AT1 receptor and NAD(P)H oxidase mediate angiotensin II-stimulated antioxidant enzymes and mitogen-activated protein kinase activity in the rat hypothalamus.

INTRODUCTION: 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. MATERIALS AND 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.

Effect of eprosartan on the sympathetic response to cold pressor test in healthy volunteers.

The aim of this study was to evaluate the effect of short-term administration of the AT1 angiotensin II receptor antagonist, eprosartan, on the sympathetic response to cold pressor test (CPT) in normotensive healthy volunteers. Sixty-nine healthy volunteers were included in this double-blind placebo-controlled study. Blood pressure and heart rate were determined before and 175 min after oral administration of placebo, losartan (50 mg) or eprosartan (600 mg). Immediately, the subjects underwent CPT and then the same hemodynamic variables were measured. CPT increased arterial blood pressure (systolic, diastolic and mean) and HR in placebo-treated group. Pretreatment with a single dose of losartan or eprosartan blunted CPT-induced pressor response, but not the rise in heart rate. Our results demonstrate that endogenous angiotensin II, through stimulation of AT1 receptor, supports sympathetic mediated stress-response in humans.