Received for publication August 3, 2004.
Revised October 28, 2004.
Accepted for publication October 29, 2004.

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

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 acute 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 15-30 min, were blunted by co-administration of a selective GABA_A or GABA_B 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, was reversed by selective glucocorticoid type II receptor (GR) antagonist, mifepristone (100 or 200 pmol), phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002 (20 nmol), or nitric oxide synthase inhibitor, L-NMMA (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, p85, in a ligand-dependent manner, and promoted serine/threonine kinase Akt phosphorylation that was blocked by co-administration 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 GABA_A and GABA_B receptors and a GR-dependent but nontranscriptional mechanism that involves activation of PI3K/Akt pathway.

Key words: GABAA, GABAC, Glucorticoids/Mineralocorticoids, Protein Kinases (other)

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