title: Changes in GABAergic inputs in the paraventricular nucleus maintain sympathetic vasomotor tone in chronic heart failure.
abstract: The paraventricular nucleus (PVN) of the hypothalamus is an important region of the brain involved in the regulation of sympathetic vasomotor tone. Accumulating evidence supports the idea that a change in hypothalamic γ-aminobutyric acid (GABA)-ergic inhibitory and glutamatergic excitatory inputs contribute to the exacerbated sympathetic drive in chronic heart failure (HF). The purpose of this study was to determine whether a possible imbalance between glutamatergic and GABAergic inputs to the PVN contributes to increased sympathetic outflow in HF in two different sympathetic territories. Renal (RSNA) and splanchnic sympathetic nerve activity (SSNA), mean arterial blood pressure (MAP) and heart rate were recorded from urethane-anesthetized HF or sham rats. The NMDA-glutamate and GABA-A receptor densities within the PVN were quantified in HF and sham rats by autoradiography. Bilateral microinjection of kynurenic acid (4nmol) into the PVN decreased MAP and RSNA and SSNA in HF but not in sham rats. Furthermore, in response to GABA-A blockade in the PVN by bicuculline (400 pmol), hypertension and SSNA were reduced in HF compared to sham. The quantification of ionotropic NMDA receptors and GABA-A receptors in the PVN showed a significant reduction of GABA-A in HF rats; however, the NMDA density in the PVN did not differ between groups. Thus, this study provides evidence that the sympathoexcitation is maintained by an imbalance between GABAergic and glutamatergic inputs in the PVN in HF. The reduced GABAergic input results in relatively augmented glutamatergic actions in the PVN of HF rats.
authors.affiliation: Cardiovascular Division, Department of Physiology, Federal University of São Paulo, Escola Paulista de Medicina, Brazil.
authors.forename: B A
authors.initials: BA
authors.lastname: Carillo
authors.forename: E B
authors.initials: EB
authors.lastname: Oliveira-Sales
authors.forename: M
authors.initials: M
authors.lastname: Andersen
authors.forename: S
authors.initials: S
authors.lastname: Tufik
authors.forename: D
authors.initials: D
authors.lastname: Hipolide
authors.forename: A A
authors.initials: AA
authors.lastname: Santos
authors.forename: P J
authors.initials: PJ
authors.lastname: Tucci
authors.forename: C T
authors.initials: CT
authors.lastname: Bergamaschi
authors.forename: R R
authors.initials: RR
authors.lastname: Campos
mesh_terms: D000818:Animals; D001345:Autoradiography; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D004452:Echocardiography; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000493:pharmacokinetics; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology*; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D007668:Kidney / Q000294:innervation; D007736:Kynurenic Acid / Q000494:pharmacology; D008026:Ligation / Q000009:adverse effects; D008297:Male; D008845:Microinjections; D009118:Muscimol / Q000493:pharmacokinetics; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000503:physiopathology*; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013153:Splanchnic Nerves / Q000187:drug effects / Q000503:physiopathology*; D013729:Terpenes / Q000493:pharmacokinetics; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D018691:Excitatory Amino Acid Antagonists; D058785:GABA-A Receptor Agonists; D013729:Terpenes; D014316:Tritium; D009118:Muscimol; D016291:Dizocilpine Maleate; D010696:Phloroglucinol; D007736:Kynurenic Acid; C001654:hyperforin