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

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 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, 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 N G -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, p85␣, 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 GRindependent interaction with GABA A and GABA B receptors and a GR-dependent but nontranscriptional mechanism that involves activation of PI3K/Akt pathway.

Chronic Activation of Dorsal Hindbrain Corticosteroid Receptors Augments the Arterial Pressure Response to Acute Stress

“…Investigations of central effects of glucocorticoids on arterial pressure regulation have used intracerebroventricular administration of agonists and antagonists 26 -30 or acute microinjection of drugs into the NTS. 31 However, none of these studies investigated the effect of chronic elevations of central glucocorticoids on the cardiovascular response to acute stress. The current results provide novel evidence indicating that chronically elevated Cort can act within the central nervous system to enhance the arterial pressor response to acute stress.…”

Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress

“…Other investigators have administered glucocorticoid agonists and antagonists into the brain to investigate the central nervous system actions of glucocorticoids on blood pressure regulation, but the results have been varied due in part to differences in dose, stress level of the animals, and route of administration (26,27,59,60,62,69). Most of the previous studies have utilized intracerebroventricular administration of these drugs, confounding interpretation of the results since glucocorticoids might have opposing effects on blood pressure at different locations within the central nervous system.…”

Dexamethasone Rapidly Increases GABA Release in the Dorsal Motor Nucleus of the Vagus via Retrograde Messenger-Mediated Enhancement of TRPV1 Activity

“…These effects are prevented by vagotomy, suggesting glucocorticoid-mediated modulation of central parasympathetic circuits. Indeed, glucocorticoid agonists appear to act within the vagal complex to rapidly alter various autonomic functions related to gastrointestinal and cardiovascular control [10–13], possibly via GABA receptor-dependent effects [13], but the cellular mechanisms underlying these responses are unknown.…”

“…Rapid glucocorticoid actions on neuroendocrine or autonomic output [13–15] suggest potentially non-genomic effects in central autonomic circuits. In hypothalamic neuroendocrine and preautonomic neurons, glucocorticoids act on putative membrane-associated receptors in to rapidly stimulate the retrograde local release of endogenous cannabinoids and possibly other retrograde messengers, which in turn modulate afferent synaptic transmission [16–18].…”