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Related Experiment Videos

A decrease in angiotensin receptor binding in rat brain nuclei by antisense oligonucleotides to the angiotensin AT1

P Ambühl1, R Gyurko, M I Phillips

  • 1University of Florida, College of Medicine, Department of Physiology, Gainesville 32610, USA.

Regulatory Peptides
|October 20, 1995
PubMed
Summary

Intracerebroventricular injections of antisense oligonucleotides targeting the angiotensin type 1 (AT1) receptor mRNA reduce AT1 receptor numbers in the brain. These findings explain the blood pressure-lowering effects of AT1 receptor antisense treatment.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Cardiovascular Research

Background:

  • Intracerebroventricular (i.c.v.) administration of antisense oligonucleotides against angiotensin type 1 (AT1) receptor mRNA lowers blood pressure in spontaneously hypertensive rats (SHR).
  • This treatment also reduces angiotensin II-induced drinking in both SHR and Sprague-Dawley (SD) rats.

Purpose of the Study:

  • To quantify the impact of i.c.v. injections of AT1 receptor mRNA antisense oligonucleotides on brain angiotensin receptors.
  • To assess the specificity of the antisense oligonucleotides in altering AT1 receptor levels.

Main Methods:

  • Utilized membrane binding and autoradiographic analysis to measure angiotensin receptor numbers in rat brain tissues.
  • Administered antisense, sense, or scrambled oligonucleotides, or saline, via i.c.v. injections into SD and SHR rats.

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  • Focused analysis on hypothalamic nuclei and the anteroventral region of the third ventricle (AV3V).

    • Main Results:

    • Three daily i.c.v. injections of AT1 antisense oligonucleotides decreased AT1 receptor number by 25% in a hypothalamic tissue block in SD rats.
    • Autoradiography revealed reduced angiotensin receptor numbers in hypothalamic nuclei and AV3V following antisense treatment.
    • AT2 receptor levels remained unaltered, confirming the specificity of the AT1 antisense oligonucleotides. Single injections in SHR rats also showed significant decreases (15-30%) in the same hypothalamic area.

    Conclusions:

    • i.c.v. administration of AT1 receptor mRNA antisense oligonucleotides specifically reduces AT1 receptor density in specific brain regions.
    • The observed reduction in AT1 receptor numbers is likely responsible for the previously documented physiological effects, such as blood pressure reduction.
    • These findings support the role of central AT1 receptors in regulating cardiovascular function and fluid intake.