title: NAD(P)H oxidase inhibition attenuates neuronal chronotropic actions of angiotensin II.
abstract: It is well established that the central cardiovascular effects of angiotensin II (Ang II) involve superoxide production. However, the intracellular mechanism by which reactive oxygen species (ROS) signaling regulates neuronal Ang II actions remains to be elucidated. In the present study, we have used neuronal cells in primary cultures from the hypothalamus and brain stem areas to study the role of ROS on the cellular actions of Ang II. Ang II increases neuronal firing rate, an effect mediated by the AT(1) receptor subtype and involving inhibition of the delayed rectifier potassium current (I(Kv)). This increase in neuronal activity was associated with increases in NADPH oxidase activity and ROS levels within neurons, the latter evidenced by an increase in ethidium fluorescence. The increases in NADPH oxidase activity and ethidium fluorescence were blocked by either the AT(1) receptor antagonist losartan or by the selective NAD(P)H oxidase inhibitor gp91ds-tat. Extracellular application of the ROS scavenger, Tempol, attenuated the Ang II-induced increase in neuronal firing rate by 70%. In addition, gp91ds-tat treatment resulted in a 50% inhibition of Ang II-induced increase in firing rate. In contrast, the ROS generator Xanthine-Xanthine oxidase significantly increased neuronal firing rate. Finally, Ang II inhibited neuronal I(Kv,) and this inhibition was abolished by gp91ds-tat treatment. These observations demonstrate, for the first time, that Ang II regulates neuronal activity via a series of events that includes ROS generation and inhibition of I(Kv). This signaling seems to be a critical cellular event in central Ang II regulation of cardiovascular function.
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, McKnight Brain Institute, Gainesville, FL 32610, USA.
authors.forename: Chengwen
authors.initials: C
authors.lastname: Sun
authors.forename: Kathleen W
authors.initials: KW
authors.lastname: Sellers
authors.forename: Colin
authors.initials: C
authors.lastname: Sumners
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001933:Brain Stem / Q000166:cytology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels; D004327:Drinking Behavior / Q000187:drug effects; D006023:Glycoproteins / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D007031:Hypothalamus / Q000166:cytology; D007093:Imidazoles / Q000494:pharmacology; D007276:Injections, Intraventricular; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species; D013113:Spin Labels; D013686:Telemetry; D019820:Xanthine / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D003497:Cyclic N-Oxides; D051668:Delayed Rectifier Potassium Channels; D006023:Glycoproteins; D007093:Imidazoles; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D017382:Reactive Oxygen Species; D013113:Spin Labels; C070295:catalase-polyethylene glycol; C473031:gp91ds-tat protein, chimeric; D000804:Angiotensin II; C073402:PD 123319; D019820:Xanthine; D011092:Polyethylene Glycols; D002374:Catalase; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D019808:Losartan; C001803:tempol