AT₁ receptor and NAD(P)H oxidase mediate angiotensin II-stimulated antioxidant enzymes and mitogen-activated protein kinase activity in the rat hypothalamus.
BACKGROUND
Angiotensin II (AngII) regulates blood pressure and water and electrolyte metabolism through the stimulation of NAD(P)H oxidase and production of reactive oxygen species (ROS) such as O₂⁻, which is metabolised by superoxide dismutase, catalase and glutathione peroxidase. We assessed the role of AT₁ and AT₂ receptors, NAD(P)H oxidase and protein kinase C (PKC) in Ang II-induced sodium and water excretion and their capacity to stimulate antioxidant enzymes in the rat hypothalamus, a brain structure known to express a high density of AngII receptors.


METHODS
Male Sprague-Dawley rats were intracerebroventricularly (ICV) injected with AngII and urinary sodium and water excretion was assessed. Urine sodium concentration was determined using flame photometry. After decapitation the hypothalamus was microdissected under stereomicroscopic control. Superoxide dismutase, catalase and glutathione peroxidase activity were determined spectrophotometrically and extracellular signal-regulated kinase (ERK1/2) activation was analysed by Western blot.


RESULTS
AngII-ICV resulted in antidiuresis and natriuresis. ICV administration of losartan, PD123319, apocynin and chelerythrine blunted natriuresis. In hypothalamus, AngII increased catalase, superoxide dismutase and glutation peroxidase activity and ERK1/2 phosphorylation. These actions were prevented by losartan, apocynin and chelerythrine, and increased by PD123319.


CONCLUSIONS
AT₁ and AT₂ receptors, NAD(P)H oxidase and PKC pathway are involved in the regulation of hydromineral metabolism and antioxidant enzyme activity induced by AngII.
Silva
José
J
School of Pharmacy, Laboratory of Neuropeptides, Universidad Central de Venezuela, Caracas, Venezuela.
Pastorello
Mariella
M
Arzola
Jorge
J
Zavala
Lida E
LE
De Jesús
Sara
S
Varela
Maider
M
Matos
María Gabriela
MG
del Rosario Garrido
María
M
Israel
Anita
A
D000098:Acetophenones / Q000008:administration & dosage / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D053119:Benzophenanthridines / Q000008:administration & dosage / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects* / Q000201:enzymology*; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007276:Injections, Intraventricular; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012964:Sodium / Q000652:urine; D013482:Superoxide Dismutase / Q000378:metabolism; D014867:Water
D000098:Acetophenones; D000975:Antioxidants; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D014867:Water; D000804:Angiotensin II; C073402:PD 123319; D012964:Sodium; C056165:acetovanillone; C016299:chelerythrine; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases; D019808:Losartan