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Angiotensin II (AngII) elicits the production of superoxide (O 2 •- ) from mitochondria in numerous cell types within peripheral organs and in the brain suggesting a role for mitochondrial-produced O 2 •- in the pathogenesis of hypertension. However, it remains unclear if mitochondrial O 2 •- is causal in the development of AngII-induced hypertension, or if mitochondrial O 2 •- in the absence of elevated AngII is sufficient to increase blood pressure. Further, the tissue specific (i.e. central versus peripheral) redox regulation of AngII hypertension remains elusive. Herein, we hypothesized that increased mitochondrial O 2 •- in the absence of pro-hypertensive stimuli, such as AngII, elevates baseline systemic mean arterial pressure (MAP), and that AngII-mediated hypertension is exacerbated in animals with increased mitochondrial O 2 •- levels. To address this hypothesis, we generated novel inducible knock-down mouse models of manganese superoxide dismutase (MnSOD), the O 2 •- scavenging antioxidant enzyme specifically localized to mitochondria, targeted to either the brain subfornical organ (SFO) or peripheral tissues. Contrary to our hypothesis, knock-down of MnSOD either in the SFO or in peripheral tissues was not sufficient to alter baseline systemic MAP. Interestingly, when mice were challenged with chronic, peripheral infusion of AngII, only the MnSOD knock-down confined to the SFO, and not the periphery, demonstrated an increased sensitization and potentiated hypertension. In complementary experiments, over-expressing MnSOD in the SFO significantly decreased blood pressure in response to chronic AngII. Overall, these studies indicate that mitochondrial O 2 •- in the brain SFO works in concert with other AngII-dependent factors to drive an increase in MAP, as elevated mitochondrial O 2 •- alone, either in the SFO or peripheral tissues, failed to raise baseline blood pressure., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Many investigations have been devoted to determining the role of angiotensin II (ANG II) and aldosterone (ALD) in sodium-depletion-induced sodium appetite, but few were focused on the mechanisms mediating the salty taste changes accompanied with sodium depletion. To further elucidate the mechanism of renin-angiotensin-aldosterone system (RAAS) action in mediating sodium intake behavior and accompanied salty taste changes, the present study examined the salty taste function changes accompanied with sodium depletion induced by furosemide (Furo) combined with different doses of angiotensin converting enzyme (ACE) inhibitor, captopril (Cap). Both the peripheral and central RAAS activity and the nuclei Fos immunoreactivity (Fos-ir) expression in the forebrain area were investigated. Results showed that sodium depletion induced by Furo+low-Cap increased taste preference for hypertonic NaCl solution with amplified brain action of ANG II but without peripheral action, while Furosemide combined with a high dose of captopril can partially inhibit the formation of brain ANG II, with parallel decreased effects on salty taste changes. And the resulting elevating forebrain ANG II may activate a variety of brain areas including SFO, PVN, SON and OVLT in sodium depleted rats injected with Furo+low-Cap, which underlines salty taste function and sodium intake behavioral changes. Neurons in SFO and OVLT may be activated mainly by brain ANG II, while PVN and SON activation may not be completely ANG II dependent. These findings suggested that forebrain derived ANG II may play a critical role in the salty taste function changes accompanied with acute sodium depletion., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Although endoplasmic reticulum (ER) stress is a pathologic mechanism in a variety of chronic diseases, it is unclear what role it plays in chronic hypertension (HTN). Dysregulation of brain mechanisms controlling arterial pressure is strongly implicated in HTN, particularly in models involving angiotensin II (Ang II). We tested the hypothesis that ER stress in the brain is causally linked to Ang II-dependent HTN. Chronic systemic infusion of low-dose Ang II in C57BL/6 mice induced slowly developing HTN, which was abolished by co-infusion of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) into the lateral cerebroventricle. Investigations of the brain regions involved revealed robust increases in ER stress biomarkers and profound ER morphological abnormalities in the circumventricular subfornical organ (SFO), a region outside the blood-brain barrier and replete with Ang II receptors. Ang II-induced HTN could be prevented in this model by selective genetic supplementation of the ER chaperone 78-kDa glucose-regulated protein (GRP78) in the SFO. These data demonstrate that Ang II-dependent HTN is mediated by ER stress in the brain, particularly the SFO. To our knowledge, this is the first report that ER stress, notably brain ER stress, plays a key role in chronic HTN. Taken together, these findings may have broad implications for the pathophysiology of this disease.

The activity of subfornical organ (SFO) neurons that were antidromically identified by electrical stimulation of the rat hypothalamic paraventricular nucleus (PVN) was tested for a response to microiontophoretic application of angiotensin II (ANG II) or hemorrhage (10 ml/kg b.w.t.). Microiontophoretically (MIPh) applied ANG II caused an increased excitability in 24 out of 28 neurons tested and the excitation was blocked by MIPh-applied saralasin (Sar), a specific ANG II antagonist. Of these neurons that responded to ANG II, 14 displayed an increase in neuronal firing in response to hemorrhage, while 10 were unresponsive. The excitatory response to hemorrhage in 5 out of 14 neurons tested was prevented by MIPh-applied Sar, whereas the response of the remaining neurons was not affected. These results show that part of SFO neurons projecting to the PVN may receive neural inputs from the peripheral baroreceptors, and suggest that the inputs may be partially attributable to the involvement of central angiotensinergic circuits.

We have examined the effects of systemic angiotensin II (AII) on plasma oxytocin (OXY) concentrations in freely moving male Sprague-Dawley rats. We have also examined the role of the subfornical organ (SFO) as a CNS site at which circulating AII acts to influence secretion of this neurohypophysial peptide. OXY concentrations were measured by radioimmunoassay in plasma samples obtained by drawing blood samples through indwelling atrial catheters. In SFO intact animals (n = 8) AII infusion (1.0 microgram/kg/min) resulted in increases in plasma OXY concentrations from baseline values of 6.8 +/- 2.5 pg/ml to postinfusion concentrations of 44.9 +/- 11.9 pg/ml. In a second series of experiments electrolytic lesions were placed in the region of the SFO prior to testing the effects of AII infusion on OXY concentrations. Two further experimental groups were thus established according to the histologically verified location of lesions in either the rostral or caudal SFO. In the caudal SFO lesioned group AII infusion resulted in increases in plasma OXY concentrations from control values of 6.9 +/- 1.4 pg/ml to postinfusion levels of 45.1 +/- 9.8 pg/ml. These changes were not significantly different from the SFO intact group. In contrast rostral SFO lesions resulted in significantly elevated basal concentrations of OXY (17.4 +/- 3.4 pg/ml, n = 6) while postinfusion concentrations were found to be 22.8 +/- 4.9 pg/ml indicating that AII infusion was without effect following such lesions. These data are in accordance with the hypothesis that circulating AII acts at the SFO to influence SFO efferents which in turn activate OXY secreting neurons in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei. These neuroendocrine cells then release this peptide into the systemic circulation from the posterior pituitary.

The subfornical organ (SFO) and surrounding periventricular tissue were ablated in sheep. Such a lesion did not significantly reduce water drinking in response to intracarotid, intravenous, or intracerebroventricular infusions of [Val5]angiotensin II amide (ANG II) but caused reduced intake of water in response to intracarotid infusion of hypertonic saline. The dipsogenic response of these sheep to water deprivation for 3 days was similar to that of normal sheep subjected to water deprivation. Although the results are not conclusive in excluding the SFO from having a role in ANG II-induced drinking, they show that there are receptors outside the SFO sensitive to blood-borne ANG II that are involved in water drinking in sheep. The results also show that tissue in the SFO or its surroundings may be involved in drinking caused by acute hypertonicity.