Distribution of c-fos mRNA in the Brain Following Intracerebroventricular Injection of Nitric Oxide (NO)-Releasing Compounds: Possible Role of NO in Central Cardiovascular Regulation

We tested the hypothesis that nitric oxide (NO) plays a role in CBF autoregulation in the brain stem during hypotension. In anesthetized rats, local CBF to the brain stem was determined with laser-Doppler flowmetry, and diameters of the basilar artery and its branches were measured through an open cranial window during stepwise hemorrhagic hypotension. During topical application of 10−5 mol/L and 10−4 mol/L Nω-nitro-L-arginine (L-NNA), a nonselective inhibitor of nitric oxide synthase (NOS), CBF started to decrease at higher steps of mean arterial blood pressure in proportion to the concentration of L-NNA in stepwise hypotension (45 to 60 mm Hg in the 10−5 mol/L and 60 to 75 mm Hg in the 10−4 mol/L L-NNA group versus 30 to 45 mm Hg in the control group). Dilator response of the basilar artery to severe hypotension was significantly attenuated by topical application of L-NNA (maximum dilatation at 30 mm Hg: 16 ± 8% in the 10−5 mol/L and 12 ± 5% in the 10−4 mol/L L-NNA group versus 34 ± 4% in the control group), but that of the branches was similar between the control and L-NNA groups. Topical application of 10−5 mol/L 7-nitro indazole, a selective inhibitor of neuronal NOS, did not affect changes in CBF or vessel diameter through the entire pressure range. Thus, endothelial but not neuronal NO seems to take part in the regulation of CBF to the the brain stem during hypotension around the lower limits of CBF autoregulation. The role of NO in mediating dilatation in response to hypotension appears to be greater in large arteries than in small ones.

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Abstract P059: A A Role of Aminopeptidase A in the Brain on Cardiovascular Regulation of Conscious Rat

Hypertension ◽

10.1161/hyp.66.suppl_1.p059 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Takuto Nakamura ◽

Masanobu Yamazato ◽

Akio Ishida ◽

Yusuke Ohya

Keyword(s):

Blood Pressure ◽

Protein Expression ◽

Drinking Behavior ◽

Cardiovascular Regulation ◽

Ang Ii ◽

Hypertensive Rats ◽

Aminopeptidase A ◽

The Brain

Objective: Aminopeptidase A (APA) have important role in conversion of Ang II to Ang III. Intravenous APA administration lowers blood pressure in hypertensive rats. In contrast, APA inhibition in the brain lowers blood pressure in hypertensive rats. Therefore APA might have different role on cardiovascular regulation. However, a role of APA and Ang III on cardiovascular regulation especially in the brain has not been fully understood. Our purpose of present study was to investigate a role of APA and Ang III in the brain on cardiovascular regulation in conscious state. Method: 12-13 weeks old Wistar Kyoto rat (WKY) and 12-16 weeks old spontaneously hypertensive rat (SHR) were used. i) APA distribution in the brain was evaluated by immunohistochemistry. Protein expression of APA was evaluated by Western blotting. Enzymatic activity of APA was evaluated using L-glutamic acid γ-(4-nitroanilide) as a substrate. ii) WKY received icv administration of Ang II 25ng/2μL and Ang III 25ng/2μL. We recorded change in mean arterial pressure (MAP) in conscious and unrestraied state and measured induced drinking time. iii) SHR received icv administeration of recombinant APA 400ng/4μL. We recorded change in MAP in conscious and unrestraied state and measured induced drinking time. Result: i) APA was diffusely immunostained in the cells of brain stem including cardiovascular regulatory area such as rostral ventrolateral medulla. Protein expression and APA activity in the brain were similar between WKY (n=3) and SHR (n=3).ii) Icv administration of Ang II increased MAP by 33.8±3.8 mmHg and induced drinking behavior for 405±90 seconds (n=4). Icv administration of Ang III also increased MAP by 24.7±2.4 mmHg and induced drinking behavior for 258±62 seconds (n=3). These vasopressor activity and induced drinking behavior was completely blocked by pretretment of angiotensin receptor type 1 blocker.iii) Icv administration of APA increased MAP by 10.0±1.7 mmHg (n=3). Conclusion: These results suggested that Ang III in the brain increase blood pressure by Angiotensin type 1 receptor dependent mechanism and APA in the brain may involved in blood pressure regulation as a vasopressor enzyme.

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Modulation of cardiovascular control mechanisms and their interaction

Physiological Reviews ◽

10.1152/physrev.1996.76.1.193 ◽

1996 ◽

Vol 76 (1) ◽

pp. 193-244 ◽

Cited By ~ 126

Author(s):

P. B. Persson

Keyword(s):

Nitric Oxide ◽

Black Box ◽

Control Element ◽

Control Mechanisms ◽

Severity Of Disease ◽

The Brain ◽

Specific Control ◽

Central Level ◽

Shed Light

It is generally held that the role of a specific control element can only be understood within its physiological environment. The reviewed studies make it clear that there is a potent interplay between locally produced substances such as adenosine, nitric oxide, prostaglandins, and various others all interacting with the central level of control. This can occur at central sites (e.g., nitric oxide in the brain) or in the periphery (e.g., neural influence on autoregulation). The interactions are more or less pronounced during specific physiological challenges. Furthermore, several of these interactions are altered under pathological circumstances, and in some cases, the interactions seem to maintain or even augment the severity of disease. When more than three parameters participate in an interaction, the resulting regulation may become extremely complex. If these parameters are nonlinearly coupled with each other, the only way to shed light onto the nature of control network is by treating it as a black box. With the use of spectral analysis or nonlinear methods, it is possible to disentangle the fundamental nature of the system in terms of the complexity and stability. Therefore, modern developments in cardiovascular physiology utilizing these techniques, some of which are derived from the "chaos theory," are reviewed.

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Abstract P152: Aminopeptidase A in the Brain Exerts Cardiovascular Action via Degradation of Kallidin to Bradykinin

Hypertension ◽

10.1161/hyp.68.suppl_1.p152 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Takuto Nakamura ◽

Masanobu Yamazato ◽

Yusuke Ohya

Keyword(s):

Blood Pressure ◽

Pressor Response ◽

Cardiovascular Regulation ◽

Receptor Blocker ◽

Ang Ii ◽

Aminopeptidase A ◽

Hoe 140 ◽

Wistar Kyoto ◽

The Brain

Objective: Aminopeptidase A (APA) degrades of various sympathomodulatory peptides such as angiotensin (Ang) II, cholecystkinin-8, neurokinin B and kallidin. APA activity is increased in the brain of hypertensive rats. A centrally acting APA inhibitor prodrug is currently under investigation in clinical trial for treatment of hypertension. In previous reports, a role of APA in the brain on cardiovascular regulation was researched focus on only renin-angiotensin system. We previously reported that intracerebroventricular(icv) administration of APA increased blood pressure and that this pressor response was partially blocked by angiotensin receptor blocker. In this study, we evaluated a role of APA on cardiovascular regulation focusing on peptides other than Ang II. Method: Eleven weeks old Wistar Kyoto rats were used. We icv administrated 800 ng/8 μL of APA after pretreatment of following drugs, i) 8μL of artificial cerebrospinal fluid (aCSF) as a control, ii) 80 nmol/8 μL of amastatin which is a non-specific aminopeptidase inhibitor, iii) 1 nmol/8 μL of HOE-140 which is a bradykinin receptor blocker to evaluate the involvement of degradation of kallidin to bradykinin by APA. Result: i) Icv administration of APA after pretreatment of aCSF increased blood pressure rapidly. Blood pressure reached a peak within 1 minute. The elevated blood pressure decreased gradually and reached baseline blood pressure in 10 minutes. A peak pressor response is 25.5±1.4 mmHg (n=5). ii) Icv pretreatment of amastatin or HOE-140 did not change the blood pressure. A peak pressor response induced by APA is 13.1±4.1 mmHg (n=6, p<0.05 vs aCSF). iii) Icv pretreatment of HOE-140 did not change the blood pressure. A peak pressor response induced by APA is 21.2±1.8 mmHg (n=4, p<0.05 vs aCSF). Conclusion: 1) Icv administration of APA increased blood pressure by APA enzymatic activity. 2) Cardiovascular regulation of APA in the brain is due to not only degradation of Ang II to Ang III but also degradation of kallidin to bradykinin. Clinical implication: We think inhibition of APA in the brain may be a unique therapeutic target which affects several cardiovascular peptides in the brain.

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Role of endothelial nitric oxide synthase-derived nitric oxide in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00476.2008 ◽

2008 ◽

Vol 295 (4) ◽

pp. H1712-H1719 ◽

Cited By ~ 52

Author(s):

Osamu Handa ◽

Jancy Stephen ◽

Gediminas Cepinskas

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Nitric Oxide Synthase ◽

Mass Flux ◽

Oxidant Stress ◽

Junction Protein ◽

Cerebrovascular Endothelial Cells ◽

Oxide Synthase ◽

The Brain

Sepsis-associated encephalopathy is an early manifestation of sepsis, resulting in a diffuse dysfunction of the brain. Recently, nitric oxide (NO) has been proposed to be one of the key molecules involved in the modulation of inflammatory responses in the brain. The aim of this study was to assess the role of NO in cerebrovascular endothelial cell activation/dysfunction during the early onsets of sepsis. To this end, we employed an in vitro model of sepsis in which cultured mouse cerebrovascular endothelial cells (MCVEC) were challenged with blood plasma (20% vol/vol) obtained from sham or septic (feces-induced peritonitis, FIP; 6 h) mice. Exposing MCVEC to FIP plasma for 1 h resulted in increased production of reactive oxygen species and NO as assessed by intracellular oxidation of oxidant-sensitive fluorochrome, dihydrorhodamine 123 (DHR 123), and nitrosation of NO-specific probe, DAF-FM, respectively. The latter events were accompanied by dissociation of tight junction protein, occludin, from MCVEC cytoskeletal framework and a subsequent increase in FITC-dextran (3-kDa mol mass) flux across MCVEC grown on the permeable cell culture supports, whereas Evans blue-BSA (65-kDa mol mass) or FITC-dextran (10-kDa mol mass) flux were not affected. FIP plasma-induced oxidant stress, occludin rearrangement, and MCVEC permeability were effectively attenuated by antioxidant, 1-pyrrolidinecarbodithioic acid (PDTC; 0.5 mM), or interfering with nitric oxide synthase (NOS) activity [0.1 mM nitro-l-arginine methyl ester (l-NAME) or endothelial NOS (eNOS)-deficient MCVEC]. However, treatment of MCVEC with PDTC failed to interfere with NO production, suggesting that septic plasma-induced oxidant stress in MCVEC is primarily a NO-dependent event. Taken together, these data indicate that during early sepsis, eNOS-derived NO exhibits proinflammatory characteristics and contributes to the activation and dysfunction of cerebrovascular endothelial cells.

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Nitric Oxide: The Common Link in Different Forms of Dementia

International Journal of Science and Healthcare Research ◽

10.52403/ijshr.20210755 ◽

2021 ◽

Vol 6 (3) ◽

pp. 322-326

Author(s):

Dipak Kumar Dhar

Keyword(s):

Nitric Oxide ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nitrosative Stress ◽

Keywords Dementia ◽

Neurotoxic Effects ◽

The Common ◽

Cellular Pathogenesis ◽

The Brain

Dementia broadly refers to a global decline in cognitive and higher functions of the brain. With the gradually increasing number of aging population, the incidence of dementia has been steadily rising and expected to increase further in the coming years. The causes and forms of dementia are wide-ranging and diverse, with Alzheimer’s disease being its best studied form. With increasing knowledge about various effects and mechanisms of nitric oxide, this chemical neurotransmitter appears to be the connecting link in the cellular pathogenesis of dementia. An exhaustive search of research articles, commentaries and books published from 1990s onwards was performed with various words and combinations linked to dementia and nitric oxide. The existing medical literature shows both neuroprotective and neurotoxic effects of nitric oxide. The present article intends to delve into this topic and provide a lucid understanding of the role of nitric oxide in dementia. Keywords: Dementia, Nitric Oxide, Alzheimer’s disease, excitotoxicity, nitrosative stress.

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Comparative Genomic and Network Analysis of nNOS by Using Different Bioinformatics Approaches

Current Pharmacogenomics and Personalized Medicine ◽

10.2174/1875692118666210616165145 ◽

2021 ◽

Vol 18 ◽

Author(s):

Nymphaea Arora ◽

Vikash Prashar ◽

Tania Arora ◽

Randeep Sidhu ◽

Anshul Mishra ◽

...

Keyword(s):

Nitric Oxide ◽

Network Analysis ◽

Nitric Oxide Synthase ◽

Vascular Tone ◽

Neuronal Nitric Oxide Synthase ◽

Homologous Sequences ◽

Airway Tone ◽

Oxide Synthase ◽

The Brain

Introduction: Nitric oxide (NO) is a diatomic free radical gaseous molecule that is formed from L-arginine through NOS (Nitric oxide synthase) catalyzed reaction. NO controls vascular tone (hence blood pressure), insulin secretion, airway tone, and peristalsis and is involved in angiogenesis (growth of new blood vessels) and in the development of the nervous system. In the CNS, NO is an important messenger molecule, which is involved in various major functions in the brain. NOS has been classified into three isoforms which include nNOS (neuronal NOS), eNOS (endothelial NOS), and iNOS (inducible NOS). NOS1 is localized on chromosome 12, consisting of 1434 amino acids and 161 KDa molecular weight. nNOS is involved in synaptic transmission, regulating the tone of smooth muscles, penile erection. We studied NOS1 gene and protein network analysis through in silico techniques as human nNOS sequence was fetched from GenBank, and its homologous sequences were retrieved through BLAST search. Moreover, the results of this study exploit the role of NOS1 in various pathways, which provide ways to regulate it in various neurodegenerative diseases. Background: Previous research has revealed the role of Nitric Oxide (NO) formed from L-arginine through NOS (Nitric Oxide Synthase) as a physiological inter/intracellular messenger in the central as well as the peripheral nervous system. The diverse functions of NOS include insulin secretion, airway tone, vascular tone regulation, and in the brain, it is involved in differentiation, development, synaptic plasticity, and neurosecretion. Objective: The objective of this study is to unravel the role of neuronal Nitric Oxide Synthase (nNOS) in different pathways and its involvement as a therapeutic target in various neurodegenerative disorders, which can surely provide ways to regulate its activity in different aspects. Materials and Methods: In this study, we employed various bioinformatics tools and databases, initiating the study by fetching the neuronal Nitric Oxide Synthase (nNOS) sequence(GenBank) to find its homologous sequences(BLAST) and then exploring its physical properties and post-translational modifications, enhancing the research by network analysis(STRING), leading to its functional enrichment(Panther). Results : The results positively support the hypothesis of its role in various pathways related to neurodegeneration., Its interacting partners are the probable therapeutic targets of various neurodegenerative diseases focusing on specifically multi-target analysis. Conclusion: This study considered the evolutionary trend of physical, chemical, and biological properties of NOS1 through different phyla. The neuronal Nitric Oxide Synthase (nNOS), being one of the three isoforms of NOS (Nitric Oxide Synthase), is found to be involved in more pathways than just forming Nitric Oxide. This research provides the base for further neurological research.

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Nitric Oxide Synthesis and Regional Cerebral Blood Flow Responses to Hypercapnia and Hypoxia in the Rat

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1993.10 ◽

1993 ◽

Vol 13 (1) ◽

pp. 80-87 ◽

Cited By ~ 121

Author(s):

D. A. Pelligrino ◽

H. M. Koenig ◽

R. F. Albrecht

Keyword(s):

Nitric Oxide ◽

No Synthase ◽

Nitric Oxide Synthesis ◽

Cerebral Vasculature ◽

Regional Cerebral Blood ◽

Generating Capacity ◽

Baseline Values ◽

The Brain ◽

Hyperemic Response

The role of nitric oxide (NO) synthesis in the cerebral hyperemic responses to hypercapnia and hypoxia was investigated in anesthetized rats. Regional CBF (rCBF) measurements were obtained in the cortex (CX), subcortex (SC), brainstem (BS), and cerebellum (CE) using radiolabeled microspheres. The rCBF responses to either hypercapnia (Paco2 = 70–80 mm Hg) or hypoxia (Paco2 = 40–45 mm Hg) were compared in rat groups studied in the presence and absence of NO synthase inhibition induced via the intravenous infusion of nitro-l-arginine methyl ester (l-NAME, 3 mg kg−1 min−1). Administration of l-NAME under normocapnic/normoxic conditions produced a 40–60% reduction in baseline rCBF values, indicating the presence of a NO “tone” in the cerebral vasculature. Infusion of l-NAME resulted in a substantial attenuation, in all regions measured, of the rCBF increases that normally accompany hypercapnia. In comparing saline-infused to l-NAME-infused rats, the percentage increases in rCBF (from normocapnic baseline values) were 351% versus 166% (CX), 446% versus 199% (SC), 443% versus 206% (BS), and 483% versus 174% (CE), respectively. The rCBF changes from baseline (ΔrCBF in ml 100 g−1 min−1) were 488 versus 57 (CX), 570 versus 60 (SC), 434 versus 72 (BS), and 393 versus 45 (CE), respectively. These differences were all statistically significant ( p < 0.05). During hypoxia, when compared to rats not given l-NAME, inhibition of NO synthase activity resulted in significantly greater ( p < 0.05) percentage increases in rCBF (from normoxic baseline values) in most regions. The changes in non-l-NAME- vs. l-NAME-infused rats were 156% versus 262% (CX), 181% versus 309% (SC), and 210% versus 462% (BS), respectively. When the ΔrCBF values (from normoxic baseline levels) were compared, the changes were greater in the l-NAME group, but the differences were statistically insignificant. The results of this study indicated that NO synthesis is critically involved in the cerebral hyperemic response to hypercapnia but not hypoxia. In fact, the data obtained in the hypoxic groups suggested that reductions in O2 supply may inhibit the NO-generating capacity in the brain.

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