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Molecular Pharmacology

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Research ArticleORIGINAL ARTICLE

Receptor-Independent Activation of GABAergic Neurotransmission and Receptor-Dependent Nontranscriptional Activation of Phosphatidylinositol 3-kinase/Protein Kinase Akt Pathway in Short-Term Cardiovascular Actions of Dexamethasone at the Nucleus Tractus Solitarii of the Rat

Ling-Lin Wang, Chen-Chun Ou and Julie Y.H. Chan
Molecular Pharmacology February 2005, 67 (2) 489-498; DOI: https://doi.org/10.1124/mol.104.005595
Ling-Lin Wang
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Chen-Chun Ou
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Julie Y.H. Chan
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Abstract

Whereas glucocorticoids are important blood pressure regulators via an action on peripheral circulation, their roles in central cardiovascular regulation are less known. This study evaluated the short-term cardiovascular effect of glucocorticoid in the nucleus tractus solitarii (NTS) and delineated the underlying molecular mechanisms. In Sprague-Dawley rats maintained under propofol anesthesia, microinjection bilaterally into the NTS of a synthetic glucocorticoid, dexamethasone (Dex; 12.5, 25, 50, or 100 pmol), elicited hypertensive and tachycardiac responses. The initial cardiovascular responses, which lasted 15 to 30 min, were blunted by coadministration of a selective GABAA or GABAB receptor antagonist, bicuculline (15 pmol) or 2-hydroxy saclofen (150 pmol). The delayed responses, which endured at least 90 min and entailed maintained hypertension and tachycardia, were reversed by selective glucocorticoid type II receptor (GR) antagonist mifepristone (100 or 200 pmol), phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] (20 nmol), or nitric-oxide synthase inhibitor NG-monomethyl-l-arginine acetate (5 nmol), but not by the RNA synthesis inhibitor actinomycin D (20 nmol). Moreover, Dex induced an association of GR with the regulatory subunit of PI3K, p85α, in a ligand-dependent manner and promoted serine/threonine kinase Akt phosphorylation that was blocked by coadministration of mifepristone or LY294002. These cardiovascular and molecular responses occurred when translocation of activated GR into the nucleus was minimal. Our results indicate that Dex acts on the NTS to elicit hypertension and tachycardia via both a GR-independent interaction with GABAA and GABAB receptors and a GR-dependent but nontranscriptional mechanism that involves activation of PI3K/Akt pathway.

  • Received July 28, 2004.
  • Accepted October 29, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 67 (2)
Molecular Pharmacology
Vol. 67, Issue 2
1 Feb 2005
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Research ArticleORIGINAL ARTICLE

Receptor-Independent Activation of GABAergic Neurotransmission and Receptor-Dependent Nontranscriptional Activation of Phosphatidylinositol 3-kinase/Protein Kinase Akt Pathway in Short-Term Cardiovascular Actions of Dexamethasone at the Nucleus Tractus Solitarii of the Rat

Ling-Lin Wang, Chen-Chun Ou and Julie Y.H. Chan
Molecular Pharmacology February 1, 2005, 67 (2) 489-498; DOI: https://doi.org/10.1124/mol.104.005595

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Research ArticleORIGINAL ARTICLE

Receptor-Independent Activation of GABAergic Neurotransmission and Receptor-Dependent Nontranscriptional Activation of Phosphatidylinositol 3-kinase/Protein Kinase Akt Pathway in Short-Term Cardiovascular Actions of Dexamethasone at the Nucleus Tractus Solitarii of the Rat

Ling-Lin Wang, Chen-Chun Ou and Julie Y.H. Chan
Molecular Pharmacology February 1, 2005, 67 (2) 489-498; DOI: https://doi.org/10.1124/mol.104.005595
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