Hypertension caused by angiotensin II infusion involves increased superoxide production in the central nervous system.
Hypertension caused by angiotensin II (Ang II) infusion is associated with oxidative stress in the peripheral vasculature and kidney. The role of redox mechanisms in the central nervous system (CNS), a tissue known to be pivotal in Ang II-dependent hypertension, has not been investigated. We recently identified superoxide (O2*-) in the brain as a key signaling intermediate in the transient pressor response elicited by acute injection of Ang II directly into the CNS. Here we tested the hypothesis that hypertension caused by chronic systemic infusion of Ang II is mediated by a central neurogenic mechanism involving O2*-. Infusion of Ang II (600 ng x kg(-1) x min(-1)) over a 2-week period in mice caused a gradually developing hypertension that was correlated with marked elevations in O2*- production specifically in the subfornical organ (SFO), a brain region lying outside the blood-brain barrier and known to be a primary sensor for blood-borne Ang II. Adenoviral-mediated delivery of cytoplasmically targeted superoxide dismutase (SOD) selectively to this site prevented the hypertension and the increased O2*- production, whereas gene transfer of SOD targeted to the extracellular matrix had no effect. These data suggest that increased intracellular O2*- production in the SFO is critical in the development of Ang II-induced hypertension.
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
Sharma
Ram V
RV
Davisson
Robin L
RL
D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000008:administration & dosage / Q000633:toxicity*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D015918:Infusion Pumps, Implantable; D007263:Infusions, Parenteral; D007276:Injections, Intraventricular; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D019808:Losartan / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013356:Subfornical Organ / Q000187:drug effects* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology; D013481:Superoxides / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D007527:Isoenzymes; D011993:Recombinant Fusion Proteins; D013481:Superoxides; D000804:Angiotensin II; D013482:Superoxide Dismutase; D019808:Losartan