title: Nitric oxide inhibits the firing activity of hypothalamic paraventricular neurons that innervate the medulla oblongata: role of GABA.
abstract: Nitric oxide (NO) has been shown to modulate autonomic function by acting both peripherally and centrally. A growing body of evidence indicates that the paraventricular nucleus of the hypothalamus (PVN), an important site for autonomic and endocrine homeostasis, constitutes an important locus mediating central NO actions. However, the cellular targets and mechanisms mediating NO actions within the PVN are not completely understood. Here, we examined whether NO influences the firing activity of identified PVN neurons that innervate two functionally different autonomic centers, the dorsal vagal complex (DVC) and the rostral ventrolateral medulla (RVLM). Perforated patch-clamp recordings were performed in hypothalamic slices containing retrogradely labeled PVN neurons innervating the DVC or the RVLM. Application of the NO donors dyethylamine- or 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazino) NONOate inhibited the firing activity of both DVC- and RVLM-projecting PVN neurons. Furthermore, application of 2-(4-carboxypheny)-4,4,5,5,-tetramethilimidazoline-1-oxyl-3-oxide (carboxy-PTIO), or the relatively selective neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole alone, increased their basal firing activity, suggesting the presence of an endogenous NO inhibitory tone. GABAergic synaptic activity in PVN neurons was potentiated by NO donors, an action that involved a presynaptic mechanism. Furthermore, the NO-mediated inhibition of firing activity was blocked by the GABA(A) receptor antagonist bicuculline, suggesting that NO-inhibitory actions involved potentiation of local GABAergic synaptic activity. Immunohistochemical studies showed that approximately 25% of DVC- and RVLM-projecting PVN neurons express nNOS, suggesting that a proportion of these medullary-projecting PVN neurons contribute to the cellular source of NO within the PVN. In summary, NO has been identified as an important molecule controlling autonomic function under physiological and pathological conditions. Here, we provide information on the cellular mechanisms mediating central NO actions. Our results demonstrate for the first time that NO modulates the activity of identified populations of PVN neurons that innervate the medulla oblongata, an action that is likely mediated by enhancing synaptic GABAergic function. This work suggests that NO-GABA interaction in PVN neurons that innervate the medulla constitutes an efficient cellular mechanism mediating NO central regulation of autonomic function.
authors.affiliation: Department of Pharmacology and Toxicology, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH 45435, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: J E
authors.initials: JE
authors.lastname: Stern
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D007150:Immunohistochemistry; D008526:Medulla Oblongata / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009434:Neural Pathways / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D026602:Nitrergic Neurons / Q000187:drug effects / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009924:Organ Culture Techniques; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D020030:Nitric Oxide Donors; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D019001:Nitric Oxide Synthase