Superoxide mediates the actions of angiotensin II in the central nervous system.
Angiotensin II (Ang II) has profound effects in the central nervous system (CNS), including promotion of thirst, regulation of vasopressin secretion, and modulation of sympathetic outflow. Despite its importance in cardiovascular and volume homeostasis, angiotensinergic mechanisms are incompletely understood in the CNS. Recently, a novel signaling mechanism for Ang II involving reactive oxygen species (ROS) has been identified in a variety of peripheral tissues, but the involvement of ROS as second messengers in Ang II-mediated signaling in the CNS has not been reported. The hypothesis that superoxide is a key mediator of the actions of Ang II in the CNS was tested in mice using adenoviral vector-mediated expression of superoxide dismutase (AdSOD). Changes in blood pressure, heart rate, and drinking elicited by injection of Ang II in the CNS were abolished by prior treatment with AdSOD in the brain, whereas the cardiovascular responses to carbachol, another central vasopressor agent, were unaffected. In addition, Ang II stimulated superoxide generation in primary CNS cell cultures, and this was prevented by the Ang II receptor (Ang II type 1 subtype) antagonist losartan or AdSOD. These results identify a novel signaling mechanism mediating the actions of Ang II in the CNS. Dysregulation of this signaling cascade may be important in hypertension and heart failure triggered by Ang II acting in the CNS.
Zimmerman
Matthew C
MC
Department of Anatomy and Cell Biology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City 52242, USA.
Lazartigues
Eric
E
Lang
Julie A
JA
Sinnayah
Puspha
P
Ahmad
Iman M
IM
Spitz
Douglas R
DR
Davisson
Robin L
RL
D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D004327:Drinking Behavior / Q000187:drug effects / Q000502:physiology; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007269:Injections, Intra-Arterial; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology; D018721:Muscarinic Agonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D019076:Transgenes
D018721:Muscarinic Agonists; D013481:Superoxides; D000804:Angiotensin II; D013482:Superoxide Dismutase