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Methyl-beta-cyclodextrin prevents angiotensin II-induced tachyphylactic contractile responses in rat aorta

A Elizabeth Linder1, Keshari M Thakali, Janice M Thompson

  • 1Department of Pharmacology and Toxicology, Michigan State University, B-445 Life Sciences Building, East Lansing, MI 48824-1317, USA. linderau@msu.edu

The Journal of Pharmacology and Experimental Therapeutics
|July 20, 2007
PubMed

Insights

Caveolae, cholesterol-rich membrane invaginations, mediate tachyphylaxis to angiotensin II by facilitating AT1 receptor internalization in rat aorta. This process is crucial for the desensitization response.

Area of Science:

  • Pharmacology
  • Cell Biology
  • Cardiovascular Research

Background:

  • Tachyphylaxis, or rapid desensitization, is a common response to repeated stimulation of the angiotensin II type I (AT1) receptor.
  • Receptor internalization is a proposed mechanism for desensitization, with both clathrin-coated pits and caveolae implicated in this process.
  • Caveolae are specialized cholesterol-rich microdomains in the plasma membrane that may play a role in AT1 receptor trafficking.

Purpose of the Study:

  • To investigate the hypothesis that AT1 receptor internalization via caveolae contributes to angiotensin II-induced tachyphylaxis.
  • To elucidate the role of caveolae in the desensitization of the contractile response to angiotensin II in rat aorta.

Main Methods:

  • Cumulative concentration-effect curves (CCEC) for angiotensin II and phenylephrine were generated in endothelium-denuded rat aortic rings.
  • Methyl-beta-cyclodextrin (CD), a cholesterol-depleting agent that disassembles caveolae, was used to assess the role of caveolae.
  • Immunofluorescence and co-immunoprecipitation were employed to detect AT1 receptor presence and its interaction with caveolin-1.

Main Results:

  • Tachyphylaxis to angiotensin II was observed, indicated by a blunted second concentration-effect curve (CCEC-II) compared to the first (CCEC-I).
  • Treatment with methyl-beta-cyclodextrin abolished the tachyphylactic response to angiotensin II and prevented the loss of AT1 receptors from the membrane.
  • Caveolin-1 co-immunoprecipitated with the AT1 receptor upon stimulation, an interaction inhibited by methyl-beta-cyclodextrin.

Conclusions:

  • Caveolae are critically involved in the tachyphylactic contractile response to angiotensin II in rat aorta.
  • Angiotensin II type I receptor internalization through caveolae mediates the desensitization process.
  • Cholesterol depletion disrupts AT1 receptor-caveolin-1 interaction and prevents angiotensin II-induced tachyphylaxis.

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