Brain Stem NOS and ROS in Neural Mechanisms of Hypertension

Chan, Samuel H.H.; Chan, Julie Y.H.

doi:10.1089/ars.2013.5230

Cited by 77 publications

(71 citation statements)

References 187 publications

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“…In support of this finding, recent studies have shown that exposure to Fx increases reactive oxygen species (ROS) levels and alters the antioxidant defense system in several tissues [11,12]. In agreement with these findings, studies have shown that an increase in ROS concentration in specific regions of the CNS can result in increased arterial blood pressure [13,14].…”

Section: Introductionmentioning

confidence: 64%

Serotonin modulation in neonatal age does not impair cardiovascular physiology in adult female rats: Hemodynamics and oxidative stress analysis

et al. 2016

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Section: Introductionmentioning

confidence: 64%

Serotonin modulation in neonatal age does not impair cardiovascular physiology in adult female rats: Hemodynamics and oxidative stress analysis

et al. 2016

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“…Previous studies have shown differential responses in ABP and sympathetic outflow in response to PVN stimulation between conscious and anesthetized rats. Either electrical or chemical stimulation of the PVN in anesthetized rats evoked a depressor response accompanied with a decrease in sympathetic outflow (17,44), while in conscious rats, electrical stimulation evoked increases 4. PRR activation in brain neurons increases the mRNA levels of FOS-like antigen 1 (fosl1), inducible nitric oxide synthase (iNOS), and the NAPDH oxidase 2 subunit cybb.…”

Section: Discussionmentioning

confidence: 99%

“…NO signaling in the brain may be pro-or antihypertensive depending on the NOS isoform that generates this gas molecule and the site of action (4,35). Unlike endothelial NOS (eNOS) and neuronal NOS (nNOS), which constitutively express in endothelial cells or other specific neurons (10, 29), brain iNOS is rarely expressed in normal physiological conditions, and its expression could be dramatically enhanced in pathogenesis condition or under oxidative stress (29).…”

Section: Discussionmentioning

confidence: 99%

Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

Huber

Basu

Cecchettini

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats. Am J Physiol Heart Circ Physiol 309: H880 -H887, 2015. First published June 26, 2015 doi:10.1152/ajpheart.00095.2015.-Previous studies have indicated that hyperactivity of brain prorenin receptors (PRR) is implicated in neurogenic hypertension. However, the role of brain PRR in regulating arterial blood pressure (ABP) is not well understood. Here, we test the hypothesis that PRR activation in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA). In anaesthetized adult Sprague-Dawley (SD) rats, bilateral PVN microinjection of human prorenin (2 pmol/side) significantly increased splanchnic SNA (SSNA; 71 Ϯ 15%, n ϭ 7). Preinjection of either prorenin handle region peptide, the PRR binding blocker (PRRB), or tiron (2 nmol/side), the scavenger of reactive oxygen species (ROS), significantly attenuated the increase in SSNA (PRRB: 32 Ϯ 5% vs. control, n ϭ 6; tiron: 8 Ϯ 10% vs. control, n ϭ 5; P Ͻ 0.05) evoked by prorenin injection. We further investigated the effects of PRR activation on ROS production as well as downstream gene expression using cultured hypothalamus neurons from newborn SD rats. Incubation of brain neurons with human prorenin (100 nM) dramatically enhanced ROS production and induced a time-dependent increase in mRNA levels of inducible nitric oxide synthase (iNOS), NAPDH oxidase 2 subunit cybb, and FOS-like antigen 1 (fosl1), a marker for neuronal activation and a component of transcription factor activator protein-1 (AP-1). The maximum mRNA increase in these genes occurred 6 h following incubation (iNOS: 201-fold; cybb: 2 -fold; Ffosl1: 11-fold). The increases in iNOS and cybb mRNA were not attenuated by the AT 1 receptor antagonist losartan but abolished by the AP-1 blocker curcumin. Our results suggest that PVN PRR activation induces sympathoexcitation possibly through stimulation of an ANG II-independent, ROS-AP-1-iNOS signaling pathway. paraventricular nucleus; (pro)renin receptor; reactive oxygen species; sympathetic nerve activity NEW & NOTEWORTHY To our best knowledge, this study is the first to investigate PVN PRR-mediated ANG II-independent signaling transduction on the control of sympathetic outflow and blood pressure. Our results suggest that PVN PRR-induced sympathoexcitation is possibly mediated by ROS-AP-1-iNOS signal transduction pathways.ACCUMULATING EVIDENCE INDICATES that alteration of central (pro)renin receptor (PRR) is involved in the development of cardiovascular diseases including neurogenic hypertension (32,46). The importance of the brain PRR in cardiovascular control is further strengthened by the observation that increased PRR expression in brain cardiovascular control areas altered body fluid homeostasis (38) and genetic knockdown of the PRR induced long-term depressor effects in hypertensive animals (21,22,38). However, the detailed mechanism underlying the role of brain PRR on blood pressure regulati...

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“…Activation of tissue renin-angiotensin system is seen in human and animal models of MetS and diabetes mellitus. 42 A cross-talk between the InsR and angiotensin receptors, as in the endothelial and vascular smooth muscle cells, 43 further underscores the importance of the renin-angiotensin system in the development of endothelial dysfunction and arterial We 44,45 and others 13,14 reported previously that oxidative stress in RVLM mediates sympathoexcitation seen in neurogenic hypertension. We found in the present study that the tissue level of ROS in RVLM was significantly increased in HFD-fed animals.…”

Section: Discussionmentioning

confidence: 92%

Role of Nitric Oxide Synthase Uncoupling at Rostral Ventrolateral Medulla in Redox-Sensitive Hypertension Associated With Metabolic Syndrome

Chao

Tsay

et al. 2014

Hypertension

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Metabolic syndrome (MetS), which is rapidly becoming prevalent worldwide, is long known to be associated with hypertension and recently with oxidative stress. Of note is that oxidative stress in the rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, contributes to sympathoexcitation and hypertension. This study sought to identify the source of tissue oxidative stress in RVLM and their roles in neural mechanism of hypertension associated with MetS. Adult normotensive rats subjected to a high-fructose diet for 8 weeks developed metabolic traits of MetS, alongside increases in sympathetic vasomotor activity and blood pressure. In RVLM of these MetS rats, the tissue level of reactive oxygen species was increased, nitric oxide (NO) was decreased, and mitochondrial electron transport capacity was reduced. Whereas the protein expression of neuronal NO synthase (nNOS) or protein inhibitor of nNOS was increased, the ratio of nNOS dimer/monomer was significantly decreased. Oral intake of pioglitazone or intracisternal infusion of tempol or coenzyme Q 10 significantly abrogated all those molecular events in high-fructose diet–fed rats and ameliorated sympathoexcitation and hypertension. Gene silencing of protein inhibitor of nNOS mRNA in RVLM using lentivirus carrying small hairpin RNA inhibited protein inhibitor of nNOS expression, increased the ratio of nNOS dimer/monomer, restored NO content, and alleviated oxidative stress in RVLM of high-fructose diet–fed rats, alongside significantly reduced sympathoexcitation and hypertension. These results suggest that redox-sensitive and protein inhibitor of nNOS–mediated nNOS uncoupling is engaged in a vicious cycle that sustains the production of reactive oxygen species in RVLM, resulting in sympathoexcitation and hypertension associated with MetS.

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Brain Stem NOS and ROS in Neural Mechanisms of Hypertension

Abstract: Given the complicity of action mechanisms of brain-stem NOS and ROS in neural mechanisms of hypertension, additional studies are needed to identify the most crucial therapeutic target that is applicable not only in animal models but also in patients suffering from neurogenic hypertension.

Cited by 77 publications

References 187 publications

Serotonin modulation in neonatal age does not impair cardiovascular physiology in adult female rats: Hemodynamics and oxidative stress analysis

Serotonin modulation in neonatal age does not impair cardiovascular physiology in adult female rats: Hemodynamics and oxidative stress analysis

Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

Role of Nitric Oxide Synthase Uncoupling at Rostral Ventrolateral Medulla in Redox-Sensitive Hypertension Associated With Metabolic Syndrome

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