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.
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, p85alpha, 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 GABA(A) and GABA(B) receptors and a GR-dependent but nontranscriptional mechanism that involves activation of PI3K/Akt pathway.
Wang
Ling-Lin
LL
Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan, Republic of China.
Ou
Chen-Chun
CC
Chan
Julie Y H
JY
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000502:physiology*; D017552:Solitary Nucleus / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid; C494920:Akt1 protein, rat