartan did not affect binding to the nuclei which contain exclusively, or predominantly, AT2 receptors. 5. In the kidney, losartan blocked AII receptor binding to all anatomical sites in a dose‐dependent manner. The inhibition peaked at 1 h and persisted beyond 24 h despite the fact that PRA had returned to control, and losartan was not detectable in the circulation. In the adrenal gland, where AT1 and AT2 receptors occur in both the cortex and medulla, losartan caused partial inhibition at both regions. 6. These results indicate that losartan, administered intravenously at these doses, and/or its active metabolites, partially penetrate the blood brain barrier to selectively inhibit central AT1 receptors, and exert selective and prolonged blockade of AT1 receptors in peripheral target tissues.

KW - adrenal

KW - angiotensin II receptor

KW - autoradiography

KW - blood brain barrier

KW - brain

KW - kidney

KW - losartan

KW - pharmacology.

UR - http://www.scopus.com/inward/record.url?scp=0027993817&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027993817&partnerID=8YFLogxK

U2 - 10.1111/j.1440-1681.1994.tb02555.x

DO - 10.1111/j.1440-1681.1994.tb02555.x

M3 - Article

C2 - 7982288

AN - SCOPUS:0027993817

VL - 21

SP - 557

EP - 567

JO - Clinical and Experimental Pharmacology and Physiology

JF - Clinical and Experimental Pharmacology and Physiology

SN - 0305-1870

IS - 7

ER -