Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension

2011 ◽  
Vol 300 (4) ◽  
pp. R818-R826 ◽  
Author(s):  
Yoshitaka Hirooka ◽  
Takuya Kishi ◽  
Koji Sakai ◽  
Akira Takeshita ◽  
Kenji Sunagawa
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Nervous System ◽  
Sympathetic Nervous System ◽  
Brain Stem ◽  
Intracellular Signaling ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Sympathetic Nervous ◽  
The Brain

Nitric oxide (NO) and reactive oxygen species (ROS) play important roles in blood pressure regulation via the modulation of the autonomic nervous system, particularly in the central nervous system (CNS). In general, accumulating evidence suggests that NO inhibits, but ROS activates, the sympathetic nervous system. NO and ROS, however, interact with each other. Our consecutive studies and those of others strongly indicate that an imbalance between NO bioavailability and ROS generation in the CNS, including the brain stem, activates the sympathetic nervous system, and this mechanism is involved in the pathogenesis of neurogenic aspects of hypertension. In this review, we focus on the role of NO and ROS in the regulation of the sympathetic nervous system within the brain stem and subsequent cardiovascular control. Multiple mechanisms are proposed, including modulation of neurotransmitter release, inhibition of receptors, and alterations of intracellular signaling pathways. Together, the evidence indicates that an imbalance of NO and ROS in the CNS plays a pivotal role in the pathogenesis of hypertension.

Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors

2006 ◽  
Vol 291 (5) ◽  
pp. F932-F944 ◽  
Author(s):  
Kim E. Jie ◽  
Marianne C. Verhaar ◽  
Maarten-Jan M. Cramer ◽  
Karien van der Putten ◽  
Carlo A. J. M. Gaillard ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Nervous System ◽  
Sympathetic Nervous System ◽  
Renin Angiotensin System ◽  
Cardiorenal Syndrome ◽  
Oxygen Species ◽  
Cellular Mechanisms ◽  
Angiotensin System ◽  
Sympathetic Nervous

We have recently proposed severe cardiorenal syndrome (SCRS), in which cardiac and renal failure mutually amplify progressive failure of both organs. This frequent pathophysiological condition has an extremely poor prognosis. Interactions between inflammation, the renin-angiotensin system, the balance between the nitric oxide and reactive oxygen species and the sympathetic nervous system form the cardiorenal connectors and are cornerstones in the pathophysiology of SCRS. An absolute deficit of erythropoietin (Epo) and decreased sensitivity to Epo in this syndrome both contribute to the development of anemia, which is more pronounced than renal anemia in the absence of heart failure. Besides expression on erythroid progenitor cells, Epo receptors are present in the heart, kidney, and vascular system, in which activation results in antiapoptosis, proliferation, and possibly antioxidation and anti-inflammation. Interestingly, Epo can improve cardiac and renal function. We have therefore reviewed the literature with respect to Epo and the cardiorenal connectors. Indeed, there are indications that Epo can diminish inflammation, reduce renin-angiotensin system activity, and shift the nitric oxide and reactive oxygen species balance toward nitric oxide. Information about Epo and the sympathetic nervous system is scarce. This analysis underscores the relevance of a further understanding of clinical and cellular mechanisms underlying protective effects of Epo, because this will support better treatment of SCRS.

Real-time monitoring of peroxynitrite (ONOO−) in the rat brain by developing a ratiometric electrochemical biosensor

The Analyst ◽  
2019 ◽  
Vol 144 (6) ◽  
pp. 2150-2157 ◽  
Author(s):  
Feiyue Liu ◽  
Hui Dong ◽  
Yang Tian
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Rat Brain ◽  
Real Time ◽  
Superoxide Anion ◽  
Electrochemical Biosensor ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Real Time Monitoring ◽  
The Brain

As a reactive oxygen species (ROS), peroxynitrite (ONOO−) generated by nitric oxide (NO) and superoxide anion (O2˙−) plays important roles in physiological and pathological processes in the brain.

Abstract MP45: Prorenin Induces Intracellular Signaling And Reactive Oxygen Species In The Brainstem

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Pablo Nakagawa ◽  
Sebastiao Donato Silva ◽  
Javier Gomez ◽  
Justin L Grobe ◽  
Curt D Sigmund
Keyword(s):  
Reactive Oxygen Species ◽  
Intracellular Signaling ◽  
Reactive Oxygen ◽  
Ventrolateral Medulla ◽  
Angiotensin Receptors ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Ras Genes ◽  
Prorenin Receptor ◽  
The Brain

The activation of the brain renin angiotensin system (RAS) is required for the blood pressure (BP) elevation in models of neurogenic hypertension (HT). However, it remains unclear whether the expression of prorenin and its binding to prorenin receptor (PRR) in particular brain regions is required for the activation of the brain RAS. Compelling new evidence indicates that renin is expressed in the proximity of the rostral ventrolateral medulla (RVLM) and the nucleus ambiguous within the brainstem where RAS genes including PRR, angiotensinogen, and angiotensin receptors were also detected. Thus, we hypothesized that prorenin acts within the brainstem to induce extracellular signal-regulated kinases (ERK1/2) phosphorylation and generation of reactive oxygen species (ROS) resulting in BP elevation through a PRR-dependent mechanism. Neonatal brainstem neurons obtained from mice at postnatal day 1-3 were cultured and subsequently incubated in presence of recombinant prorenin (rProrenin; 100 nM) or vehicle. rProrenin increased the ratio of phosphorylated-to-total ERK1/2 from 0.7±0.1 A.U. at baseline to 1.0±0.1 A.U. at 30 min (54% increase; p=0.004; n=7) and 1.3±0.1 A.U. at 60 min (102% increase; p<0.0001; n=7). Both PRO20, a PRR blocker, and Ro-31, a protein kinase C inhibitor, abrogated prorenin-induced ERK1/2 phosphorylation, suggesting a PRR-dependent component to this response. Treatment with rProrenin increased NADPH oxidase activity by 47.2±9.5 % compared to vehicle control (p<0.05, n=5). RVLM-targeted stereotactic microinjection of glutamate, rProrenin, or Ang II, but not vehicle, induced an acute BP elevation in isoflurane-anesthetized C57BL/6J mice. Moreover, preliminary data indicate that RVLM-targeted ablation of PRR in PRR-flox mice attenuates the pressor response to deoxycorticosterone (DOCA)-salt in females (WT=132±3 vs KO=120±3 mmHg; p<0.05; n=3-4), but not males (n=5-8), during the first week on DOCA-salt treatment. There was no difference in BP during the 2 nd and 3 rd week of DOCA-salt. We conclude that prorenin induces PRR-mediated downstream signaling involving ERK1/2 phosphorylation and generation of ROS in brainstem neurons, which might contribute to BP elevation in neurogenic HT in sex-dependent manner.

Homocysteine and homocysteine-related compounds: an overview of the roles in the pathology of the cardiovascular and nervous systems

2018 ◽  
Vol 96 (10) ◽  
pp. 991-1003 ◽  
Author(s):  
Dragan Djuric ◽  
Vladimir Jakovljevic ◽  
Vladimir Zivkovic ◽  
Ivan Srejovic
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Nervous System ◽  
Nitric Oxide Synthase ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Sulfhydryl Group ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Oxide Synthase ◽  
Increased Activity

Homocysteine, an amino acid containing a sulfhydryl group, is an intermediate product during metabolism of the amino acids methionine and cysteine. Hyperhomocysteinemia is used as a predictive risk factor for cardiovascular disorders, the stroke progression, screening for inborn errors of methionine metabolism, and as a supplementary test for vitamin B12deficiency. Two organic systems in which homocysteine has the most harmful effects are the cardiovascular and nervous system. The adverse effects of homocysteine are achieved by the action of several different mechanisms, such as overactivation of N-methyl-d-aspartate receptors, activation of Toll-like receptor 4, disturbance in Ca2+handling, increased activity of nicotinamide adenine dinucleotide phosphate-oxidase and subsequent increase of production of reactive oxygen species, increased activity of nitric oxide synthase and nitric oxide synthase uncoupling and consequent impairment in nitric oxide and reactive oxygen species synthesis. Increased production of reactive species during hyperhomocysteinemia is related with increased expression of several proinflammatory cytokines, including IL-1β, IL-6, TNF-α, MCP-1, and intracellular adhesion molecule-1. All these mechanisms contribute to the emergence of diseases like atherosclerosis and related complications such as myocardial infarction, stroke, aortic aneurysm, as well as Alzheimer disease and epilepsy. This review provides evidence that supports the causal role for hyperhomocysteinemia in the development of cardiovascular disease and nervous system disorders.

scholarly journals Neural regulation of hypoxia-inducible factors and redox state drives the pathogenesis of hypertension in a rodent model of sleep apnea

2015 ◽  
Vol 119 (10) ◽  
pp. 1152-1156 ◽  
Author(s):  
Gregg L. Semenza ◽  
Nanduri R. Prabhakar
Keyword(s):  
Nervous System ◽  
Sleep Apnea ◽  
Sympathetic Nervous System ◽  
Brain Stem ◽  
Carotid Body ◽  
Sympathetic Neurons ◽  
Ventrolateral Medulla ◽  
Obstructive Sleep ◽  
Sympathetic Nervous ◽  
The Brain

Obstructive sleep apnea (OSA) is one of the most common causes of hypertension in western societies. OSA causes chronic intermittent hypoxia (CIH) in specialized O2-sensing glomus cells of the carotid body. CIH generates increased reactive oxygen species (ROS) that trigger a feedforward mechanism in which increased intracellular calcium levels ([Ca2+]i) trigger increased HIF-1α synthesis and increased HIF-2α degradation. As a result, the normal homeostatic balance between HIF-1α-dependent prooxidant and HIF-2α-dependent antioxidant enzymes is disrupted, leading to further increases in ROS. Carotid body sensory nerves project to the nucleus tractus solitarii, from which the information is relayed via interneurons to the rostral ventrolateral medulla in the brain stem, which sends sympathetic neurons to the adrenal medulla to stimulate the release of epinephrine and norepinephrine, catecholamines that increase blood pressure. At each synapse, neurotransmitters trigger increased [Ca2+]i, HIF-1α:HIF-2α, and Nox2:Sod2 activity that generates increased ROS levels. These responses are not observed in other regions of the brain stem that do not receive input from the carotid body or signal to the sympathetic nervous system. Thus sympathetic nervous system homeostasis is dependent on a balance between HIF-1α and HIF-2α, disruption of which results in hypertension in OSA patients.

scholarly journals Intermittent hypoxia activates peptidylglycine α-amidating monooxygenase in rat brain stem via reactive oxygen species-mediated proteolytic processing

2009 ◽  
Vol 106 (1) ◽  
pp. 12-19 ◽  
Author(s):  
Suresh D. Sharma ◽  
Gayatri Raghuraman ◽  
Myeong-Seon Lee ◽  
Nanduri R. Prabhakar ◽  
Ganesh K. Kumar
Keyword(s):  
Reactive Oxygen Species ◽  
Substance P ◽  
Neuropeptide Y ◽  
Brain Stem ◽  
Rat Brain ◽  
Intermittent Hypoxia ◽  
Reactive Oxygen ◽  
Proteolytic Processing ◽  
Oxygen Species ◽  
The Brain

Intermittent hypoxia (IH) associated with sleep apneas leads to cardiorespiratory abnormalities that may involve altered neuropeptide signaling. The effects of IH on neuropeptide synthesis have not been investigated. Peptidylglycine α-amidating monooxygenase (PAM; EC 1.14.17.3) catalyzes the α-amidation of neuropeptides, which confers biological activity to a large number of neuropeptides. PAM consists of O2-sensitive peptidylglycine α-hydroxylating monooxygenase (PHM) and peptidyl-α-hydroxyglycine α-amidating lyase (PAL) activities. Here, we examined whether IH alters neuropeptide synthesis by affecting PAM activity and, if so, by what mechanisms. Experiments were performed on the brain stem of adult male rats exposed to IH (5% O2for 15 s followed by 21% O2for 5 min; 8 h/day for up to 10 days) or continuous hypoxia (0.4 atm for 10 days). Analysis of brain stem extracts showed that IH, but not continuous hypoxia, increased PHM, but not PAL, activity of PAM and that the increase of PHM activity was associated with a concomitant elevation in the levels of α-amidated forms of substance P and neuropeptide Y. IH increased the relative abundance of 42- and 35-kDa forms of PHM (∼1.6- and 2.7-fold, respectively), suggesting enhanced proteolytic processing of PHM, which appears to be mediated by an IH-induced increase of endoprotease activity. Kinetic analysis showed that IH increases Vmaxbut has no effect on Km. IH increased generation of reactive oxygen species in the brain stem, and systemic administration of antioxidant prevented IH-evoked increases of PHM activity, proteolytic processing of PHM, endoprotease activity, and elevations in substance P and neuropeptide Y amide levels. Taken together, these results demonstrate that IH activates PHM in rat brain stem via reactive oxygen species-dependent posttranslational proteolytic processing and further suggest that PAM activation may contribute to IH-mediated peptidergic neurotransmission in rat brain stem.

Reactive Oxygen Species Mediate Central Cardiorespiratory Network Responses to Acute Intermittent Hypoxia

2007 ◽  
Vol 97 (3) ◽  
pp. 2059-2066 ◽  
Author(s):  
Kathleen J. S. Griffioen ◽  
Harriet W. Kamendi ◽  
Christopher J. Gorini ◽  
Evguenia Bouairi ◽  
David Mendelowitz
Keyword(s):  
Reactive Oxygen Species ◽  
Brain Stem ◽  
Intermittent Hypoxia ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Ventrolateral Medulla ◽  
Oxygen Species ◽  
Episodic Hypoxia ◽  
Excitatory Neurotransmission ◽  
The Brain

Although oxidative stress and reactive oxygen species generation is typically associated with localized neuronal injury, reactive oxygen species have also recently been shown to act as a physiological signal in neuronal plasticity. Here we define an essential role for reactive oxygen species as a critical stimulus for cardiorespiratory reflex responses to acute episodic hypoxia in the brain stem. To examine central cardiorespiratory responses to episodic hypoxia, we used an in vitro medullary slice that allows simultaneous examination of rhythmic respiratory-related activity and synaptic neurotransmission to cardioinhibitory vagal neurons. We show that whereas continuous hypoxia does not stimulate excitatory neurotransmission to cardioinhibitory vagal neurons, acute intermittent hypoxia of equivalent duration incrementally recruits an inspiratory-evoked excitatory neurotransmission to cardioinhibitory vagal neurons during intermittent hypoxia. This recruitment was dependent on the generation of reactive oxygen species. Further, we demonstrate that reactive oxygen species are incrementally generated in glutamatergic neurons in the ventrolateral medulla during intermittent hypoxia. These results suggest a neurochemical basis for the pronounced bradycardia that protects the heart against injury during intermittent hypoxia and demonstrates a novel role of reactive oxygen species in the brain stem.

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