Het eerste onderstaande recent (2015) gepubliceerde onderzoek (vertaald naar het Nederlands), verklaard nu duidelijk wat de rede is waarom stikstofmonoxide zo belangrijk is en waarom het kan helpen met onze geriatrische problemen waaronder ArMD en Glaugoom.  Sinds Nov. 2015 is er een verklaring voor wat bij artsen voor jaren nog niet bekend was. Cruciaal in dit onderzoeksresultaat is dat een bloedstroom met minder Stikstofmonoxide in het bloed, de geïnhaleerde zuurstof niet of minder goed zal afgeven aan de lichaamscellen, waardoor gezondheidsproblemen (Geriatrisch) zich kunnen ontwikkelen.  Dit gegeven in combinatie met de wetenschap dat de natuurlijke aanmaak van Stikstofmonoxide steeds minder wordt naarmate we ouder worden, is dit de oorzaak van vele ouderdomsproblemen waaronder ArMD, Glaucoom, vergrote prostaat, slaapproblemen etc.. Door nu ons Stikstofmonoxide gehalte weer op te voeren naar een level van vroeger kunnen vele problemen worden voorkomen dan wel worden genezen. 

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Studie toont aan dat bloedcellen stikstofmonoxide nodig hebben om zuurstof te leveren.

 

 

 

Moleculaire en functionele basis is gelegd voor stikstofmonoxide als onderdeel voor leverantie van zuurstof en kooldioxide in Respirator Cycli.  (Zuurstofvoorziening)

Deze Ontdekking kan leiden tot behandeling van rode bloedcel-disfunctie bij hart- en vaatziekten en bloedstoornissen.

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April 10, 2015

(vertaling van Engels naar het Nederlands) 
"Nieuwe bevindingen over rode bloedcellen en het leveren van zuurstof van de longen naar weefsel (cellen) kan betekenen dat het tijd is om de handboeken over HOE de ademhalingscyclus werkt te herschrijven".
In de records  van de “National Academy of Sciences’ (2015), cardioloog  Jonathan Stamler,  een professor in de geneeskunde aan de Case Western Reserve University School of Medicijnen in Cleveland, USA, en collega's beschrijven hoe zij in een studie laten zien dat de "Respiratoire Cyclus"  bestaat uit drie gassen en niet alleen uit  twee gassen.

In de huidige wetenschap wordt beschreven dat  de ademhalingscyclus  voor transport via het bloed gebruik maakt  van twee gassen te weten; - zuurstof en kooldioxide -.  Rode bloedcellen halen vers ingeademde zuurstof op van de longen op en dragen dit naar de cellen in het weefsels van het lichaam, en brengen kooldioxide terug, - een afvalproduct van de stofwisseling - dat wordt uitgeademd uit de longen. Maar gelet op wat men nu heeft ontdekt,  Prof. Stamler en collega's stellen dat de ademhalingscyclus ook nog een derde gas gebruikt,  - n.l.  stikstofmonoxide -  (Nitric Oxide) een gas dat de afgifte van zuurstof uit rode bloedcellen naar de cellen in het weefsels controleert en mogelijk maakt.  In hun studie tonen zij aan dat het hemoglobine - het eiwit in rode bloedcellen dat het zuurstof opneemt uit de longen -  ook stikstofmonoxide moet bevatten  om de bloedvaten te kunnen openen om zorg te kunnen dragen voor de levering van de zuurstof aan het weefsel.
 

Prof. Stamler zegt "de bloedtoevoer naar de weefsels is in de meeste gevallen eigenlijk belangrijker dan de hoeveelheid  zuurstof  wat wordt gedragen door hemoglobine.   ERGO: de respiratoire cyclus is eigenlijk een drie-gas-systeem."

Hij en zijn collega's zeggen dat hun bevindingen ons begrip van de ademhalingscyclus zal transformeren en levens kan redden. Dit blijkt uit deze moleculaire studie, en is de basis van de bloedstroom controle bij de ademhalingscyclus. Sinds enige tijd hebben artsen al geweten dat er een onbalans bestaat tussen de hoeveelheid zuurstof in het bloed wat wordt vervoerd en de hoeveelheid zuurstof  dat aan het weefsel wordt afgeleverd – maar men wist niet  waarom.  Prof. Stamler zegt dat met hun studie de moleculaire basis  en daarmee de regeling van de bloedstroom in de ademhalingscyclus is ontdekt. Het team gelooft dat stikstofmonoxide is de sleutel is tot zuurstof levering - en zonder stikstofmonoxide de respiratoire cyclus kan niet worden uitgevoerd. Prof. Stamler legt uit:  "In de hemoglobine eiwit  zit de werking die het mogelijk maakt om in een combinatie met stikstofmonoxide de zuurstof te leveren."

 

In eerder werk liet het team al zien dat de ademhalingscyclus al meer was dan alleen een uitwisseling van kooldioxide en zuurstof. Ze ontdekten dat rode bloedcellen ook stikstofmonoxide bevatte, maar de onderliggende biologie was nog niet duidelijk.  In deze nieuwe studie, laten de onderzoekers zien hoe stikstofmonoxide de bloedstroom regelt in de kleine bloedvaten in het weefsel een proces dat bekend staat als "de doorbloeding autoregulatie."  (tot zover de vertaling van Engels naar Nederlands)

Geschreven door Catharine Paddock PhD.  Bron:   https://www.ncbi.nlm.nih.gov/pubmed/25810253

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Molecular and Functional Basis Established for Nitric Oxide Joining Oxygen and Carbon Dioxide in Respiratory Cycle 

Discovery Could Lead to Treatment Focus on Red Blood Cell Dysfunction in Cardiovascular Diseases and Blood Disorders

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Study shows blood cells need nitric oxide to deliver oxygen

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New findings on how red blood cells deliver oxygen from the lungs to tissue in may mean it is time to rewrite the text books on how the respiratory cycle works.  (De originele text) 

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In the Proceedings of the National Academy of Sciences, cardiologist Jonathan Stamler, a professor of medicine at Case Western Reserve University School of Medicine in Cleveland, OH, and colleagues describe how they conducted a study that shows the respiratory cycle involves three gases and not just two. The current convention describes the respiratory cycle as using blood to transport two gases - oxygen and carbon dioxide. Red blood cells pick up freshly inhaled oxygen from the lungs and carry it to cells in the tissues of the body, and bring back carbon dioxide - a waste product of metabolism - to be exhaled from the lungs. But because of what they have found, Prof. Stamler and colleagues argue that the respiratory cycle also involves a third gas - nitric oxide - that controls the release of oxygen from red blood cells into the tissues that need it. In their study they show that hemoglobin - the protein in red blood cells that picks up oxygen from the lungs - also needs to carry nitric oxide to enable blood vessels to open and supply the oxygen to tissues. Prof. Stamler says "blood flow to tissues is actually more important in most circumstances than how much oxygen is carried by hemoglobin. So the respiratory cycle is actually a three-gas system."

He and his colleagues say their findings will transform our understanding of the respiratory cycle and could save lives. Study reveals molecular basis of blood flow control in the respiratory cycle. For some time doctors have known there is an imbalance between the amount of oxygen transported in the blood and the amount that is delivered to tissues - but not why.

Prof. Stamler says their study shows they have discovered the molecular basis of what controls blood flow in the respiratory cycle. The team believes nitric oxide is the key to oxygen delivery - and without it the respiratory cycle cannot run. Prof. Stamler explains:

"It's in the hemoglobin protein itself, which has the ability to deliver the nitric oxide together with oxygen." In previous work, the team showed the cycle was more than just an exchange of carbon dioxide and oxygen. They discovered red blood cells carried and also released nitric oxide, but the underlying biology was not clear. In this new study, the researchers show how nitric oxide controls the blood flow in small blood vessels inside tissue in a process known as "blood flow autoregulation."  For their investigation, they used mice engineered to lack the ability to carry nitric oxide in their red blood vessels.  Inability to carry nitric oxide in red blood cells means no oxygen gets into tissue.  They found the mice could not oxygenate their muscle tissue - their blood flow autoregulation just did not work in the absence of nitric oxide. Even though their red blood cells were able to carry a full load of oxygen - they just could not unload it.  And when the researchers induced slight oxygen deprivation (hypoxia) in the mice, the blood flow to their organs dropped sharply, triggering heart attacks and heart failure.

In normal mice, the lack of oxygen prompts a spike in blood flow, so more oxygenated blood reaches tissues and cells. This did not happen in the mice whose red blood cells lacked nitric oxide.  Prof. Stamler explains how the mice had red blood cells "that by all traditional measures are completely normal in carrying oxygen and releasing it and then in picking up carbon dioxide, yet these animals cannot oxygenate their tissues. Lacking nitric oxide in red cells, oxygen deficiency could not induce vasodilation, which is essential for sustaining life as we know it."

The study shows that when the mechanism that releases nitric oxide from the amino acid binding site in the hemoglobin is working, the blood vessels dilate and allow oxygen-rich red blood cells to flow into the tissue.

The findings also provide evidence that blood flow is not just under the control of blood vessels - red blood cells are also involved. This has not been appreciated before, with some scientists hypothesizing instead that the lack of blood flow that causes heart attacks and strokes is nothing to do with red blood cells - it is all about what happens in blood vessels. The authors suggest this view needs to be revised, as Prof. Stamler explains:  "Within the tissues, the tiny vessels and the red blood cells together make up the critical entity controlling blood flow. Red blood cell dysfunction is likely a hidden contributor to diseases of the heart, lung and blood such as heart attack, heart failure, stroke and ischemic injury to kidneys." Implications for blood transfusions and the nation's blood supply.  The study also has implications for blood transfusions. Recent evidence shows blood transfusions lacking nitric oxide are linked to higher risk of heart attacks, disease and death.

Prof. Stamler says the effects being reported in these cases are similar to what they observed in the mice - the common factor is lack of nitric oxide.  "It's not enough to increase to oxygen content of blood by transfusion; if the nitric oxide mechanism is shot, oxygen cannot make it to its destination. We know that blood in a blood bank is deficient in nitric oxide, so infusing that blood may cause plugging of blood vessels in tissues, making things worse," he notes, and concludes:  "Essentially, blood flow cannot autoregulate (increase) without nitric oxide. In terms of developing future therapies, the goal must be restoring red blood cell function, complete with nitric oxide delivery capability. As for the nation's blood supply, the blood should be replenished with nitric oxide."  Funds for the research came from the National Institutes of Health, Defense Advanced Research Projects Agency, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center.

In 2013, Medical News Today learned of another small study that suggested the shelf life of blood is nearer 3 than 6 weeks. In blood banks, the standard shelf life of blood for transfusion is 6 weeks, but research led by an expert from the Johns Hopkins University School of Medicine found that after 3 weeks, red blood cells are no longer flexible enough to squeeze through the tiny blood vessels to deliver oxygen where it is most needed.

Written by Catharine Paddock PhD

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Stikstofmonoxide of Nitric oxide in het algemeen:

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Hieronder vindt u enkele uit letterlijk duizenden studies over  Nitric Oxide (Stikstofmonoxide) (NO)  Deze studies geven een eenvoudig beeld wat Stikstofmonoxide betekend voor ons lichaam. Het geeft ondermeer aan dat the Stikstof oxide wordt geproduceerd in onze sinussen, dat het een belangrijk gas is voor vele functies in ons lichaam en dat het biologisch en automatisch afneemt naarmate wij ouder worden.  Indien gewenst kunt U, zei het niet 100% , de studies vertalen met google translater.  (Voor de vertaler, klik hier)  <kopieer de text en plak het in de vertaler van Engels naar Nederlands>   

  

1)

Nitric oxide and the paranasal sinuses.

Anat Rec (Hoboken). Lundberg JO1.

2008 Nov;291(11):1479-84.

doi: 10.1002/ar.20782.

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The discovery within the paranasal sinuses for the production of nitric oxide (NO) has altered the traditional explanations of sinus physiology. This review article reports the ongoing investigation of sinus physiology beginning with the discovery of NO gas production in the paranasal sinuses that occurred in 1995, and the impact that finding has had both in the basic science and clinical arenas. It was shown that healthy paranasal sinus epithelium expresses an inducible NO synthase that continuously generates large amounts of NO, a pluripotent gaseous messenger with potent vasodilating, and antimicrobial activity. This NO can be measured noninvasively in nasally exhaled breath. The role of NO in the sinuses is likely to enhance local host defense mechanisms via direct inhibition of pathogen growth and stimulation of mucociliary activity. The NO concentration in a healthy sinus exceeds those that are needed for antibacterial effects in vitro. In patients with primary ciliary dyskinesia (PCD) and in cystic fibrosis, nasal NO is extremely low. This defect NO generation likely contributes to the great susceptibility to chronic sinusitis in these patients. In addition, the low-nasal NO is of diagnostic value especially in PCD, where nasal NO is very low or absent. Intriguingly, NO gas from the nose and sinuses is inhaled with every breath and reaches the lungs in a more diluted form to enhance pulmonary oxygen uptake via local vasodilation. In this sense NO may be regarded as an "aerocrine" hormone that is produced in the nose and sinuses and transported to a distal site of action with every inhalation.

Copyright 2008 Wiley-Liss, Inc.

Source:  

http://www.ncbi.nlm.nih.gov/pubmed/18951492

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2) 

Nitric oxide and geriatrics: Implications in
diagnostics and treatment of the elderly.

Source:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/

Abstract:

The nation’s aging population is growing rapidly. By 2030, the number of adults age 65

and older will nearly double to 70 million. Americans are living longer and older adults

can now live for many years with multiple chronic illnesses but with a substantial cost

to health care. Twenty percent of the Medicare population has at least five chronic

conditions i.e., hypertension, diabetes, arthritis, etc. Studies in experimental models

and even humans reveal that constitutive production of nitric oxide (NO) is reduced with

aging and this circumstance may be relevant to a number of diseases that plague the aging

population. NO is a multifunctional signaling molecule, intricately involved with maintaining a host of physiological processes including, but not limited to, host defense, neuronal communication and the regulation of vascular tone. NO is one of the most important signaling molecules in our body, and loss of NO function is one of the earliest indicators or markers of disease. Clinical studies provide evidence that insufficient NO production is associated with all major cardiovascular risk factors, such as hyperlipidemia, diabetes, hypertension, smoking and severity of atherosclerosis, and also has a profound predictive value for disease progression including cardiovascular and Alzheimers disease. Thirty plus years after its discovery and over 13 years since a Nobel Prize was awarded for its discovery, there have been no hallmark therapeutic breakthroughs or even NO based diagnostics. We will review the current state of the science surrounding NO in the etiology of a number of different diseases in the geriatric patient. From these observations, it can be concluded that enzymatic production of NO declines steadily with increasing age in healthy human subjects. Implementing strategies to diagnose and treat NO insufficiency may provide enormous benefit to the geriatric patient. J Geriatr Cardiol 2011; 8: 230−242. doi: 10.3724/SP.J.1263.2011.00230   

Source:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390088/

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3)   

Nitrite: A physiological store of nitric oxide and modulator of mitochondrial function

Received 19 November 2012

ABSTRACT

Nitrite, long considered a biological lyinertmetabolite of nitricoxide (NO) oxidation, is now accepted as a physiological storage pool of NO that can be reduced to bioactive NO in hypoxic conditions to mediate a spectrum of physiological responses in blood and tissue. This graphical review will provide a broad overview of the role of nitrite in physiology, focusing on its formation and reduction to NO as well as its regulation of the mitochondrion—an emerging subcellular target for its biological actions in tissues. 2013 The Author. Published by Elsevier B.V.

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BASIC EXPLENATION: 

This study shows the definitive relationship between Nitric oxide and Nitrite, and the way how NO is stored in the body. Before scientists believed that nitric oxide as a second, half-life gas, disappear after receiving in the body. This study shows that NO will be stored in the body as nitrite, until the moment the body needs it. 

Source:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661298/

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Stikstofmonoxide in AMD en Glaucoom 

4)

Seeing is believing:
NO therapy for glaucoma? Focus on “Role of nitric oxide in murine conventional outflow physiology”

Natasha M. Rogers, Jeffrey S. Isenberg

American Journal of Physiology - Cell Physiology Published 15 August 2015 Vol. 309 no. 4, C203-C204 DOI: 10.1152/ajpcell.00180.2015​

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nitric oxide (NO), a highly reactive, naturally occurring biogas in mammals, is critical to regulating vessel health, but it is a potential toxin at high concentrations. NO is produced at modest levels by the synthetic enzyme endothelial NO synthase (eNOS), which resides in all vascular endothelial cells. It is also made by several closely related synthetic enzymes unique to inflammatory and neural cells. In the cardiovascular system, NO plays an important role in suppressing inflammation, platelet activation, and thrombosis, relaxing vasoconstriction in resistance arteries and lowering blood pressure. Data from human cohorts have shown a strong link between loss of NO signaling and cardiovascular, cerebrovascular, renal, and metabolic diseases. This has led to the development and application of NO-targeting therapies to a range of clinical conditions (2).

More recently, the physiological role of NO and its pathophysiological loss have been documented in other disease models. Primary open-angle glaucoma (POAG), a common ocular disorder associated with raised intraocular pressure, affects ∼2% of the US population and is the second-leading cause of blindness world-wide due to death of retinal ganglion cells in the optic disk or retinal nerve (5). The mainstays of treatment of POAG include 1) decreasing aqueous humor production through adrenergic receptor modulation or carbonic anhydrase inhibition or 2) accentuating aqueous humor outflow through the trabecular meshwork using cholinomimetics or prostaglandins. Both are incompletely effective. Recent work has suggested that NO and activators of the cytoplasmic NO receptor soluble guanylate cyclase (4) may have beneficial effects and some therapeutic advantages in disease. Ocular hypotensive events equivalent to a reduction in intraocular pressure seen with standard treatments have been demonstrated in response to activation of the NO-cGMP pathway in humans (10). However, the role of eNOS-derived NO in the eye in health and disease is incompletely known. Human studies have demonstrated ciliary muscle and trabecular outflow pathways enriched in eNOS expression (7). Conversely, eNOS polymorphisms have been associated with POAG in certain human populations (1).

In this issue of American Journal of Physiology Cell Physiology, Chang and colleagues (3) provide additional preclinical insight into the role of NO, in general, and endogenous NO, in particular, in controlling ocular aqueous outflow. Employing an elegant whole eye preparation that allowed for controlled perfusion, the authors confirmed that exogenous NO, delivered as the prodrug S-nitroso-N-acetylpenicillamine, increased aqueous outflow. Supporting a role for eNOS, eyes from global mutant mice that express human eNOS linked to GFP (eNOS-GFP) and eyes from wild-type mice displayed decreased aqueous outflow following treatment with the peptide cavtratin, which putatively targets caveolin-1 and, thus, should inhibit eNOS. Of some note, eNOS-GFP mutant eyes were more sensitive to the effects of the eNOS inhibitory peptide than were the wild-type eyes. Outflow rates were decreased under several other conditions in eNOS-GFP mutant eyes compared with wild-type eyes. These results raise questions as to the fidelity of the NO signal in the mutant mice that require additional investigation. Also treatment of wild-type eyes with a low concentration (10 μM) of the nonspecific eNOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME) decreased aqueous outflow, whereas 100 μM l-NAME had no effect on the outflow rate. These multiple unexpected findings may derive from 1) the nature of the ex vivo system employed, as it lacks autonomic neural input, 2) the known threshold effect of exogenous NO (9), 3) differences in NO signaling between wild-type and eNOS-GFP mutant eyes, or 4) yet to be determined nuances in NO signaling within the eye.

It is also not known from the present study if and how eNOS modulates vascular endothelial growth factor (VEGF) signaling in the eye. This is of some relevance, as eNOS, NO, and VEGF are well known to engage in complex cross-talk interactions in other vascular beds. Nonetheless, the work of Chang et al. (3) is novel, as it provides some evidence for a role for endogenous NO as derived from eNOS to alter the aqueous outflow from the eye. This is a step forward in this area, as other reports have evaluated only the effects of excess NO delivered exogenously or pharmacological inhibition of NO signaling on ocular outflow.

This study raises several interesting questions regarding the potential translational aspect of NO therapy. Reduction in NO signaling is associated with increasing age (8), a known risk factor for POAG development, while aging populations with glaucoma are at increased risk for subsequent development of cardiovascular disease (6). Furthermore, as NO has been a therapeutic target for some time in patients with cardiovascular diseases, the results of the present work suggest additional studies to determine if patients treated with an NO-targeting therapy for reasons unrelated to eye disease are protected from developing glaucoma or if the use of such agents slows or stabilizes the process once it starts. Such data would provide an impetus for considering manipulation of NO signaling as part of the pharmacological armamentarium for glaucoma.

GRANTS

This work was supported by National Heart, Lung, and Blood Institute Grants P01 HL-103455, R01 HL-108954, and 1R01 HL-112914-01A1 (J. S. Isenberg) and an American Society of Transplantation Basic Science Fellowship (N. M. Rogers). This work was also supported by the Institute for Transfusion Medicine, the Hemophilia Center of Western Pennsylvania, and the Heart, Blood, Lung, and Vascular Medicine Institute of the University of Pittsburgh (J. S. Isenberg).

DISCLOSURES

J. S. Isenberg serves as Chair of the Scientific Advisory Board of Vasculox, Inc. (St. Louis, MO) and Radiation Control Technologies, Inc. (Jersey City, NJ) and has equity interest in the same. N. M. Rogers has no conflicts of interest, financial or otherwise, to declare.

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5) (Nederlands) 

Vertaling van Engels naar Nederlands van de studie:
Lage Stikstofmonoxide synthese (RSZ) in de ogen met leeftijdsgebonden macula-degeneratie (AMD) 

Exp Eye Res. 2010 Jan;90(1):155-67. doi: 10.1016/j.exer.2009.10.004. Epub 2009 Oct 15.

Stikstofoxide (NO) productie door vasculaire endotheel is belangrijk bij de regulatie van de bloedstroom. Verminderde productie van Stikstofoxide  NO kan de bloedstroom en ook andere vasculaire functies aantasten. We onderzochten de expressie van drie nitric oxide synthase (NOS) iso vormen in de retina en choroidea van oudere menselijke ogen en ogen met AMD. Alkalische fosfatase immunohistochemie werd uitgevoerd met antilichamen tegen induceerbaar (iNOS), neuronaal (nNOS), en endotheel (eNOS) noss op gecryopreserveerd secties in oudere do

nor-ogen ter controle (n = 13) en AMD ogen (n = 22). CD34 antilichaam werd gebruikt als een endotheelcel (EC) marker. Drie gemaskeerde onafhankelijke waarnemers scoorde de intensiteit van de immunohistochemische reactieproduct.  De gemiddelde scores van de leeftijd van de controle en AMD ogen werden statistisch vergeleken. In de leeftijd van controle netvlies, nNOS was ganglioncellen (RGC) en neuronen van beide nucleaire lagen. In choroidea, perivasculaire zenuwvezels en retinale pigment epitheel (RPE) cellen waren nNOS +. eNOS en iNOS werden beperkt tot de retinale en choroïdale vasculaire EC. Sommige cellen (vermoedelijk melanocyten of dendritische cellen) in choroid waren ook eNOS +. AMD ogen was de nNOS (Stikstofoxide) significant lager in RGC, neuronen, retinale vaten en RPE (p <of = 0,05) vergeleken met de oudere ogen ter controle.  iNOS en eNOS toonde geen significante verschillen tussen leeftijd controle en AMD ogen behalve dat er beduidend minder eNOS in choroïdale bloedvaten (p = 0,006) en choroïdale cellen (p = 0,03) van AMD ogen. Hoewel er niet direct gemeten, suggereren deze bevindingen dat er minder NO (Stikstofoxide) aanwezig is in AMD ogen. De daling van het netvlies nNOS in AMD ogen is waarschijnlijk gerelateerd aan neuronale degeneratie. De daling van nNOS en eNOS in AMD choroideus kon worden geassocieerd met vaatvernauwing en hemodynamische veranderingen.

Deze studie, zoals meerder andere studies, geeft aan dat een van de oorzaken van AMD en ook zo in Glaucoom, een vermindering van Stikstofmonoxide is, het geen met de Hummer Mask kan worden voorkomen. Het gebruik van de Hummer Mask, voorkomt veroudering van de bloedvaten, die allen betrekking hebben op de afgifte van zuurstof aan de cellen.  Deze studies in combinatie met de recente studie…….. waarin wordt vastgesteld dat Stikstofmonoxide onontbeerlijk is voor de afgifte van zuurstof, geeft aan waardoor ADM / Glaucoom door verminderde stikstofmonoxide, kan ontstaan.  

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5) (english)

Low Nitric Oxide Synthases (NOS) in Eyes with Age-related Macular Degeneration (AMD)

Exp Eye Res. 2010 Jan;90(1):155-67. doi: 10.1016/j.exer.2009.10.004. Epub 2009 Oct 15.

Low nitric oxide synthases (NOSs) in eyes with age-related macular degeneration (AMD).

Bhutto IA1, Baba T, Merges C, McLeod DS, Lutty GA.

Abstract:

Nitric oxide (NO) production by vascular endothelium is important in regulation of blood flow. Reduced production of NO can adversely affect blood flow and other vascular functions. We investigated the expression of three nitric oxide synthase (NOS) isoforms in retina and choroid of aged human eyes and eyes with AMD. Alkaline phosphatase immunohistochemistry was performed using antibodies against inducible (iNOS), neuronal (nNOS), and endothelial (eNOS) NOSs on cryopreserved sections from aged control donor eyes (n = 13) and eyes with AMD (n = 22). CD34 antibody was used as an endothelial cell (EC) marker. Three independent masked observers scored the intensity of the immunohistochemical reaction product. Mean scores from the aged control and AMD eyes were statistically compared. In aged control retinas, nNOS was in ganglion cells (RGCs) and neurons of both nuclear layers. In choroid, perivascular nerve fibers and retinal pigment epithelial (RPE) cells were nNOS+. eNOS and iNOS were confined to the retinal and choroidal vascular ECs. Some cells presumably melanocytes or dendritic cells in choroid were also eNOS+. In AMD eyes, nNOS was significantly lower in RGCs, neurons, retinal vessels and RPE (p < or = 0.05) compared to the aged control eyes. iNOS and eNOS showed no significant differences between aged control and AMD eyes except that there was significantly less eNOS in choroidal arteries (p = 0.006) and choroidal cells (p = 0.03) of AMD eyes. Although NO was not measured directly, these findings suggest that there is less NO produced in AMD eyes. The decrease in retinal nNOS in AMD eyes is probably related to neuronal degeneration. The decrease in nNOS and eNOS in AMD choroid could be associated with vasoconstriction and hemodynamic changes.

http://www.ncbi.nlm.nih.gov/pubmed/19836390

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6)

Br J Ophthalmol. 2001 Dec;85(12):1426-8.

Plasma malondialdehyde and nitric oxide levels in age related macular degeneration.

Totan Y1, Cekiç O, Borazan M, Uz E, Sögüt S, Akyol O. (Author information)

Abstract

AIMS:

To evaluate alteration of plasma malondialdehyde (MDA) and nitric oxide (NO) levels in patients with exudative age related macular degeneration (ARMD).

METHODS:

Plasma nitrite plus nitrate concentrations as an index of plasma NO levels and plasma MDA level as a marker of lipid peroxidation were measured in patients with exudative ARMD and age and sex matched healthy subjects.

RESULTS:

Significantly higher MDA and lower NO levels were detected in plasma of patients with ARMD compared with their controls (p=0.01, p=0.001, respectively).

CONCLUSION:

The results may support involvement of oxidative damage and vascular theory in the pathogenesis of ARMD as part of the ageing process.

Bron:http://www.ncbi.nlm.nih.gov/pubmed/11734513

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7)

The future started: nitric oxide in glaucoma.

[Article in Romanian]

Stefan C1, Dumitrica DM, Ardeleanu C.

Author information

Abstract

Nitric oxide (NO) is an important messenger intra and extra molecular implicated in vasodilatation, contractility, neurotransmission, neurotoxicity and inflammation. NO is formed from L-arginine by nitric oxide synthase (NOS). Nitric oxide synthase has three isoforms: NOS- 1 neuronal, NOS-2 inducible and NOS-3 endothelial (role in vasodilatation). Nitric oxide has a demonstrate role in many neurodegenerative diseases like: glaucoma, Alzheimer disease, multiple sclerosis and cerebral-cardio-vascular diseases.

PURPOSE:

To investigate the activity of the NOS by immunohistochemistry in patients with primary open angle glaucoma (POAG).

METHODS:

Observational, prospective, clinical study, during 9 months on one group of 9 patients with POAG that have underwent filtering surgery - trabeculectomy. The fragments of trabecular meshwork harvested during surgery were studied by immunohistochemistry for NOS. The exclusion criteria at the beginning of the study were any ocular or general pathology associated.

RESULTS AND CONCLUSIONS:

After laboratory analyses in patients with primary open angle glaucoma we observed the presence of the activity of NOS in trabecular meshwork. The trabecular distribution of NOS suggests an important role of nitric oxide in the future therapies for the glaucoma. The increase of nitric oxide makes vasodilatation and improves contractility in the trabecular meshwork; the final effect being the decrease of intraocular pressure and on the other hand the contra-apoptotic effect giving neuroprotection.

PMID: 18543682

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8)

Nitric oxide proxies and ocular perfusion pressure in primary open angle glaucoma

F Galassi,1 G Renieri,1 A Sodi,1 F Ucci,1 L Vannozzi,1 and E Masini2

Author information ► Article notes ► Copyright and License information ►

This article has been cited by other articles in PMC.

Abstract

Background: To investigate the levels of nitric oxide (NO) markers in plasma and aqueous humour of patients with primary open angle glaucoma (POAG) and their relation to ocular perfusion pressure.

Methods: Cyclic guanosine monophosphate (cGMP) and nitrite (NO2 −) were determined in plasma and aqueous humour of 38 patients with POAG and 46 controls. Blood pressure and IOP were measured to calculate ocular perfusion pressure (PP).

Results: cGMP and NO2 − plasma levels were significantly decreased in glaucoma patients compared with controls (p = 0.001 v p = 0.004). In the aqueous humour of subjects with POAG, cGMP and NO2 − concentrations were also lower than in normal eyes (p = 0.0001 v p = 0.001). There was a linear association between cGMP in plasma and aqueous humour in glaucomas and controls (r = 0.514, p = 0.029 and r = 0.558, p = 0.004) and this relation differed in the two groups (p = 0.003). Considering glaucoma patients with controls, a positive correlation was found between cGMP and PP (r = 0.379, p = 0.01) and between NO2 − and PP (r = 0.339, p = 0.040). The cGMP/PP correlation was of borderline statistical significance in controls (p = 0.050), whereas it did not attain statistical significance in POAG, as well as the association between NO2 − and PP when glaucomas and controls were considered separately.

Conclusions: The authors found alterations of NO markers in the plasma and aqueous humour of glaucoma patients. Primary or secondary impaired NO balance could alter ocular perfusion pressure.

Keywords: primary open angle glaucoma, nitric oxide, ocular perfusion pressure

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In Nederland is nog weinig onderzoek gedaan naar Glaucoom/ARMD en Stikstofmonoxide. In andere lnden zoals Duitsland, Engeland en Amerika is men veel verder met o.a. "Stickstoffoxid" en "Nitric Oxide".  Wij hebben wel een andere bron (Nederlands) gevonden waarin de relatie Glaucoom-Stikstof Oxide-en Gladdespieren (smooth musclels) wordt gelegd.  (klik hier)  

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9)

Humming Greatly Increases Nasal Nitric Oxide

Eddie Weitzberg , and Jon O. N. Lundberg

+ Author Affiliations

DOI: http://dx.doi.org/10.1164/rccm.200202-138BC

PubMed: 12119224

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Abstract

The paranasal sinuses are major producers of nitric oxide (NO). We hypothesized that oscillating airflow produced by humming would enhance sinus ventilation and thereby increase nasal NO levels. Ten healthy subjects took part in the study. Nasal NO was measured with a chemiluminescence technique during humming and quiet single-breath exhalations at a fixed flow rate. NO increased 15-fold during humming compared with quiet exhalation. In a two-compartment model of the nose and sinus, oscillating airflow caused a dramatic increase in gas exchange between the cavities. Obstruction of the sinus ostium is a central event in the pathogenesis of sinusitis. Nasal NO measurements during humming may be a useful noninvasive test of sinus NO production and ostial patency. In addition, any therapeutic effects of the improved sinus ventilation caused by humming should be investigated.

The gas nitric oxide (NO) is released in the human respiratory tract. The major part of NO found in exhaled air originates in the nasal airways, and it can be measured noninvasively with different sampling techniques (1). A large production of NO takes place in the paranasal sinuses (2). The sinuses communicate with the nasal cavity through ostia, and the rate of gas exchange between these cavities is dependent, for example, on the size of the ostia (3). Proper ventilation is essential for maintenance of sinus integrity, and blockage of the ostium is a central event in pathogenesis of sinusitis (3, 4).

The concentrations of NO in the healthy sinuses are very high, sometimes more than 20 parts per million (2). We hypothesized that the oscillating airflow produced by humming would speed up the exchange of air between the sinuses and the nasal cavity and thereby increase nasal NO output.
 

Methods

Ten healthy nonsmoking subjects (age 34–48 years, all males) without any history of allergy or airway disorder took part in the study. NO was measured in oral and nasal single-breath exhalations using a chemiluminescence system developed to meet the criteria of the guidelines of the American Thoracic Society (5) for exhaled NO measurements (NIOX, Aerocrine AB, Stockholm, Sweden). A tight-fitting mask covering the nose was used for nasal measurements, and a mouthpiece was used for oral exhalations. The subjects exhaled at a fixed flow rate (0.20 L/s) for 5 seconds either quietly or with nasal humming or oral phonation. NO levels were calculated as the mean concentration during the last 70% of the exhalation. The fixed flow rate was achieved by a dynamic flow restrictor in the analyzing system. An elastic membrane valve in the restrictor mechanically adjusts flow rate and keeps exhalation at 0.20 L/second within a range of exhalation pressures. The resulting mean exhalation flow rate was monitored, and variation was minimal (less than 0.02 L/second).

We also measured NO levels in a two-compartment model resembling the nasal cavity and one sinus. A syringe (the sinus), filled with 20 ml of NO gas (10 parts per million, AGA AB, Lidingö, Sweden), was connected vertically to a plastic cylinder (the nasal cavity) via a luer fitting. The diameter of the syringe tip (representing the ostium) was varied between 0 and 3.2 mm. A subject performed a single-breath oral exhalation (0.20 L/second) through the cylinder with or without phonation, and resulting NO levels were measured in the chemiluminescence system described previously here. To estimate the exchange of air between the two cavities, we also measured remaining NO levels in the syringe (ostial size, 2.4 mm) after a single full oral exhalation (20 seconds) with or without oscillating airflow (phonation).

 

DISCUSSION

Here we show that nasal NO levels increases dramatically during humming compared with normal quiet nasal exhalation. This effect is likely due to increased contribution of NO from the paranasal sinuses. Humming causes the air to oscillate, which in turn seems to increase the exchange of air between the sinuses and the nasal cavity. This was also confirmed in the two-compartment model system where humming resulted in a great increase in NO levels (Figure 2). The volume in the syringe, the NO concentration, as well as the diameter of the syringe tip (representing the sinus ostium) were chosen because they resemble physiologic values for these parameters (2, 3). The normal size of an ostium is approximately 2.4 mm (3). Interestingly, NO levels were strongly dependent on the diameter of the syringe tip. This implies that the increase in nasal NO during humming is dependent on ostial size. In this first study, we used a rather fixed model, changing only the diameter of the syringe tip. It is possible that several other factors will influence the rate of exchange between the two cavities, for example, flow rate, pressure, sound frequency, and the volumes of the communicating cavities. Because nasal NO is known to be very flow-dependent, special care was taken to perform all measurements at a fixed exhalation flow rate. In this study, we used a flow rate of 0.20 L/second, and the variation was minimal. Naturally, the model we used here cannot be directly compared with the situation in vivo. For example, airflow is rather turbulent in the nasal passages, whereas the flow in the model cylinder during quiet breathing is probably more laminar. Moreover, the sinus ostia are complex structures that continuously undergo dynamic changes. Nevertheless, the model used here may be helpful in understanding some of the factors that determine nasal NO levels during humming. We cannot exclude that humming increases NO release also from other sources within the nose. For example, the sound waves may generally increase the release of NO solved in the epithelial cells and fluid linings.

Sinusitis is a very common disease causing much human suffering and enormous costs for society. The self-reported prevalence of chronic sinusitis in the United States is as high as 14% of the population (4). There are several problems involved in the diagnosis and treatment of this disorder. For example, headache, rhinorrhea, and nasal congestion are extremely common, but these symptoms do not necessarily imply sinusitis. Proper ventilation of the sinuses is essential for sinus integrity. In fact, occlusion of the ostia is considered a key factor in the pathogenesis of sinusitis (4). Such occlusion may be due, for example, to an acute viral infection causing swelling of the mucosa. The basic principles of treatment are to cure any infection present and to promote sinus drainage, for example, with nasal decongestants, sinus irrigation, or surgery (4).

Aust and Drettner have described a method to measure sinus ostial function (3). However, this test is invasive and somewhat cumbersome to perform. An easy noninvasive method that could be used to measure sinus ostial patency could be most useful. Such a test could help to identify subjects who are at risk of developing sinusitis. Also, it could be used to monitor the effects of surgical or medical interventions aimed for prevention of sinusitis. Obviously, further extensive studies are needed before we know whether the method described here fulfils the criteria of such a test. Nevertheless, it is tempting to speculate that measurements of nasal NO release during humming and quiet breathing can give important information about sinus ostial function.

The data presented here indicate that humming is an extremely effective means of increasing sinus ventilation. In fact, in our model system, almost the entire volume (96%) of a normal maxillary sinus (20 ml) was exchanged in a single exhalation during phonation, as compared with less than 4% during quiet exhalation. It will therefore be of great interest to study whether daily periods of humming can reduce the risk for sinusitis in patients susceptible to upper airway infections.

We conclude that humming causes a dramatic increase in sinus ventilation and nasal NO release. Measurement of nasal NO during humming is an easy noninvasive test that can give valuable information about ostial function and NO production in the sinuses.

The authors thank Professor Johan Sundberg for valuable discussions during the preparation of this manuscript.

The work was supported by grants from the Swedish Research Board and the Swedish Heart and Lung Foundation.

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ED

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Human Reproduction Update 1997, Vol. 3, No. 5 pp. 455–466 _ European Society for Human Reproduction and Embryology

Erectile dysfunction: an overview

Andrea Fabbri1, Antonio Aversa and Aldo Isidori

Cattedra di Andrologia, Dipartimento di Fisiopatologia Medica, Università di Roma ‘La Sapienza’, 00161 Rome, Italy

TABLE OF CONTENTS

Introduction 455

Pathophysiology 456

Diagnostic approach 460

Therapies 461

Conclusions 464

Acknowledgements 464

References 464

Erectile dysfunction is a common (affecting 10–20 million men in the USA) and multifactorial disease due to organic and/or psychological factors that strongly impairs the quality of life in man. During the past decade many advances in the understanding of the pathophysiology of erectile dysfunction have been made and new therapeutic strategies have become available. It

has been established that an insufficient production of nitric oxide by penile nerve terminals and/or vascular endothelium may result in an impaired erection or complete impotence. Nowadays, intracavernous injection of vasoactive drugs represents a standardized approach for the diagnosis, and the treatment of choice, for erectile dysfunction, but is not widely accepted by the patients. The possibility of treating erectile dysfunction with intraurethral administration of prostaglandin-E1

has recently become available in the USA, and is a therapy more acceptable to the patients. Other noninvasive medical therapies are undergoing evaluation.

Key words: diagnosis/erection/nitric oxide/therapy

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BRON: https://www.ncbi.nlm.nih.gov/pubmed/9528911

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ED UROLOGY 

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Rev Urol. 2006 Winter; 8(1): 14–22.

PMCID: PMC1471770

Medical Therapy for Benign Prostatic Hyperplasia: New Terminology, New Concepts, Better Choices

Steven A Kaplan, MD

Author information ► Copyright and License information ►

This article has been cited by other articles in PMC.

Medical Therapy for Benign Prostatic Hyperplasia: New Terminology, New Concepts, Better Choices

Steven A Kaplan, MD

Author information ► Copyright and License information ►

This article has been cited by other articles in PMC.

Other potential pathophysiologic mechanisms common to LUTS and ED have been reported. These include age-related atherosclerosis-induced vascular insufficiency in the bladder and corpora and autonomic nervous system hyperactivity potentially mediated by nitric oxide pathways.39–41

McVary and McKenna42 have pro-posed that common etiologic factors, such as diabetes, smoking, and hyperinsulinemia, result in reduced nitric oxide synthase and nitric oxide levels. This leads to smooth muscle cell proliferation, increases in smooth muscle contractility, reduced compliance, and both LUTS and ED. Of interest, there are significant amounts of phosphodiesterase (PDE) types 4 and 5 in the transition zone of the prostate.43

BRON:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1471770/

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ED

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r J Pharmacol. 2011 Jul; 163(5): 891–907.

doi:  10.1111/j.1476-5381.2011.01332.x

PMCID: PMC3130937

Novel drug targets for the pharmacotherapy of benign prostatic hyperplasia (BPH)

S Ventura, VL Oliver, CW White, JH Xie, JM Haynes, and B Exintaris

Author information ► Article notes ► Copyright and License information ►

This article has been cited by other articles in PMC.

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Novel targets: nitric oxide

The human prostate stroma receives dense nitrergic innervation which has been found to be reduced in BPH patients (Bloch et al., 1997). Studies have shown that nitric oxide donors inhibit noradrenaline-mediated contractions and induce smooth muscle relaxation in human prostate tissue (Hedlund et al., 1997) (Table 3). Similarly, inhibitors of nitric oxide synthesis have been found to decrease electrically induced relaxations (Takeda et al., 1995; Hedlund et al., 1997). Thus, nitric oxide has been postulated to play a significant role in regulating prostate smooth muscle relaxation through stimulation of cGMP production (Figure 4) and, in turn, activation of KATPchannels (Cook et al., 2002). Targeting this pathway has been investigated in clinical trials which show that lower urinary tract symptoms associated with BPH improve under the influence of agents that enhance nitric oxide activity such as direct nitric oxide donors (Klotz et al., 1999) or PDE5 inhibitors such as sildenafil (Sairam et al., 2002).

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BRON:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130937/

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Rev Urol. 2004 Summer; 6(3): 121–127.

PMCID: PMC1472825

Lower Urinary Tract Symptoms, Benign Prostatic Hyperplasia, Erectile Dysfunction, and Phosphodiesterase-5 Inhibitors

Claus G Roehrborn, MD, FACS

Author information ► Copyright and License information ►

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Many patients who present to their healthcare provider with lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) will also have erectile dysfunction (ED), and vice versa. Although α-adrenergic receptor blockers and 5-α-reductase inhibitors are highly effective in treating BPH-associated LUTS, these agents have sexual adverse effects that cause many men to discontinue therapy. The discovery of nitric oxide as a major factor in the mechanism of erection has led to the development of new drugs for ED, including the phosphodiesterase (PDE) inhibitors. Preliminary data support the theory that inhibition of PDE isoenzymes in the prostate may improve LUTS due to BPH through relaxation of prostatic smooth muscle. Further studies of PDE inhibitors in men with ED and BPH-associated LUTS are indicated.

Key words: Benign prostatic hyperplasia, Erectile dysfunction, Lower urinary tract symptoms, Phosphodiesterase

Two conditions that occur with relatively high frequ

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Bron: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472825/

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L'oreal

Proof L’oreal NO in crème, some ingredients are kept secret, underneath the patent from L'oreal to activate Nitric oxide local in the skin. 

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No-synthase inhibitors 
Patent # US 7083799 B1

Inventors            Paolo Giacomoni
Original Assignee             L'oreal

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ABSTRACT
The use of an effective amount of at least one nitric oxide synthase inhibitor in a cosmetic composition or for making a pharmaceutical composition is disclosed, said inhibitor or pharmaceutical composition being intended to reduce the skin irritant effect of topically applied cosmetic or pharmaceutical substances. A cosmetic or pharmaceutical composition containing an effective amount of at least one nitric oxide synthase

Bron: Patent # US 7083799 B1 https://worldwide.espacenet.com/publicationDetails/biblio?CC=US&NR=7083799B1&KC=B1&FT=D

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