title: Contribution of central nervous system endothelial nitric oxide synthase to neurohumoral activation in heart failure rats.
abstract: Neurohumoral activation, a hallmark in heart failure (HF), is linked to the progression and mortality of HF patients. Thus, elucidating its precise underlying mechanisms is of critical importance. Other than its classic peripheral vasodilatory actions, the gas NO is a pivotal neurotransmitter in the central nervous system control of the circulation. While accumulating evidence supports a contribution of blunted NO function to neurohumoral activation in HF, the precise cellular sources, and NO synthase (NOS) isoforms involved, remain unknown. Here, we used a multidisciplinary approach to study the expression, cellular distribution, and functional relevance of the endothelial NOS isoform within the hypothalamic paraventricular nucleus in sham and HF rats. Our results show high expression of endothelial NOS in the paraventricular nucleus (mostly confined to astroglial cells), which contributes to constitutive NO bioavailability, as well as tonic inhibition of presympathetic neuronal activity and sympathoexcitatory outflow from the paraventricular nucleus. A diminished endothelial NOS expression and endothelial NOS-derived NO availability were found in the paraventricular nucleus of HF rats, resulting, in turn, in blunted NO inhibitory actions on neuronal activity and sympathoexcitatory outflow. Taken together, our study supports blunted central nervous system endothelial NOS-derived NO as a pathophysiological mechanism underlying neurohumoral activation in HF.
authors.affiliation: Georgia Health Sciences University, Department of Physiology, 1120 15th St, Augusta, GA 30912, USA.
authors.forename: Vinicia C
authors.initials: VC
authors.lastname: Biancardi
authors.forename: Sook J
authors.initials: SJ
authors.lastname: Son
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sonner
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.forename: Kaushik P
authors.initials: KP
authors.lastname: Patel
authors.forename: Javier E
authors.initials: JE
authors.lastname: Stern
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism; D002490:Central Nervous System / Q000201:enzymology* / Q000378:metabolism; D004452:Echocardiography; D055785:Gene Knockdown Techniques; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism*; D006439:Hemodynamics; D007150:Immunohistochemistry; D008297:Male; D008526:Medulla Oblongata / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010286:Paraventricular Hypothalamic Nucleus / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D018377:Neurotransmitter Agents; D016376:Oligonucleotides, Antisense; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III