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    Effect of sildenafil citrate (Viagra) on the ocular circulation. Grunwald J E,Siu K K,Jacob S S,Dupont J American journal of ophthalmology PURPOSE:Sildenafil citrate induces vasodilation by enhancing the smooth muscle relaxant effects of nitric oxide. We have previously reported that nitrate compounds, a different group of nitric oxide-mediated vasodilators used mainly for the treatment of ischemic cardiac diseases, produce an increase in optic nerve head circulation and retinal venous vasodilation. The purpose of the present investigation was to evaluate the effect of sildenafil on ocular circulation. METHODS:In a double-blind, randomized, crossover trial, 15 healthy male volunteers received 100-mg doses of sildenafil citrate (Viagra; Pfizer, Inc, New York, New York) or matching placebo on 2 separate days. Laser Doppler flowmetry was used to assess foveolar choroidal and optic nerve rim circulatory parameters. Measurements were obtained in one eye at baseline, 1 hour, and 5 hours after dosing. Blood pressure and intraocular pressure were monitored, and perfusion pressure was calculated. RESULTS:Mean optic nerve head blood flow measurements at baseline, 1 hour, and 5 hours were 11.6 +/- 2.2 arbitrary units (+/- SD), 12.5 +/- 2.8, and 12.1 +/- 2.4 after sildenafil and 11.9 +/- 2.5, 12.6 +/- 3.1, and 13.0 +/- 3.0 after placebo, respectively. When compared with placebo, no significant change in mean blood pressure, intraocular pressure, perfusion pressure, or choroidal or optic nerve circulatory parameters were observed after sildenafil treatment. The power to detect a 20% change in optic nerve head and choroidal blood flow after sildenafil was approximately 90%. CONCLUSIONS:In comparison with placebo, no significant change in optic nerve rim or foveolar choroidal blood flow was observed after treatment with sildenafil. This suggests that nitrate compounds and sildenafil may differentially affect ocular circulation. Furthermore, no significant effects on intraocular pressure, systemic blood pressure, or ocular perfusion pressure were detected after sildenafil treatment. 10.1016/s0002-9394(00)00944-2
    Vasospasm in glaucoma: clinical and laboratory aspects. Delaney Yvonne,Walshe Tony E,O'Brien Colm Optometry and vision science : official publication of the American Academy of Optometry During the last decade, the presumed etiology of glaucoma has moved from a pure pressure concept to a combined mechanical and vascular theory. Evidence of a localized vascular insufficiency leading to perfusion deficits of ocular structures, including the optic nerve head, the retina, the choroid, and the retrobulbar vessels, is now clear. This article evaluates the role of vasospasm as the primary cause of such a vascular failure. The role of both ocular and systemic vasospasms and their clinical correlations are discussed. At a cellular level, the function of the modulating role of the vascular endothelium is reviewed. Evidence of abnormalities of the vascular endothelium and its vasoactive peptides as a conduit for vasospasm is mounting. Herein lies exciting prospects for potential pharmacologic targets in future glaucoma management. 10.1097/01.opx.0000225877.13217.01
    Intravenous administration of L-arginine increases retinal and choroidal blood flow. Garhöfer Gerhard,Resch Hemma,Lung Solveig,Weigert Günther,Schmetterer Leopold American journal of ophthalmology PURPOSE:Nitric oxide (NO) is among the most important regulators of ocular perfusion. L-arginine, an amino acid, is the precursor of NO synthesis. The aim of the present study was to determine whether administration of L-arginine affects ocular blood flow. DESIGN:L-arginine (1 g/min) or placebo was administered intravenously for 30 minutes in 12 healthy volunteers in a randomized, double-masked, two-way cross-over design. METHODS:Ocular hemodynamics were measured before, in the last 10 minutes of the infusion period, as well as 30 minutes after cessation of the administration. Retinal vessel diameters were measured with a retinal vessel analyzer, red blood cell velocities with bidirectional laser Doppler velocimetry, and pulsatile choroidal blood flow was measured using laser interferometry. RESULTS:L-arginine significantly decreased mean arterial pressure by -8 +/- 5% and -6 +/- 7% at the two time points (P < .01), respectively. Intravenous administration of L-arginine increased choroidal blood flow by +10 +/- 6% and +12 +/- 7%, respectively. Retinal venous diameters decreased by -2.5 +/- 2.1% and -1.4 +/- 2.7%, respectively, whereas red blood cell velocity significantly increased after administration of L-arginine by +22 +/- 23% and +20 +/- 19% at the two time points. Thus, calculated blood flow in retinal veins, increased by +21 +/- 18% and +21 +/- 19% before and after the end of L-arginine infusion. CONCLUSIONS:Intravenous administration of L-arginine increases retinal and choroidal blood flow in healthy volunteers. Whether this effect is related to an increased NO-production or an unidentified mechanism remains to be clarified. However, administration of L-arginine might be an interesting new approach to therapeutically increase ocular blood flow in ocular vascular disease. 10.1016/j.ajo.2005.02.016
    Ocular hemodynamic effects of nitrovasodilators in healthy subjects. Schmidl D,Polska E,Kiss B,Sacu S,Garhofer G,Schmetterer L Clinical pharmacology and therapeutics Nitric oxide (NO) plays a key role in the regulation of ocular blood flow and may be an interesting therapeutic target in ocular ischemic disease. In the present study, we hypothesized that NO-releasing drugs may increase blood flow to the head of the optic nerve and also in the choroid. The study employed a randomized, placebo-controlled, double blind, four-way crossover design. On separate study days, 12 healthy subjects received infusions of nitroglycerin, isosorbide dinitrate, sodium nitroprusside, or placebo. All three study drugs reduced the mean arterial pressure (MAP) and ocular perfusion pressure (OPP) (P < 0.001). None of the administered drugs increased the ocular hemodynamic variables. By contrast, vascular resistance decreased dose dependently during administration of the study drugs (P < 0.001). These results indicate that systemic administration of NO-donor drugs is associated with a decrease in vascular resistance in the ocular vasculature. However, because these drugs also reduce blood pressure, they do not improve perfusion to the posterior eye pole. 10.1038/clpt.2009.186
    A study on the prevention and treatment of myopia with nacre on chicks. Xu H,Huang K,Gao Q,Gao Z,Han X Pharmacological research The contents of mineral elements and amino acids in the hydrolysate of the traditional Chinese mineral medicine nacre have been determined. It has long since been proved by the practice of doctors of traditional Chinese medicine that pearl can be used to treat eye diseases. Based on such an understanding, a study is made of the influence of the said medicine on the incidence of myopia. First a form-sense-deprived model (FDM) for chicks is developed and the effect of the said medicine on the elongation of axis oculi is determined with an Abbe's comparator and an A-mode ultrasound instrument. The activity of superoxide dismutase (SOD), nitric oxide synthetase (NOS), and the content of nitric oxide (NO) in the retino-pigmental epithelium choroid homogenate are also analysed. The role of the said traditional Chinese mineral medicine in preventing and treating myopia is explained with respect to the above findings. The results obtained will provide a basis for using nacre, a traditional Chinese mineral medicine, to prevent and treat myopia. 10.1006/phrs.2000.0780
    Ischemia-induced nitrotyrosine formation and nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase in human retinal pigment epithelium in vivo. Kawaji Takahiro,Elner Victor M,Yang Dong-Li,Clark Andrea,Petty Howard R Redox report : communications in free radical research Reactive oxidative compounds including superoxide anions and nitric oxide are believed to play a central role in many blinding eye diseases. In the present study, we examine the effect of ischemia on human retinal pigment epithelial (RPE) cells in an unusual clinical case. We show that ischemia leads to extensive nitrotyrosine deposition in the RPE and choroid, thus indicating NO-dependent oxidative stress. We also show for the first time the in vivo translocation of glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) to the nuclei of RPE cells. This enzyme's nuclear translocation has previously been demonstrated in vitro where it is a marker of apoptosis. Furthermore, nitrotyrosine deposition and GAPDH translocation have been duplicated in vitro using human RPE cells. Thus, nitrotyrosine formation and GAPDH trafficking to the nucleus may be observed during ischemic conditions. 10.1179/174329211X12968219310710
    Regional regulation of choroidal blood flow by autonomic innervation in the rat. Steinle J J,Krizsan-Agbas D,Smith P G American journal of physiology. Regulatory, integrative and comparative physiology Regional influences of parasympathetic and sympathetic innervation on choroidal blood flow were investigated in anesthetized rats. Parasympathetic pterygopalatine neurons were activated by electrically stimulating the superior salivatory nucleus, whereas sympathetic neurons were activated by cervical sympathetic trunk stimulation and uveal blood flow was measured by laser Doppler flowmetry. Parasympathetic stimulation increased flux in the anterior choroid and nasal vortex veins but not in the posterior choroid. Vasodilation was blocked completely by the neuronal nitric oxide synthase inhibitor 1-(2-trifluoromethylphenyl)imidazole but was unaffected by atropine. Sympathetic stimulation decreased flux in all regions, and this was blocked by prazosin. Parasympathetic stimulation did not affect vasoconstrictor responses to sympathetic stimulation in the posterior choroid but attenuated the decrease in blood flow through the anterior choroid and vortex veins via a nitrergic mechanism. We conclude that sympathetic alpha-noradrenergic vasoconstriction occurs throughout the choroid, whereas parasympathetic nitrergic vasodilation plays a selective role in modulating blood flow in anterior tissues of the eye. 10.1152/ajpregu.2000.279.1.R202
    Nitric oxide and choroidal blood flow regulation. Mann R M,Riva C E,Stone R A,Barnes G E,Cranstoun S D Investigative ophthalmology & visual science PURPOSE:Nitric oxide (NO) has been found to be an endothelial-derived relaxing factor mediating the vasodilatation that results from the stimulation of muscarinic endothelial receptors. It also has been identified as a putative neurotransmitter of parasympathetic origin in choroidal perivascular autonomic fibers. The authors investigated a potential role of NO in choroidal blood flow (ChBF) regulation. METHODS:Local ChBF in the tapetal region of 26 anesthetized cats was measured by laser Doppler flowmetry. Cats were infused through the femoral vein with increasing dosages of acetylcholine (ACh); N omega-nitro-L-arginine (NNL-A), a specific inhibitor of NO synthesis; L-arginine; and D-arginine. ChBF and mean arterial pressure (MAP) were continuously recorded. RESULTS:Infusion of 20 micrograms/minute ACh induced a 68% increase in ChBF despite a 9% decrease in MAP. Infusion of 16 mg/minute NNL-A attenuated the ACh-induced increase in ChBF by 46% and increased MAP by 40%. Infusion of different dosages of NNL-A without prior administration of ACh caused ChBF to fall below and MAP to rise above baseline in a dose-dependent fashion. Infusion of L-arginine prior to ACh infusion enhanced by 27% the ACh-induced increase in ChBF, whereas D-arginine had no effect on this increase. CONCLUSIONS:These findings suggest the presence of a local vasodilatory cholinergic mechanism in the choroid, inducing the release of NO. They also suggest that release of NO in the choroid may maintain basal blood flow to this tissue.
    Nitric oxide: a review of its role in retinal function and disease. Goldstein I M,Ostwald P,Roth S Vision research Nitric oxide synthase (NOS), the enzyme that catalyzes the formation of nitric oxide from L-arginine, exists in three major isoforms, neuronal, endothelial, and immunologic. Neuronal and endothelial isoforms are constitutively expressed, and require calcium for activation. Both of these isoforms can be induced (i.e., new protein synthesis occurs) under appropriate conditions. The immunologic isoform is not constitutively expressed, and requires induction usually by immunologic activation; calcium is not necessary for its activation. Neuronal and immunologic NOS have been detected in the retina. Neuronal NOS may be responsible for producing nitric oxide in photoreceptors and bipolar cells. Nitric oxide stimulates guanylate cyclase of photoreceptor rod cells and increases calcium channel currents. In the retina of cats, NOS inhibition impairs phototransduction as assessed by the electroretinogram. Inducible nitric oxide synthase, found in Müller cells and in retinal pigment epithelium, may be involved in normal phagocytosis of the retinal outer segment, in infectious and ischemic processes, and in the pathogenesis of diabetic retinopathy. Nitric oxide contributes to basal tone in the retinal circulation. To date, findings are conflicting with respect to its role in retinal autoregulation. During glucose and oxygen deprivation, nitric oxide may increase blood flow and prevent platelet aggregation, but it may also mediate the toxic effects of excitatory amino acid release. This reactive, short-lived gas is involved in diverse processes within the retina, and its significance continues to be actively studied.
    Role of NO in choroidal blood flow regulation during isometric exercise in healthy humans. Luksch Alexandra,Polska Elzbieta,Imhof Andrea,Schering Joanne,Fuchsjäger-Mayrl Gabriele,Wolzt Michael,Schmetterer Leopold Investigative ophthalmology & visual science PURPOSE:Nitric oxide (NO) is an important regulator of basal choroidal blood flow. Animal experiments indicate that NO is also involved in choroidal blood flow regulation during changes in ocular perfusion pressure and inhibition of NO synthase (NOS) has been reported to shift choroidal pressure-flow curves to the right. The hypothesis for the study was that inhibition of NOS may influence choroidal blood flow during isometric exercise. METHODS:To test this hypothesis, a randomized, double-masked, placebo-controlled, three-way crossover study was performed in 12 healthy male volunteers. Subjects received on different study days intravenous infusions of N(G)-monomethyl-L-arginine (L-NMMA), phenylephrine, or placebo. During these infusion periods, subjects were asked to squat for 6 minutes. Choroidal blood flow was assessed with laser Doppler flowmetry, and ocular perfusion pressure (OPP) was calculated from mean arterial pressure and intraocular pressure. RESULTS:L-NMMA and phenylephrine increased resting OPP by 10% and 13%, respectively, but only L-NMMA reduced resting choroidal blood flow (-17%, P < 0.001). The relative increase in OPP during isometric exercise was comparable with all drugs administered. Isometric exercise increased choroidal blood flow during administration of placebo and phenylephrine, but not during administration of L-NMMA (P < 0.001 vs. placebo). CONCLUSIONS:These data indicate that NO plays an important role in the regulation of choroidal blood flow during isometric exercise. 10.1167/iovs.02-0177
    Ocular blood flow changes after dynamic exercise in humans. Okuno T,Sugiyama T,Kohyama M,Kojima S,Oku H,Ikeda T Eye (London, England) PURPOSE:To investigate control mechanisms for ocular blood flow changes after dynamic exercise using two different methods. METHODS:Changes over time in the tissue blood flow in the retina and choroid-retina of healthy volunteers were determined after dynamic exercise (Master's double two-step test), using scanning laser Doppler flowmetry (SLDF) and laser speckle flowgraphy (LSFG). Changes in intraocular pressure (IOP), blood pressure, plasma CO(2) gas concentration (pCO(2)), and levels of nitric oxide (NO) metabolites were examined. RESULTS:Retinal blood flow measured by SLDF increased significantly only at 15 min after exercise. In contrast, normalized blur (NB) values in the choroid-retina, obtained by LSFG, increased significantly up to 60 min after exercise. Ocular perfusion pressure (OPP), calculated from IOP and blood pressure, increased significantly immediately and 15 min after exercise. The plasma NO metabolite levels increased significantly, although pCO(2) levels were unchanged. CONCLUSIONS:Dynamic exercise changes OPP and produces increased tissue blood flow in the retina in the immediate postexercise period, while blood flow increases more persistently in the choroid-retina. Difference in control of blood flow in these two regions may be related to stronger autoregulatory mechanism of blood flow in the retina. Nitric oxide may play a role in the regulation of blood flow. 10.1038/sj.eye.6702004
    Light modulation, not choroidal vasomotor action, is a regulator of refractive compensation to signed optical blur. Murphy Melanie J,Crewther David P,Goodyear Melinda J,Crewther Sheila G British journal of pharmacology BACKGROUND AND PURPOSE:The nitric oxide system has two proposed sites and mechanisms of action within the ocular growth/refractive compensation platform-neuromodulatory effects on retinal physiology, and vascular/smooth muscle effects in the choroid. The relative contribution of these mechanisms are tested here with drugs that perturb the nitric oxide system and with slow flicker modulation of the ON and OFF pathways of the retina. EXPERIMENTAL APPROACH:Intravitreal injection of saline or 900 nmol N(G) -nitro-L-arginine methyl ester or L-arginine in saline was followed by monocular defocus with ±10 D lens (or no lens), from days 5-9 under standard diurnal (SD) or daytime 1 Hz ramped flicker conditions. Biometric, electrophysiological and histological analyses were conducted. KEY RESULTS:After 4 days of SD conditions, both drugs enhanced electroretinogram (ERG) b-wave cf. d-wave amplitudes compared with saline and reduced refractive compensation to -10 D lenses. Under flicker conditions compensation to +10 D lenses was suppressed. Choroidal thinning was observed in the drug, no lens groups under SD conditions, whereas choroidal thickening was seen in most groups under flicker conditions, irrespective of refractive outcomes. CONCLUSIONS AND IMPLICATIONS:As choroidal thickness was not predictive of final refractive compensation across any of the variables of drug, defocus sign or light condition, it is unlikely that choroidal thickness is a primary mechanism underlying refractive compensation across the range of parameters of this study. Rather, the changes in refractive compensation observed under these particular drug and light conditions are more likely due to a neuromodulatory action on retinal ON and OFF pathways. 10.1111/j.1476-5381.2011.01347.x
    Molecular mechanisms of (R,R)ZX-5 on NO synthesis and its anti-angiogenic effect. Pan Li,Hu Jia-Liang,Wang Wen-Jing,Zhang Xiao-Juan,Wei Jin,Liu Zhen-Dong,Zhang Yi-Hua,Xu Han-Mei International journal of molecular sciences (R,R)ZX-5 is a NO regulatory compound, which could significantly increase choroidal blood flow in New Zealand rabbit. The aim of this paper is to investigate the molecular mechanism of (R,R)ZX-5 promoting NO production. Besides this, we also investigated the antiangiogenic activity of (R,R)ZX-5. Analysis of Western blot showed that (R,R)ZX-5 up-regulated the expression of Akt, p-Akt (Thr473), eNOS and p-eNOS (Ser1177), down-regulated the expression of Cyclin D1 in human retinal endothelial cells and escalated the intracellular free Ca(2+) concentration. Additionally, (R,R)ZX-5 inhibited the growth of blood vessels in the chick chorioallantoic membrane model. It is concluded that (R,R)ZX-5 promotes choroidal blood flow through PI3K/Akt-eNOS and Akt-Ca(2+)-eNOS pathways. Additionally, (R,R)ZX-5 can inhibit angiogenesis. 10.3390/ijms13032717
    Effects of adrenomedullin on ocular hemodynamic parameters in the choroid and the ophthalmic artery. Dorner Guido T,Garhöfer Gerhard,Huemer Karl-Heinz,Golestani Elisabeth,Zawinka Claudia,Schmetterer Leopold,Wolzt Michael Investigative ophthalmology & visual science PURPOSE:Adrenomedullin acts as a vasodilator and may play a role in inflammatory processes in the eye. This study was designed to determine whether nitric oxide formation is involved in the response to adrenomedullin in the ocular vasculature in vivo. METHODS:The effects of systemic intravenous adrenomedullin (3.2-16.0 pmol/[kg. min])) on choroidal blood flow were assessed by measurement of fundus pulsation amplitude and laser Doppler flow in the macula, and on blood flow in the ophthalmic artery by ultrasound Doppler flow in pilot studies (n = 7). Subsequently, in a double-blind randomized placebo-controlled crossover study in eight healthy male subjects the effects of 12.8 pmol/(kg. min) adrenomedullin on ocular and systemic hemodynamics were investigated. Adrenomedullin was co-infused with the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (3 mg/kg bolus and 30 micro g/[kg. min] continuous intravenous infusion) or vehicle control on separate study days. RESULTS:Adrenomedullin dose dependently increased choroidal blood flow and flow velocity in the ophthalmic artery. N(G)-monomethyl-L-arginine reduced the effect of adrenomedullin on fundus pulsation amplitude, but did not alter the flow response in the ophthalmic artery. Systemic hemodynamics were unaffected by adrenomedullin infusion. CONCLUSIONS:Ocular blood flow is sensitive to changes in adrenomedullin concentrations. The acute vasodilator effects of adrenomedullin are nitric oxide-dependent in the choroid, but not in the ophthalmic artery. 10.1167/iovs.02-0855
    Oxidants, nitric oxide and prostanoids in the developing ocular vasculature: a basis for ischemic retinopathy. Hardy P,Dumont I,Bhattacharya M,Hou X,Lachapelle P,Varma D R,Chemtob S Cardiovascular research The choroid is the main source of oxygen to the retina. In contrast to the adult, the absence of autoregulation of choroidal blood flow in the newborn leads to hyperoxygenation of the retina. In the immature retina which contains relatively low levels of antioxidants this hyperoxygenation favors peroxidation including the generation of biologically active isoprostanes, and results in vasoconstriction and vascular cytotoxicity leading to ischemia, which predisposes to the development of a vasoproliferative retinopathy, commonly termed retinopathy of prematurity. During frequently encountered oxidative stress to the perinate, the combined absence of vascular autoregulation and excessive oxygen delivery to the eyes of the developing subject is largely the result of a complex epigenetic and genetic interplay between prostanoids and nitric oxide (NO) systems on vasomotor regulation. The effects of certain prostaglandins are NO-dependent; conversely, those of NO have also been found to be largely prostaglandin I(2)-mediated in the eye; and NO synthase expression seems to be significantly regulated by other prostaglandins apparently through activation of functional perinuclear prostanoid receptors which affect gene transcription. The increased production of both prostaglandins and NO in the perinate augment ocular blood flow and as a result oxygen delivery to an immature retina partly devoid of antioxidant defenses. The ensuing peroxidation results in impaired circulation (partly thromboxane A(2)-dependent) and vascular integrity, leading to ischemia which predisposes to abnormal preretinal neovascularization, a major feature of ischemic retinopathy. Because tissue oxygenation is largely dependent upon circulation and critical in the generation of reactive oxygen species, and since the latter exert a major contribution in the pathogenesis of retinopathy of prematurity, it is important to understand the mechanisms that govern ocular blood flow. In this review we focus on the important and complex interaction between prostanoid, NO and peroxidation products on circulatory control of the immature retina. 10.1016/s0008-6363(00)00084-5
    Role of NO in the control of choroidal blood flow during a decrease in ocular perfusion pressure. Simader Christian,Lung Solveig,Weigert Günther,Kolodjaschna Julia,Fuchsjäger-Mayrl Gabriele,Schmetterer Leopold,Polska Elzbieta Investigative ophthalmology & visual science PURPOSE:The study was conducted to investigate whether the L-arginine/nitric oxide system plays a role in choroidal blood flow (ChBF) regulation during a decrease in ocular perfusion pressure (OPP). METHODS:Experiments were performed on 3 days in a randomized double-masked, placebo-controlled, three-way crossover design. On different study days, subjects received intravenous infusions of N(G)-monomethyl-L-arginine (L-NMMA), phenylephrine, or placebo. Intraocular pressure was raised in stepwise increments using the suction cup METHOD:Choroidal blood flow (ChBF, laser Doppler flowmetry), mean arterial blood pressure (MAP), and IOP were assessed. Ocular perfusion pressure was calculated as OPP = 23(MAP - IOP). For correlation analysis all OPP/ChBF data pairs from all subjects were pooled independent of time point of measurement. Then, the pooled data were sorted according to OPP, and correlation analyses were performed. RESULTS:L-NMMA and phenylephrine increased resting OPP by +17% +/- 18% and +14% +/- 21%, respectively (P < 0.05). L-NMMA reduced resting ChBF by -21% +/- 17% (P < 0.05). The relative decrease in OPP during suction cup application was comparable with all drugs administered. The decrease in OPP was paralleled by a significant decrease in ChBF (maximum between -39% and -47%), which was less pronounced, however, than the decrease in OPP (maximum between -69% and -74%). Neither placebo nor L-NMMA, nor phenylephrine, influenced the OPP/ChBF relationship. CONCLUSIONS:The data confirm previously published observations that the choroid shows some regulatory capacity during reduced OPP. The L-arginine/nitric oxide-system plays a role in the maintenance of basal vascular tone but seems not to be involved in the choroidal vasodilator response when IOP is increased. 10.1167/iovs.07-1614
    Role of nitric oxide in the control of ocular blood flow. Schmetterer L,Polak K Progress in retinal and eye research In the recent years it has been recognized that nitric oxide is an important regulator of ocular blood flow. Nitric oxide is involved in the control of basal blood flow in the choroid, optic nerve and the retina. In addition, nitric oxide mediates a number of vasodilator responses in ocular vessels to agonists such as acetylcholine, bradykinin, histamine, substance P and insulin. Nitric oxide also plays a role in hypercapnia-induced vasodilation in the choroid and is a modulator of pressure autoregulation in this vascular bed. Abnormalities of the L-arginine/nitric oxide system have been observed in a variety of ocular diseases including glaucoma, diabetic retinopathy and retinopathy of prematurity. This makes the L-arginine/nitric oxide pathway an attractive target for therapeutic interventions. Additional research is required, particularly in characterizing the role of the three nitric oxide synthase isoforms in the control of ocular perfusion, to implement this concept into the clinical management of ocular diseases. 10.1016/s1350-9462(01)00014-3
    Effect of nitric oxide synthesis inhibition on post-occlusive choroidal blood flow in rats. Koss M C Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics Experiments were designed to study involvement of nitric oxide on vascular responses to ocular ischemia in the anesthetized rat. Anterior choroidal blood flow was measured using laser-Doppler flowmetry. In some experiments, cerebral cortical blood flow also was measured. Ischemia was produced by either occlusion of the cephalic blood supply or more locally via a ligature tightened around the eye stalk. Arterial blood pressure and choroidal blood flow was continuously measured before, during and after a 20 min ischemic challenge. Both methods of ischemia reduced choroidal blood flow (>90%) with no consistent ocular hyperemia seen upon reperfusion. No significant differences in response pattern between the two ischemia techniques were apparent. Treatment with the non-selective inhibitor of nitric oxide (L-NAME 2 mg/kg, i.v.) did not alter either basal choroidal blood flow or the pattern of reperfusion. A larger dose of L-NAME (50 mg/kg, i.v.) reduced both basal choroidal blood flow and the final reperfusion level (most likely due to continued depression of the basal ocular choroidal blood flow). Neither D-NAME nor the neuronal nitric oxide synthase inhibitor, 7-nitroindazole, altered basal anterior choroidal blood flow or the reperfusion pattern seen after reperfusion. The results confirm our previous observations that inhibition of endothelial nitric oxide lowers. basal choroidal blood flow in the rat eye. However, in contrast to the cerebral circulation where L-NAME greatly attenuates initial reperfusion to the cerebral cortex, inhibition of nitric oxide synthase does not appear to notably further influence anterior choroidal reperfusion. 10.1089/jop.2000.16.55
    Blockade of nitric-oxide synthase reduces choroidal neovascularization. Ando Akira,Yang Amy,Nambu Hiroyuki,Campochiaro Peter A Molecular pharmacology Nitric oxide (NO) promotes retinal and choroidal neovascularization, although different isoforms of nitric-oxide synthetase (NOS) are critical in each. Deficiency of endothelial NOS (eNOS) suppresses retinal but not choroidal neovascularization, whereas deficiency of neuronal NOS (nNOS) or inducible NOS (iNOS) suppresses choroidal, but not retinal neovascularization. In this study, we investigated the effect of N(G)-monomethyl-L-arginine (L-NMMA), a nonspecific NOS inhibitor, in three models of ocular neovascularization. Oral administration of L-NMMA caused significant inhibition of choroidal neovascularization in mice with laser-induced rupture of Bruch's membrane and significantly inhibited subretinal neovascularization in transgenic mice with expression of vascular endothelial growth factor (VEGF) in photoreceptors (rho/VEGF mice) but did not inhibit retinal neovascularization in mice with ischemic retinopathy. By extensive mating among mice deficient in NOS isoforms, triple homozygous mutant mice deficient in all three NOS isoforms were produced. These mice had marked suppression of choroidal neovascularization at sites of rupture of Bruch's membrane and near-complete suppression of subretinal neovascularization in rho/VEGF mice but showed no difference in ischemia-induced retinal neovascularization compared with wild-type mice. These data indicate that NO is an important stimulator of choroidal neovascularization and that reduction of NO by pharmacologic or genetic means is a good treatment strategy. However, the situation is more complex for ischemia-induced retinal neovascularization for which NO produced in endothelial cells by eNOS is stimulatory, but NO produced in other retinal cells by iNOS and/or nNOS is inhibitory. Selective inhibitors of eNOS may be needed for treatment of retinal neovascularization. 10.1124/mol.62.3.539
    Effects of inhibition of nitric oxide synthase on basal anterior segment ocular blood flows and on potential autoregulatory mechanisms. Koss M C Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics Experiments were undertaken to determine the role played by nitric oxide (NO) in basal ocular blood flow in the anterior aspect of the eye. Subsequent studies focused on existence of autoregulatory mechanisms and on the potential involvement of NO. Cats were anesthetized with pentobarbital (36 mg/kg, i.p.). A femoral artery and vein were cannulated for measuring blood pressure and for drug administration, respectively. Anterior segment blood flow was measured in a continuous fashion from the long posterior ciliary artery (LPCA) using ultrasonic flowmetry and from the anterior choroid using laser-Doppler flowmetry. A needle was placed into the anterior chamber, and autoregulatory mechanisms were studied by decreasing ocular perfusion pressure via stepwise elevations of IOP. Non-selective inhibition of NO synthase with L-NAME (20 mg/kg, i.v.) significantly decreased basal blood flow from both sites. L-NAME (5 mg/kg, i.v.) was without effect as was D-NAME (25 mg/kg, i.v.). Increasing IOP produced a linear decrease on LPCA blood flow indicating absence of autoregulation. In contrast, stepwise elevation of IOP produced a delayed, non-linear response in the anterior choroid suggestive of a strong autoregulatory response. Neither response to elevated ocular perfusion pressure was further altered by inhibition of NO synthase with L-NAME (20 mg/kg, i.v.). The results confirm previous reports that nitric oxide plays a pivotal role in maintenance of basal ocular blood flow. Autoregulation was not seen in the LPCA. In contrast, there was a clear autoregulatory response in the anterior choroid, although neither response was altered by inhibition of NO synthase. 10.1089/108076801753162735
    Regulation of endothelial nitric oxide synthase by PGD(2) in the developing choroid. Dumont I,Hardy P,Peri K G,Hou X,Molotchnikoff S,Varma D R,Chemtob S American journal of physiology. Heart and circulatory physiology We investigated if prostaglandins might regulate the increased choroidal endothelial (e) nitric oxide synthase (NOS) expression in the perinate. Prostaglandins, eNOS mRNA, immunoreactive protein and activity, and nitrite [stable metabolite of nitric oxide (NO)] production were markedly higher in newborn (1 day old) than juvenile (6-8 wk old) pig choroid. Treatment of isolated newborn choroids with the prostaglandin synthase inhibitor ibuprofen for 24 h reduced eNOS mRNA and nitrite production to values in juveniles. This effect was equally observed with the PGD(2) receptor (DP) blocker BW A868C and was prevented by cotreatment with PGD(2) but not other prostaglandins; similar observations were made on NOS activity in vivo. PGD(2) also increased eNOS expression on choroids of juveniles, and this effect was blocked by BW A868C. The manifestation of this upregulation of eNOS by PGD(2) on the control of choroidal vasomotor response was tested by using NO-dependent vasorelaxants, ACh, bradykinin (Bk), and substance P (SP). ACh-, Bk-, and SP-elicited choroidal vasorelaxation was greater in saline-treated newborn than juvenile pigs. Ibuprofen (24 h) decreased ACh-, Bk-, and SP-evoked vasorelaxation in newborns, whereas PGD(2) increased that in juveniles and prevented the ibuprofen-induced attenuated relaxation in newborns; infusion of N(omega)-monomethyl-L-arginine in choroids of those animals treated with PGD(2) reversed the augmented vasorelaxation to ACh, Bk, and SP. Finally, PGD(2)-induced upregulation of NOS in the perinate was also reflected by curtailed choroidal blood flow autoregulatory response to increased perfusion pressure. In conclusion, PGD(2) exhibits a major role in upregulating eNOS expression and activity in the choroid, which in turn results in greater NO-mediated vasorelaxation; a new mechanism for eNOS regulation via DP is hereby disclosed. The relationship between PGD(2) and eNOS in the developing subject provides an explanation for the interactive role of these two factors in the absent choroidal blood flow autoregulation in the perinate. 10.1152/ajpheart.2000.278.1.H60
    Relationship between nitric oxide production and choroidal blood flow. Xuan Bo,Xu Xin-Rong,Chiou George C Y,Zhang Yi-Hua,Peng Si-Xun Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics PURPOSE:To invent a drug which can specifically facilitate choroid blood flow via increase of nitric oxide (NO). METHOD:Cell culture was used for in vitro experiments to determine the production of NO by NO donors and colored microsphere technique was used for in vivo experiments to determine the blood flow in various tissues of rabbit eyes. RESULTS:ZX-5 and ZX-4 are two geographic isomers with ZX-5 as trans-form and ZX-4 as cis-form. (1-phenyl-3-[3-methoxy-2-propoxy-5-[4-(3,4,5-trimethoxy-phenyl)-1,3-d lane-2-yl]phenyl]thiourea). It was found that ZX-5 released significant amount of NO at 3, 10, 30 microg/ml concentrations and increased choroid blood flow at 1%, 50 microl instillation into eyes. It was not effective on the blood flow of iris or ciliary body. The corresponding ZX-4 was not effective on ocular blood flow nor it released NO. CONCLUSION:ZX-5 can specifically increase the choroidal blood flow which could be useful to suppress the choroidal neovascularization in age-related macular degeneration (AMD). It is hoped that ZX-5 type of compounds could be used for the treatment/prevention of AMD in the elderly. 10.1089/108076803321908365
    Nitric oxide is proangiogenic in the retina and choroid. Ando Akira,Yang Amy,Mori Keisuke,Yamada Haruhiko,Yamada Eri,Takahashi Kyoichi,Saikia Jina,Kim Min,Melia Michele,Fishman Mark,Huang Paul,Campochiaro Peter A Journal of cellular physiology Nitric oxide (NO) has been shown to have proangiogenic or antiangiogenic effects depending upon the setting. In this study, we used mice with targeted deletion of one of the three isoforms of nitric oxide synthase (NOS) to investigate the effects of NO in ocular neovascularization. In transgenic mice with increased expression of vascular endothelial growth factor (VEGF) in photoreceptors, deficiency of any of the three isoforms caused a significant decrease in subretinal neovascularization, but no alteration of VEGF expression. In mice with laser-induced rupture of Bruch's membrane, deficiency of inducible NOS (iNOS) or neuronal NOS (nNOS), but not endothelial NOS (eNOS), caused a significant decrease in choroidal neovascularization. In mice with oxygen-induced ischemic retinopathy, deficiency of eNOS, but not iNOS or nNOS caused a significant decrease in retinal neovascularization and decreased expression of VEGF. These data suggest that NO contributes to both retinal and choroidal neovascularization and that different isoforms of NOS are involved in different settings and different disease processes. A broad spectrum NOS inhibitor may have therapeutic potential for treatment of both retinal and choroidal neovascularization. 10.1002/jcp.10083
    Role of nitric oxide in choroidal blood flow regulation during light/dark transitions. Huemer Karl-Heinz,Garhofer Gerhard,Aggermann Tina,Kolodjaschna Julia,Schmetterer Leopold,Fuchsjäger-Mayrl Gabriele Investigative ophthalmology & visual science PURPOSE:Several studies have recently shown that a transition from light to dark is associated with a reduction in choroidal blood flow. The mechanism underlying this effect is unclear but may be related to changes in neural input. In the present study, the authors hypothesized that either the alpha-receptor agonist phenylephrine or the nitric oxide synthase (NOS) inhibitor L-NMMA may alter the choroidal blood flow response during a transition from light to dark. METHODS:In 15 healthy male nonsmoking subjects, the response of choroidal perfusion was studied in a randomized placebo-controlled three-way crossover study. Phenylephrine, L-NMMA or placebo was administered on different study days, and the effect of a light/dark transition on choroidal perfusion parameters was studied. Subfoveal choroidal blood flow and fundus pulsation amplitude were assessed with laser Doppler flowmetry and laser interferometry, respectively. RESULTS:Before drug administration, a transition from light to dark reduced both choroidal hemodynamic parameters by 11% to 20%. Neither phenylephrine nor placebo altered basal choroidal blood flow or choroidal blood flow responses to the light/dark transitions. By contrast, the NOS inhibitor L-NMMA significantly reduced basal choroidal blood flow by 20.5% +/- 5.9% (P < 0.001) and basal fundus pulsation amplitude by 21.5% +/- 4.8% (P < 0.001). In addition, the response of subfoveal choroidal blood flow (-6.2% +/- 3.2%; P = 0.008) and fundus pulsation amplitude (-4.2% +/- 2.4%; P < 0.001) to the light/dark transition was significantly diminished. CONCLUSIONS:The present study indicates that NO plays a role in the choroidal blood flow decrease during a transition from light to dark. Given that L-NMMA is a nonspecific inhibitor of NOS, the present study does not clarify whether this NO is from endothelial or neural sources. 10.1167/iovs.07-0176
    Endothelin-induced changes in blood flow in STZ-diabetic and non-diabetic rats: relation to nitric oxide synthase and cyclooxygenase inhibition. Granstam Sven-Olof,Granstam Elisabet The journal of physiological sciences : JPS In this study, using the microsphere method, the hemodynamic response to endothelin-1 (ET-1) in healthy and streptozotocin (STZ)-diabetic rats was evaluated as well as the influences of inhibition of nitric oxide (NO)-synthase using L-NAME (Nω-nitro-L: -arginine methyl ester) and the cyclooxygenase inhibitor indomethacin. Blood flow (Q) was measured in tissues of interest for vascular complications in diabetes such as kidney, eye, brain, heart and skeletal muscle with the main focus on ophthalmic circulation. Under resting conditions, evidence for renal vasoconstriction was found in diabetic animals. In both groups, administration of L-NAME reduced Q in all investigated tissues indicating a basal NO influence. In the normal rats, ET-1 induced a significant increase in blood pressure and intense vasoconstriction in all tissues except in the choroid of the eye and in the brain, where it induced an increased Q. In the STZ-diabetic rats, effects of ET-1 were less pronounced. Pretreatment with L-NAME, but not the cyclooxygenase inhibitor, abolished the ET-1-induced vasodilation in the choroid of both groups. Administration of ET A receptor antagonist BQ-123 reduced the ET-1-induced vasodilation in the choroid only in diabetic animals. In conclusion, evidence for altered vascular endothelial response to ET-1 in STZ-diabetic animals was found particularly in the ophthalmic circulation. The findings suggest differential involvement of receptors in the response to ET-1 in normal and STZ-diabetic animals. 10.1007/s12576-011-0171-x
    Co-expression of endothelial and neuronal nitric oxide synthases in the developing vasculatures of the human fetal eye. McLeod D Scott,Baba Takayuki,Bhutto Imran A,Lutty Gerard A Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie BACKGROUND:Nitric oxide (NO) is a multifunctional gaseous molecule that regulates various physiological functions in both neuronal and non-neuronal cells. NO is synthesized by nitric oxide synthases (NOSs), of which three isoforms have been identified. Neuronal NOS (nNOS) and endothelial NOS (eNOS) constitutively produce low levels of NO as a cell-signaling molecule in response to an increase in intracellular calcium concentration. Recent data have revealed a predominant role of eNOS in both angiogenesis and vasculogenesis. METHODS:The immunohistochemical localization of nNOS and eNOS was investigated during embryonic and fetal ocular vascular development from 7 to 21 weeks gestation (WG) on sections of cryopreserved tissue. RESULTS:eNOS was confined to endothelial cells of developing vessels at all ages studied. nNOS was prominent in nuclei of vascular endothelial and smooth muscle cells in the fetal vasculature of vitreous and choriocapillaris. nNOS was also prominent in the nuclei of CXCR4(+) progenitors in the inner retina and inner neuroblastic layer. CONCLUSIONS:These findings demonstrate co-expression of n- and eNOS isoforms in different compartments of vasoformative cells during development. Nuclear nNOS was present in vascular and nonvascular progenitors as well as endothelial cells and pericytes. This suggests that nNOS may play a role in the transcription regulatory systems in endothelial cells and pericytes during ocular hemo-vasculogenesis, vasculogenesis, and angiogenesis. 10.1007/s00417-012-1969-9
    Dual electroretinogram/nitric oxide carbon fiber microelectrode for direct measurement of nitric oxide in the in vivo retina. Guthrie Micah J,Kang-Mieler Jennifer J IEEE transactions on bio-medical engineering Nitric oxide (NO) plays an important physiological role in normal and pathological retinas. Intraretinal NO concentrations have not been directly measured due to lack of NO electrodes capable of determining their location in the retina. The microelectrodes described here allow recording of the intraretinal electroretinogram (ERG) and NO concentration from the same location, with ERGs used to determine retinal depth. Double-barreled electrodes were constructed with one barrel serving as a reference/voltage recording barrel and the other containing a Nafion-coated carbon fiber used to detect NO amperometrically. Nafion coating imparted a high selectivity for NO versus ascorbic acid (2000:1). In vivo rodent experiments demonstrated that the electrodes could record intraretinal ERGs and NO current with minimal retinal thickness deformation (9%), allowing for retinal NO depth profile measurements. Comparison of NO depth profiles under control conditions and under nitric oxide synthase (NOS) inhibition by 5 mM L-NG-Nitroarginine methyl ester (L-NAME) verified that the recorded current was attributable to NO. NO concentrations from control profiles ( n = 4) were 2.37 ± 0.34 μM at the choroid and 1.12 ± 0.14 μM at the retinal surface. NO concentrations from L-NAME profiles ( n = 4) were significantly lower at 0.83 ± 0.15 μM at the choroid ( p = 0.006) and 0.27 ± 0.04 μM at the retinal surface ( p = 0.001). Localized regions of increased NO (100-400 nM) were seen in the inner retina under control conditions but not after L-NAME. The dual ERG-NO electrode may be a valuable tool in evaluating the role of NO in normal and diseased retinas. 10.1109/TBME.2013.2281541
    Choroidal blood flow compensation in rats for arterial blood pressure decreases is neuronal nitric oxide-dependent but compensation for arterial blood pressure increases is not. Reiner Anton,Li Chunyan,Del Mar Nobel,Fitzgerald Malinda E C Experimental eye research Choroidal blood flow (ChBF) compensates for changes in arterial blood pressure (ABP) and thereby remains relatively stable within a +/-40 mmHg range of basal ABP in rabbits, humans and pigeons. In the present study, we investigated if ChBF can compensate for increases and decreases in ABP in rats. ChBF was continuously monitored using laser Doppler flowmetry in anesthetized rats, and ABP measured via the femoral artery. At multiple intervals over a 2-4 h period during which ABP varied freely, ChBF and ABP were sampled and the results compiled across rats. We found that ChBF remained near baseline over an ABP range from 40 mmHg above basal ABP (90-100 mmHg) to 40 mmHg below basal ABP, but largely followed ABP linearly below 60 mmHg. Choroidal vascular resistance increased linearly as BP increased above 100 mmHg, and decreased linearly as BP declined from basal to 60 mmHg, but resistance declined no further below 60 mmHg. Inhibition of nitric oxide (NO) formation by either a selective inhibitor of neuronal nitric oxide synthase (NOS) (N(omega)-propyl-L-arginine) or a nonselective inhibitor of both neuronal NOS and endothelial NOS (N(omega)-nitro-l-arginine methyl ester) did not affect compensation above 100 mmHg ABP, but did cause ChBF to linearly follow declines in BP below 90 mmHg. In NOS-inhibited rats, vascular resistance increased linearly with BP above 100 mmHg, but remained at baseline below 90 mmHg. These findings reveal that ChBF in rats, as in rabbits, humans and pigeons, compensates for rises and/or declines in arterial blood pressure so as to remain relatively stable within a physiological range of ABPs. The ChBF compensation for low ABP in rats is dependent on choroidal vasodilation caused by neuronal NO formation but not the compensation for elevated BP, implicating parasympathetic nervous system vasodilation in the ChBF compensation to low ABP. 10.1016/j.exer.2010.03.006
    Cannabinoids Regulate the Diameter of Pericyte-Containing Retinal Capillaries in Rats. Zong Yuan,Zhou Xujiao,Cheng Jingyi,Yu Jian,Wu Jihong,Jiang Chunhui Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology BACKGROUND/AIMS:Cannabinoids are vasoactive substances that act as key regulators of arterial tone in the blood vessels supplying peripheral tissues and the central nervous system. We therefore investigated the effect of cannabinoids on retinal capillaries and pericytes. METHODS:The effects of cannabinoids on capillary diameters were determined using an ex vivo whole-mount rat retinal model. Western blotting, quantitative PCR, and immunohistochemistry were performed to explore the underlying mechanism. RESULTS:Endogenous cannabinoid 2-arachidonoylglycerol and anandamide and exogenous cannabinoid (R-(+)-WIN55212-2) dilated the noradrenaline-precontracted capillaries in a concentration-dependent manner (1 µM to 0.1 mM). The extent of vasorelaxation was positively correlated with changes in pericyte width. The effects of R-(+)-WIN55212-2 on vasorelaxation and pericyte width were inhibited by a cannabinoid receptor type-1 (CB1) antagonist, AM251 or rimonabant (SR141716A), the nitric oxide synthase inhibitor l-NAME, and the guanylate cyclase inhibitor ODQ. They were also abolished by the removal of the endothelium, but not by the cannabinoid receptor-2 antagonist SR144528, the endothelial cannabinoid receptor antagonist O-1918, or the cyclooxygenase inhibitor indomethacin. CONCLUSION:The exogenous cannabinoid R-(+)-WIN55212-2 promotes the vasorelaxation of pericyte-containing rat retinal capillaries. This effect of R-(+)-WIN55212-2 is dependent on CB1 and the nitric oxide-cyclic guanosine monophosphate pathway, and requires an intact endothelium. 10.1159/000484193
    Ocular growth and metabolomics are dependent upon the spectral content of ambient white light. Najjar Raymond P,Chao De La Barca Juan Manuel,Barathi Veluchamy A,Ho Candice Ee Hua,Lock Jing Zhan,Muralidharan Arumugam R,Tan Royston K Y,Dhand Chetna,Lakshminarayanan Rajamani,Reynier Pascal,Milea Dan Scientific reports Myopia results from an excessive axial growth of the eye, causing abnormal projection of remote images in front of the retina. Without adequate interventions, myopia is forecasted to affect 50% of the world population by 2050. Exposure to outdoor light plays a critical role in preventing myopia in children, possibly through the brightness and blue-shifted spectral composition of sunlight, which lacks in artificial indoor lighting. Here, we evaluated the impact of moderate levels of ambient standard white (SW: 233.1 lux, 3900 K) and blue-enriched white (BEW: 223.8 lux, 9700 K) lights on ocular growth and metabolomics in a chicken-model of form-deprivation myopia. Compared to SW light, BEW light decreased aberrant ocular axial elongation and accelerated recovery from form-deprivation. Furthermore, the metabolomic profiles in the vitreous and retinas of recovering form-deprived eyes were distinct from control eyes and were dependent on the spectral content of ambient light. For instance, exposure to BEW light was associated with deep lipid remodeling and metabolic changes related to energy production, cell proliferation, collagen turnover and nitric oxide metabolism. This study provides new insight on light-dependent modulations in ocular growth and metabolomics. If replicable in humans, our findings open new potential avenues for spectrally-tailored light-therapy strategies for myopia. 10.1038/s41598-021-87201-2
    Prevention of axial elongation in myopia by the trace element zinc. Huibi X,Kaixun H,Qiuhua G,Yushan Z,Xiuxian H Biological trace element research The effect of the trace element zinc on the change in the axial length and diopters and the variations of activities of superoxide dismutase (SOD) and nitric oxide synthase (NOS), and the content of NO in the retino pigmental epithelium choroid homogenate of the myopic eyes in form-sense-deprived chicks were studied. The results show that zinc can inhibit the elongation of axis oculi and increase the diopters in myopia. Meanwhile, the activities of SOD and NOS and the content of NO are significantly increased compared with the model group, indicating that zinc can be used to prevent and treat myopia to a certain extent. 10.1385/BTER:79:1:39
    The effect of the nonspecific nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester on the choroidal compensatory response to myopic defocus in chickens. Nickla Debora L,Wildsoet Christine F Optometry and vision science : official publication of the American Academy of Optometry PURPOSE:Chick eyes show rapid compensation to retinal defocus. One component of this mechanism involves changes in the thickness of the choroid: when the retina is exposed to myopic defocus, the choroid thickens, pushing the retina forward; conversely, when the eye is exposed to hyperopic defocus, the choroid thins. The underlying mechanism(s) for these changes are unknown. We tested the hypothesis that nitric oxide might play a role. METHODS:We examined the effect of the nonspecific nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on the compensatory choroidal thickening in response to myopic defocus using two visual paradigms: first, in previously form-deprived "recovering" eyes and, second, in eyes wearing +15 D spectacle lenses. L-NAME was injected intravitreally after removal of the diffuser or immediately before putting on the lenses. In addition, we looked at the effect of L-NAME on experimentally thickened choroids (induced by 1 week of recovery from deprivation myopia or 1 week of +15 D lens wear) and on choroids of normal eyes. Eyes were measured using A-scan ultrasonography before the injections and at subsequent intervals for several days. As a control for the injection procedure, eyes with the same visual conditions were injected with saline. Fellow eyes were untreated and uninjected. RESULTS:L-NAME inhibited choroidal thickening in both previously form-deprived eyes (2 vs. 117 microm; p < 0.001) and eyes wearing +15 D lenses (3 vs. 137 microm; p < 0.02). The effect was rapid, transient, and dose dependent (ED50, 0.26 micromoles). L-NAME produced thinning in experimentally thickened choroids (recovering: -116 microm; lenses: -219 microm) and in normal choroids (-47 microm) within 7 hours. CONCLUSIONS:Nitric oxide may play a role in modulating choroidal thickness. The mechanism is as yet unknown.
    Choroidal changes in lens-induced myopia in guinea pigs. Yu Ting,Xie Xiaofeng,Wei Huixia,Shen Hui,Wu Qiuxin,Zhang Xiuyan,Ji HaiFeng,Tian QingMei,Song Jike,Bi Hongsheng Microvascular research INTRODUCTION:This study aimed to determine the role of the choroid in lens-induced myopia (LIM) in guinea pigs. METHODS:Guinea pigs were randomly divided into two groups: a normal control (NC) group and a LIM group. Refraction and axial length (AL) were measured by streak retinoscopy and A-scan ultrasonography. The choroidal thickness (ChT), vessel density of the choriocapillaris (VDCC) and vessel density of the choroidal layer (VDCL) were assessed by Spectral-domain Optical Coherence Tomography Angiography (SD-OCT). In addition, the choroidal expression of nitric oxide synthase (NOS) enzymes at the mRNA and protein levels was analyzed by real-time fluorescence quantitative PCR, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. RESULTS:In the LIM group, refraction and AL were increased significantly compared with those in the NC group at 2 weeks (refraction: LIM vs. NC, -4.23 ± 0.43 D vs. 2.20 ± 0.48 D; AL: LIM vs. NC, 8.36 ± 0.05 mm vs. 8.22 ± 0.03 mm) and 4 weeks (refraction: LIM vs. NC, -5.88 ± 0.49 D vs. 1.63 ± 0.41 D; AL: 8.57 ± 0.06 mm vs. 8.40 ± 0.04 mm). The ChT and VDCC were decreased significantly compared with those in the NC group at 2 weeks (ChT: LIM vs. NC, 60.92 ± 8.15 μm vs. 79.11 ± 7.47 μm; VDCC: LIM vs. NC, 23.43 ± 3.85% vs. 28.74 ± 4.11%) and 4 weeks (ChT: LIM vs. NC, 48.43 ± 6.85 μm vs. 76.38 ± 7.84 μm; VDCC: LIM vs. NC, 21.29 ± 2.17% vs. 27.64 ± 2.91%). The VDCL was also decreased compared with that in the NC group at 2 weeks and 4 weeks (NC vs. LIM, 24.87 ± 5.16% vs. 22.45 ± 3.26%; 23.37 ± 5.85% vs. 21.39 ± 2.62%; all P > 0.05). Moreover, the ChT was positively correlated with the VDCC and VDCL. The mRNA and protein expression of NOS enzymes (eNOS and nNOS) was increased. CONCLUSIONS:During the development of myopia, the ChT, VDCC and VDCL were decreased, while NOS expression in the choroid was increased. The expression of NOS was negatively correlated with the ChT, VDCC and VDCL. NO may play an important role in regulating the choroid during myopia development. 10.1016/j.mvr.2021.104213
    Inhibiting the transient choroidal thickening response using the nitric oxide synthase inhibitor l-NAME prevents the ameliorative effects of visual experience on ocular growth in two different visual paradigms. Nickla Debora L,Wilken Erika,Lytle Grace,Yom Sung,Mertz James Experimental eye research It is generally accepted that the increase in choroidal thickness in response to myopic defocus in chicks acts to move the retina towards the image plane. It may also constitute part of the signal cascade in the visual regulation of eye growth. To test this, we used the nitric oxide synthase inhibitor l-NAME to inhibit the defocus induced choroidal thickening under two different visual conditions, and looked at the effects on ocular growth rate. Exp. 1: Deprivation/Vision: chicks were monocularly deprived of form vision with translucent diffusers from day 6 to day 9. In the middle of each day the diffusers were removed for 2 h. One group received an intravitreal injection of 30 microl l-NAME (16 micromole; n=12) prior to the vision, a second group received injections of physiological saline (n=11). Exp. 2: Recovery/Vision: chicks were made myopic by form deprivation from day 6 to day 10. On days 11 to 14 the diffusers were removed for 2 h per day for 4 days to allow eyes to "recover" from the myopia. One group received an injection of l-NAME prior to vision (n=8), the other saline (n=6). Refractive errors were measured with a refractometer at the start (days 6 and 11) and end (days 10 and 15, respectively) of both experiments. Ocular dimensions were measured with high frequency A-scan ultrasonography at the start and end, and on the third experimental day immediately before and after the period of vision. Choroidal retinoic acid synthesis was measured by HPLC. Finally, NO production and scleral proteoglycan synthesis were measured in eyes wearing positive lenses 6 and 24h after an injection of l-NAME. l-NAME prevented the transient vision-induced choroidal thickening in both experiments. Furthermore, l-NAME inhibited the protective effect of brief daily vision: eyes became significantly more myopic than saline controls (exp. 1: -9 D vs -2.7D; exp. 2: -0.9 D vs +4.3 D; p<0.005 for both) and grew faster (change in lens-sclera: exp. 1: 295 vs 158 microm; exp. 2: 147 vs 39 microm; p<0.05 for both). Notably, l-NAME inhibited the growth of the anterior chamber (exp. 1: 88 vs 185 microm; exp. 2: 147 vs 254 microm; p<0.01 for both). Injections of l-NAME after the periods of vision had no effect on growth at the back of the eye, but still had an inhibitory effect on the anterior chamber. Retinoic acid levels in the drug-injected choroids were significantly decreased compared to controls. In eyes responding to positive lenses, l-NAME inhibited NO synthesis and disinhibited scleral glycosaminoglycan synthesis 6h after the injection. In summary, preventing the transient vision-induced increases in choroidal thickness altered ocular growth rate in a consistent manner under two different visual conditions, in both preventing the vision-induced reduction in growth rate. This supports the hypothesis that visually-induced changes in choroidal thickness play a role in the visual regulation of ocular growth. 10.1016/j.exer.2006.01.029
    Effect of a nitric oxide synthase inhibitor on lens-induced myopia. Fujikado T,Tsujikawa K,Tamura M,Hosohata J,Kawasaki Y,Tano Y Ophthalmic research PURPOSE:It has still not been determined whether the retinal mechanism causing form-deprivation myopia (FDM) is different from that causing lens-induced myopia (LIM). We previously reported that FDM was blocked by an intravitreal injection of the nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). In this study, we investigated the effect of L-NAME on LIM in chicks. METHOD:The left eyes of 6-day-old chicks were injected with 30 microl of nontoxic concentrations of L-NAME (< or = 360 mM) or saline. The right eyes were injected with 30 microl of saline. A -16 dpt lens was placed in front of the left eye for 6 days. Another group of 6 chicks were injected with 180 mM L-NAME (left eye) and with saline (right eye) before placing -16 dpt lenses in front of both eyes. After removing the lens, the refraction and the axial length were measured. The effect of L-NAME (180 mM) on the retina of a separate group of chicks was examined by electroretinography 60 min after an intravitreal injection in non-LIM-treated eyes. RESULTS:The eyes of chicks that were injected with 180 or 360 mM L-NAME were less myopic and had significantly shorter axial lengths than control eyes. A significant decrease of the On response and an increase of the Off response were observed. CONCLUSION:The injection of L-NAME into developing chick eyes that were then covered with a -16 dpt lens resulted in a modifications of retinal function and an inhibition of the development of myopia. These results, combined with the earlier findings, suggest that NO modulates a common retinal pathway that leads to both LIM and FDM. 10.1159/000055647
    Nitric oxide synthase inhibitors prevent the growth-inhibiting effects of quinpirole. Nickla Debora L,Lee Laimeng,Totonelly Kristen Optometry and vision science : official publication of the American Academy of Optometry PURPOSE:Both dopamine and nitric oxide (NO) have been implicated in the signal cascade mediating ocular growth inhibition. If both are part of the same pathway, which precedes the other? We tested the hypothesis that dopamine acts upstream of NO, by using two NOS inhibitors in combination with the dopamine agonist quinpirole, and measured the effects on ocular growth rate. METHODS:Chicks wore -10 D lenses or diffusers (FD) for 4 days starting at age 13 days. Experimental eyes received daily 20 μL injections of the following: quinpirole-lens: n = 12, FD: n = 20; n-ω-propyl-L-arginine (NPA)-lens: n = 6, FD: n = 4; quinpirole + NPA-lens: n = 17, FD: n = 19; and quinpirole + L-NIO-lens: n = 12, FD: n = 12. Saline injections were done as controls. High-frequency ultrasonography was done at the start, and on day 5, prior to injections and 3 hours later. Refractions were measured on day 5. RESULTS:As expected, quinpirole prevented the development of axial myopia in both paradigms. When quinpirole was combined with either NOS inhibitor, however, eyes became myopic compared to quinpirole (FD: NPA: -5.9 D vs. -3.4 D; L-NIO: -5.8 D vs. -3.4 D; lens: NPA: -3.5 D vs. -0.4 D; p < 0.05 for all; L-NIO was not significant). This was the result of a disinhibition of vitreous chamber growth versus quinpirole (FD: NPA: 401 vs. 275 μm/4 d; L-NIO: 440 vs. 275 μm/4 d; LENS: NPA: 407 vs. 253µm/4 d; L-NIO: 403 vs. 253 μm/4 d; p < 0.05). Only NPA prevented the quinpirole-induced choroidal thickening in lens-wearing eyes (0 vs. 31 μm/3 h; p < 0.05). Choroidal thickening was not inhibited by either drug in FD eyes. CONCLUSIONS:Dopamine acts upstream of NO and the choroidal response in the signal cascade mediating ocular growth inhibition in both form deprivation and negative lens wear. That neither NOS inhibitor inhibits choroidal thickening in FD eyes suggests that the choroidal mechanisms differ in the two paradigms. 10.1097/OPX.0000000000000041
    Prolonged use of nitric oxide donor sodium nitroprusside induces ocular hypertension in mice. Hu Chunchun,Zhang Yu,Song Maomao,Deng Yonghui,Sun Xinghuai,Lei Yuan Experimental eye research Nitric oxide (NO) donors are promising therapeutic candidates for treating intraocular hypertension (IOP) and glaucoma. This study aims to investigate the effect of prolonged use of NO donor sodium nitroprusside (SNP) on IOP. Since SNP has a short biological half-life, a nanoparticle drug delivery system (mesoporous silica nanoparticles) has been used to deliver SNP to the target tissues (trabecular meshwork and Schlemm's canal). We find that the sustained use of NO donor initially reduced IOP followed, surprisingly, by IOP elevation, which could not recover by drug withdraw but could be reversed by the antioxidant MnTMPyP application. The IOP elevation and normalization coincide with increased and reduced protein nitration in the mouse conventional outflow tissue. These findings suggest that the prolonged use of NO donor SNP may be problematic as it can cause outflow tissue damage by protein nitration. MnTMPyP is protective of the nitrative damage which could be considered to be co-applied with NO donors. 10.1016/j.exer.2020.108280
    Inhibiting the neuronal isoform of nitric oxide synthase has similar effects on the compensatory choroidal and axial responses to myopic defocus in chicks as does the non-specific inhibitor L-NAME. Nickla Debora L,Damyanova Petya,Lytle Grace Experimental eye research In birds, the choroid plays a role in the visual regulation of eye growth, thickening in response to myopic defocus, and thinning in response to hyperopic defocus, in both cases moving the retina towards the image plane. This response is rapid, occurring within hours of the defocus stimulus. These changes are consistently associated with slower changes in the sclera, that result in the appropriate changes in axial elongation, decreasing growth in response to myopic defocus and increasing it in response to hyperopic defocus. The molecular mechanisms underlying the scleral response involve changes in the synthesis of extracellular matrix molecules, however, those underlying the changes in choroidal thickness are not known. However, evidence suggests that it may involve the gaseous signal molecule nitric oxide, as nitric oxide is a potent smooth muscle relaxant, and injections of the non-specific nitric oxide synthase inhibitor L-NAME transiently inhibits the thickening response. Interestingly, it also dis-inhibits ocular growth, in accordance with a mechanistic link between the two responses. If nitric oxide is part of the signal cascade underlying the visual regulation of eye growth, it would be important to ascertain the source of the molecule. As a first step towards doing so, we used various more specific NOS inhibitors and studied their effects on the choroidal and growth responses. Birds (7-12 days old) were fitted with +10 D lenses on one eye. On that day, single intravitreal injections (30 microl) of the following inhibitors were used: nNOS inhibitor N(omega)-propyl-L-arginine (n=12), iNOS inhibitor L-NIL (n=16), eNOS/iNOS inhibitor L-NIO (n=15), non-specific inhibitor L-NMMA (n=30) or physiological saline (n=18). Ocular dimensions were measured using high-frequency A-scan ultrasonography at the start of the experiment, and at 7, 24 and 48 h after. We found that the nNOS inhibitor N(omega)-propyl-L-arginine had the same inhibitory effects on the choroidal response, and dis-inhibition of the growth response, as did L-NAME; neither of the other inhibitors had any effect except L-NMMA. We conclude that the choroidal compensatory response is influenced by nNOS, possibly from the intrinsic choroidal neurons, or the parasympathetic innervation from the ciliary and/or pterygopalatine ganglia. 10.1016/j.exer.2009.01.012
    Nitric Oxide (NO) Mediates the Inhibition of Form-Deprivation Myopia by Atropine in Chicks. Carr Brittany J,Stell William K Scientific reports Myopia is the most common childhood refractive disorder. Atropine inhibits myopia progression, but its mechanism is unknown. Here, we show that myopia-prevention by atropine requires production of nitric oxide (NO). Form-deprivation myopia (FDM) was induced in week-old chicks by diffusers over the right eye (OD); the left eye (OS) remained ungoggled. On post-goggling days 1, 3, and 5, OD received intravitreally 20 µL of phosphate-buffered saline (vehicle), or vehicle plus: NO source: L-arginine (L-Arg, 60-6,000 nmol) or sodium nitroprusside (SNP, 10-1,000 nmol); atropine (240 nmol); NO inhibitors: L-NIO or L-NMMA (6 nmol); negative controls: D-Arg (10 µmol) or D-NMMA (6 nmol); or atropine plus L-NIO, L-NMMA, or D-NMMA; OS received vehicle. On day 6 post-goggling, refractive error, axial length, equatorial diameter, and wet weight were measured. Vehicle-injected goggled eyes developed significant FDM. This was inhibited by L-Arg (ED50 = 400 nmol) or SNP (ED50 = 20 nmol), but not D-Arg. Higher-dose SNP, but not L-Arg, was toxic to retina/RPE. Atropine inhibited FDM as expected; adding NOS-inhibitors (L-NIO, L-NMMA) to atropine inhibited this effect dose-dependently, but adding D-NMMA did not. Equatorial diameter, wet weight, and metrics of control eyes were not affected by any treatment. In summary, intraocular NO inhibits myopia dose-dependently and is obligatory for inhibition of myopia by atropine. 10.1038/s41598-016-0002-7
    A Review of Nitric Oxide for the Treatment of Glaucomatous Disease. Aliancy Joah,Stamer W Daniel,Wirostko Barbara Ophthalmology and therapy Glaucoma is the leading cause of irreversible blindness worldwide, affecting 64.3 million people. An estimated 60.5 million people are affected by primary open angle glaucoma globally, and this will increase to 111.8 million by 2040. The definition of glaucoma has evolved greatly over time. Although multiple risk factors such as ischemia, inflammation, myopia, race, age and low ocular perfusion pressure may play a role, intraocular pressure (IOP) is still the main risk factor we can easily identify and modify. Currently, both medical and surgical interventions aim to reduce IOP. Effective IOP reduction controls and prevents the progression in many cases of glaucoma. Although this multifactorial disease's true pathophysiology is difficult to elucidate, physiologic mediators including nitric oxide (NO) are being evaluated as novel ways to impact progression by both lowering IOP and improving optic nerve head perfusion. Latanoprostene bunod 0.024% is an emerging therapeutic agent that has shown promise in clinical trials. As a nitric oxide-donating prostaglandin F2-alpha receptor agonist, it has proven to effectively, and with good tolerability, reduce IOP in glaucoma and ocular hypertensive patients. Latanoprostene bunod capitalizes on NO's ability to modulate the conventional aqueous humor outflow system, directly improving outflow through the trabecular meshwork, Schlemm's canal and distal scleral vessels. Importantly, targeting the conventional outflow tissues with NO-donating drugs represents an opportunity to restore outflow function, which will most likely have a beneficial consequence of additional IOP-lowering effects with dampening of diurnal and other IOP fluctuations, the benefit of a healthy trabecular meshwork. 10.1007/s40123-017-0094-6
    Insufficient Sun Exposure Has Become a Real Public Health Problem. Alfredsson Lars,Armstrong Bruce K,Butterfield D Allan,Chowdhury Rajiv,de Gruijl Frank R,Feelisch Martin,Garland Cedric F,Hart Prue H,Hoel David G,Jacobsen Ramune,Lindqvist Pelle G,Llewellyn David J,Tiemeier Henning,Weller Richard B,Young Antony R International journal of environmental research and public health This article aims to alert the medical community and public health authorities to accumulating evidence on health benefits from sun exposure, which suggests that insufficient sun exposure is a significant public health problem. Studies in the past decade indicate that insufficient sun exposure may be responsible for 340,000 deaths in the United States and 480,000 deaths in Europe per year, and an increased incidence of breast cancer, colorectal cancer, hypertension, cardiovascular disease, metabolic syndrome, multiple sclerosis, Alzheimer's disease, autism, asthma, type 1 diabetes and myopia. Vitamin D has long been considered the principal mediator of beneficial effects of sun exposure. However, oral vitamin D supplementation has not been convincingly shown to prevent the above conditions; thus, serum 25(OH)D as an indicator of vitamin D status may be a proxy for and not a mediator of beneficial effects of sun exposure. New candidate mechanisms include the release of nitric oxide from the skin and direct effects of ultraviolet radiation (UVR) on peripheral blood cells. Collectively, this evidence indicates it would be wise for people living outside the tropics to ensure they expose their skin sufficiently to the sun. To minimize the harms of excessive sun exposure, great care must be taken to avoid sunburn, and sun exposure during high ambient UVR seasons should be obtained incrementally at not more than 5-30 min a day (depending on skin type and UV index), in season-appropriate clothing and with eyes closed or protected by sunglasses that filter UVR. 10.3390/ijerph17145014
    Review: effects of nitric oxide on eye diseases and their treatment. Chiou G C Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics Both underproduction and overproduction of nitric oxide (NO) could lead to various eye diseases. It is known that endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are activated in normal tissues to produce NO for physiological functions. Thus, underproduction of NO results in various eye diseases which could be corrected by providing NOS substrates or NO donors to lower the intraocular pressure, increase ocular blood flow, relax ciliary muscle, etc. On the other hand, immunological NOS (iNOS) is inducible only in pathological conditions by endotoxins, inflammation, and certain cytokines, such as interleukin-1 (IL-1), IL-6, TNF (tumor necrosis factor) and the like. Once induced, iNOS will produce large amounts of NO for long periods of time, so that NO is converted into NO2, nitrite, peroxynitrite and free radicals to induce pathophysiological actions, such as optic nerve degeneration and posterior retinal degeneration lesion, which lead to glaucoma, retinopathy, age-related macular degeneration (AMD), myopia, cataracts and uveitis. To treat/prevent these eye diseases, inhibitors of iNOS activity and/or iNOS induction could be tried. 10.1089/10807680151125555
    Oxidative stress in myopia. Francisco Bosch-Morell,Salvador Mérida,Amparo Navea Oxidative medicine and cellular longevity Myopia affected approximately 1.6 billion people worldwide in 2000, and it is expected to increase to 2.5 billion by 2020. Although optical problems can be corrected by optics or surgical procedures, normal myopia and high myopia are still an unsolved medical problem. They frequently predispose people who have them to suffer from other eye pathologies: retinal detachment, glaucoma, macular hemorrhage, cataracts, and so on being one of the main causes of visual deterioration and blindness. Genetic and environmental factors have been associated with myopia. Nevertheless, lack of knowledge in the underlying physiopathological molecular mechanisms has not permitted an adequate diagnosis, prevention, or treatment to be found. Nowadays several pieces of evidence indicate that oxidative stress may help explain the altered regulatory pathways in myopia and the appearance of associated eye diseases. On the one hand, oxidative damage associated with hypoxia myopic can alter the neuromodulation that nitric oxide and dopamine have in eye growth. On the other hand, radical superoxide or peroxynitrite production damage retina, vitreous, lens, and so on contributing to the appearance of retinopathies, retinal detachment, cataracts and so on. The objective of this review is to suggest that oxidative stress is one of the key pieces that can help solve this complex eye problem. 10.1155/2015/750637
    Nitric Oxide Interaction with the Eye. Erdinest Nir,London Naomi,Ovadia Haim,Levinger Nadav Vision (Basel, Switzerland) Nitric oxide (NO) is acknowledged as a vital intercellular messenger in multiple systems in the body. Medicine has focused on its functions and therapeutic applications for decades, especially in cardiovascular and nervous systems, and its role in immunological responses. This review was composed to demonstrate the prevalence of NO in components of the ocular system, including corneal cells and multiple cells in the retina. It discussed NO's assistance during the immune, inflammation and wound-healing processes. NO is identified as a vascular endothelial relaxant that can alter the choroidal blood flow and prompt or suppress vascular changes in age-related macular degeneration and diabetes, as well as the blood supply to the optic nerve, possibly influencing the progression of glaucoma. It will provide a deeper understanding of the role of NO in ocular homeostasis, the delicate balance between overproduction or underproduction and the effect on the processes from aqueous outflow and subsequent intraocular pressure to axial elongation and the development of myopia. This review also recognized the research and investigation of therapies being developed to target the NO complex and treat various ocular diseases. 10.3390/vision5020029