Na+/K+-ATPase plays a major role in mediating cutaneous thermal hyperemia achieved by local skin heating to 39 ºC

2021 ◽  
Author(s):  
Naoto Fujii ◽  
Glen P. Kenny ◽  
Tatsuro Amano ◽  
Yasushi Honda ◽  
Narihiko Kondo ◽  
...  
Keyword(s):  
Control Site ◽  
Atpase Inhibitor ◽  
Local Skin ◽  
Nos Inhibitors ◽  
Forearm Skin ◽  
Lactated Ringer's Solution ◽  
Nos Inhibitor ◽  
Baseline Values ◽  
Oxide Synthase ◽  
Cutaneous Vascular Conductance

Na+/K+-ATPase is integrally involved in mediating cutaneous vasodilation during an exercise-heat stress, which includes an interactive role with nitric oxide synthase (NOS). Here, we assessed if Na+/K+-ATPase also contributes to cutaneous thermal hyperemia induced by local skin heating, which is commonly employed to assess cutaneous endothelium-dependent vasodilation. Further, we assessed the extent to which NOS contributes to this response. Cutaneous vascular conductance (CVC) was measured continuously at four forearm skin sites in eleven young adults (4 women). After baseline measurement, local skin temperature was increased from 33 to 39 ºC to induce cutaneous thermal hyperemia. Once a plateau in CVC was achieved, each skin site was continuously perfused via intradermal microdialysis with either: 1) lactated Ringer's solution (control), 2) 6 mM ouabain, a Na+/K+-ATPase inhibitor, 3) 20 mM L-NAME, a NOS inhibitor, or 4) a combination of both. Relative the control site, CVC during the plateau phase of cutaneous thermal hyperemia (~50%max) was reduced by the lone inhibition of Na+/K+-ATPase (-19±8%max, P = 0.038) and NOS (-32±4%max, P < 0.001) as well as the combined inhibition of both (-37±9%max, P < 0.001). The magnitude of reduction was similar between NOS inhibition alone and combined inhibition (P = 1.000). The administration of Na+/K+-ATPase and NOS inhibitors fully abolished the plateau of CVC with values returning to pre-heating baseline values (P = 0.439). We show that Na+/K+-ATPase contributes to cutaneous thermal hyperemia during local skin heating to 39 ºC, and this response is partially mediated by NOS.

Influence of hyperoxia on skin vasomotor control in normothermic and heat-stressed humans

2007 ◽  
Vol 103 (6) ◽  
pp. 2026-2033 ◽  
Author(s):  
Fumio Yamazaki ◽  
Kazuo Takahara ◽  
Ryoko Sone ◽  
John M. Johnson
Keyword(s):  
Thermal Conditions ◽  
Inhibitory Effects ◽  
Doppler Flowmetry ◽  
Vasoconstrictor Response ◽  
Forearm Skin ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Cutaneous Vascular Conductance ◽  
Male Subjects ◽  
Cutaneous Vasoconstriction

Hyperoxia induces skin vasoconstriction in humans, but the mechanism is still unclear. In the present study we examined whether the vasoconstrictor response to hyperoxia is through activated adrenergic function ( protocol 1) or through inhibitory effects on nitric oxide synthase (NOS) and/or cyclooxygenase (COX) ( protocol 2). We also tested whether any such vasoconstrictor effect is altered by body heating. In protocol 1 ( n = 11 male subjects), release of norepinephrine from adrenergic terminals in the forearm skin was blocked locally by iontophoresis of bretylium (BT). In protocol 2, the NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME) and the nonselective COX antagonist ketorolac (Keto) were separately administered by intradermal microdialysis in 11 male subjects. In the two protocols, subjects breathed 21% (room air) or 100% O2 in both normothermia and hyperthermia. Skin blood flow (SkBF) was monitored by laser-Doppler flowmetry. Cutaneous vascular conductance (CVC) was calculated as the ratio of SkBF to blood pressure measured by Finapres. In protocol 1, breathing 100% O2 decreased ( P < 0.05) CVC at the BT-treated and at untreated sites from the levels of CVC during 21% O2 breathing both in normothermia and hyperthermia. In protocol 2, the administration of l-NAME inhibited ( P < 0.05) the reduction of CVC during 100% O2 breathing in both thermal conditions. The administration of Keto inhibited ( P < 0.05) the reduction of CVC during 100% O2 breathing in hyperthermia but not in normothermia. These results suggest that skin vasoconstriction with hyperoxia is partly due to the decreased activity of functional NOS in normothermia and hyperthermia. We found no significant role for adrenergic mechanisms in hyperoxic vasoconstriction. Decreased production of vasodilator prostaglandins may play a role in hyperoxia-induced cutaneous vasoconstriction in heat-stressed humans.

scholarly journals Oral atorvastatin therapy increases nitric oxide-dependent cutaneous vasodilation in humans by decreasing ascorbate-sensitive oxidants

2011 ◽  
Vol 301 (3) ◽  
pp. R763-R768 ◽  
Author(s):  
Lacy A. Holowatz ◽  
W. Larry Kenney
Keyword(s):  
Nitric Oxide ◽  
Local Heating ◽  
Oxidant Stress ◽  
Microvascular Dysfunction ◽  
Local Skin ◽  
Cutaneous Vasodilation ◽  
Before And After ◽  
Atorvastatin Therapy ◽  
Oxide Synthase ◽  
Cutaneous Vascular Conductance

Elevated low-density lipoproteins (LDL) are associated with cutaneous microvascular dysfunction partially mediated by increased arginase activity, which is decreased following a systemic atorvastatin therapy. We hypothesized that increased ascorbate-sensitive oxidant stress, partially mediated through uncoupled nitric oxide synthase (NOS) induced by upregulated arginase, contributes to cutaneous microvascular dysfunction in hypercholesterolemic (HC) humans. Four microdialysis fibers were placed in the skin of nine HC (LDL = 177 ± 6 mg/dl) men and women before and after 3 mo of a systemic atorvastatin intervention and at baseline in nine normocholesterolemic (NC) (LDL = 95 ± 4 mg/dl) subjects. Sites served as control, NOS inhibited, L-ascorbate, and arginase-inhibited+L-ascorbate. Skin blood flow was measured while local skin heating (42°C) induced NO-dependent vasodilation. After the established plateau in all sites, 20 mM ≪ngname≫ was infused to quantify NO-dependent vasodilation. Data were normalized to maximum cutaneous vascular conductance (CVC) (sodium nitroprusside + 43°C). The plateau in vasodilation during local heating (HC: 78 ± 4 vs. NC: 96 ± 2% CVCmax, P < 0.01) and NO-dependent vasodilation (HC: 40 ± 4 vs. NC: 54 ± 4% CVCmax, P < 0.01) was reduced in the HC group. Acute L-ascorbate alone (91 ± 5% CVCmax, P < 0.001) or combined with arginase inhibition (96 ± 3% CVCmax, P < 0.001) augmented the plateau in vasodilation in the HC group but not the NC group (ascorbate: 96 ± 2; combo: 93 ± 4% CVCmax, both P > 0.05). After the atorvastatin intervention NO-dependent vasodilation was augmented in the HC group (HC postatorvastatin: 64 ± 4% CVCmax, P < 0.01), and there was no further effect of ascorbate alone (58 ± 4% CVCmax, P > 0.05) or combined with arginase inhibition (67 ± 4% CVCmax, P > 0.05). Increased ascorbate-sensitive oxidants contribute to hypercholesteromic associated cutaneous microvascular dysfunction which is partially reversed with atorvastatin therapy.

Role of inwardly rectifying K+ channels in K+-induced cerebral vasodilatation in vivo

2000 ◽  
Vol 279 (6) ◽  
pp. H2704-H2712 ◽  
Author(s):  
Sophocles Chrissobolis ◽  
James Ziogas ◽  
Yi Chu ◽  
Frank M. Faraci ◽  
Christopher G. Sobey
Keyword(s):  
Basilar Artery ◽  
Channel Activity ◽  
Atpase Inhibitor ◽  
Kir Channel ◽  
Cerebral Vasodilatation ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Inwardly Rectifying

We tested whether activation of inwardly rectifying K+ (Kir) channels, Na+-K+-ATPase, or nitric oxide synthase (NOS) play a role in K+-induced dilatation of the rat basilar artery in vivo. When cerebrospinal fluid [K+] was elevated from 3 to 5, 10, 15, 20, and 30 mM, a reproducible concentration-dependent vasodilator response was elicited (change in diameter = 9 ± 1, 27 ± 4, 35 ± 4, 43 ± 12, and 47 ± 16%, respectively). Responses to K+ were inhibited by ∼50% by the Kir channel inhibitor BaCl2 (30 and 100 μM). In contrast, neither ouabain (1–100 μM, a Na+-K+-ATPase inhibitor) nor N G-nitro-l-arginine (30 μM, a NOS inhibitor) had any effect on K+-induced vasodilatation. These concentrations of K+ also hyperpolarized smooth muscle in isolated segments of basilar artery, and these hyperpolarizations were virtually abolished by 30 μM BaCl2. RT-PCR experiments confirmed the presence of mRNA for Kir2.1 in the basilar artery. Thus K+-induced dilatation of the basilar artery in vivo appears to partly involve hyperpolarization mediated by Kir channel activity and possibly another mechanism that does not involve hyperpolarization, activation of Na+-K+-ATPase, or NOS.

Leakage responses to l-NAME differ with the fluorescent dye used to label albumin

1999 ◽  
Vol 276 (1) ◽  
pp. H333-H339 ◽  
Author(s):  
Rolando E. Rumbaut ◽  
Norman R. Harris ◽  
Arshad J. Sial ◽  
Virginia H. Huxley ◽  
D. Neil Granger
Keyword(s):  
Nitric Oxide ◽  
Fluorescent Dyes ◽  
Albumin Leakage ◽  
Nos Inhibitors ◽  
Microvascular Transport ◽  
Nos Inhibitor ◽  
Sulforhodamine 101 ◽  
Oxide Synthase ◽  
Texas Red ◽  
Transport Of Macromolecules

Nitric oxide synthase (NOS) inhibitors have been reported to increase as well as to decrease microvascular transport of macromolecules in a variety of models. This study was performed to determine whether the influence of NOS inhibition on albumin leakage was dependent on the fluorescent dyes used to label albumin. Albumin leakage was assessed in rat mesenteric venules during control conditions and after exposure to the NOS inhibitor N G-nitro-l-arginine methyl ester (l-NAME). Albumin was labeled with any one of four dyes: FITC, sulforhodamine 101 [Texas Red (TR)], dichlorotriazinyl aminofluorescein (DTAF), or Oregon Green 514 (OG). Superfusion withl-NAME (10−4 M) was accompanied by an increase in leakage of FITC-labeled albumin ( n = 12) but not of albumin labeled with DTAF ( n = 10), TR ( n = 10), or OG ( n = 4). In vessels perfused with both FITC- and TR-labeled albumin ( n = 12), superfusion with l-NAME increased leakage of FITC- but not TR-labeled albumin. In conclusion, albumin leakage responses tol-NAME differ among various fluorescent dyes. Therefore, caution is advised in comparison of albumin leakage results that utilize different fluorescent dyes.

Induction of Chronic Lymphocytic Leukemia (CLL) Apoptosis by Nitric Oxide Synthase (NOS) Inhibitors: Drug Efficacy Correlates with Lipid Solubility and NOS1 Dissociation Constant.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5044-5044
Author(s):  
Marc C. Levesque ◽  
Dipak K. Ghosh ◽  
Bethany E. Beasley ◽  
Youwei Chen ◽  
Alicia D. Volkheimer ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cell Death ◽  
Nitric Oxide Synthase ◽  
Cell Apoptosis ◽  
Weak Correlation ◽  
Nos Inhibitors ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Specific Inhibitors ◽  
Inducible Nos

Abstract The viability of CLL cells may be dependent on the autocrine production of nitric oxide because nitric oxide synthase (NOS) inhibitors induce CLL cell apoptosis and CLL cells express inducible NOS (NOS2). Our previous study indicated that the non-specific NOS inhibitor NMMA induced CLL cell apoptosis but only at high concentrations (&gt; 1 mM) (Levesque et al., Leukemia17:442, 2003). Therefore, we performed the current study to identify NOS inhibitors that induce CLL cell apoptosis at lower concentrations and to understand factors that promote NOS inhibitor-induced CLL cell toxicity. We isolated and enriched CLL cells from the blood of CLL patients and cultured the CLL cells in media containing various concentrations of 21 different NOS inhibitors. We determined CLL cell viability following culture with each NOS inhibitor. We found that NOS inhibitors with specificity for neuronal NOS (NOS1) induced CLL cell death at concentrations lower than non-specific NOS inhibitors and lower than inducible NOS (NOS2) specific inhibitors. There was a weak correlation (r2 = 0.29, p = 0.1608) of the NOS1 (but not NOS2) half-maximal inhibitory concentration (IC50) of each NOS inhibitor for purified recombinant NOS and its ability to induce CLL cell death. We confirmed the specificity of the NOS inhibitors by inhibition of purified recombinant NOS1 and NOS2 enzyme activity, and we confirmed that NOS1 specific inhibitors induced CLL cell death by apoptosis. Because there was only a weak correlation of the NOS1 IC50 with NOS inhibitor induced CLL cell death, we considered whether other factors such as the Kd and hydrophobicity of each compound correlated with CLL cell death. We found that there was a direct correlation between the NOS1 (but not NOS2) dissociation constant (Kd) of NOS inhibitors and CLL cell death (r2 = 0.77, p = 0.0041) and a direct correlation of the partitioning coefficient (a measure of hydrophobicity) of each NOS inhibitor and its ability to induce CLL cell death (r2 = 0.68, p &lt; 0.0001). Therefore, NOS inhibitors that bound tightly to NOS1 and were hydrophobic induced CLL cell death at lower concentrations. There was variable expression of CLL cell NOS1 mRNA (6 of 28 samples positive) and we were unable to demonstrate CLL cell expression of NOS1 protein by immunoblotting. This suggests that if NOS1 is present in CLL cells, it exists at very low levels. Taken together, we believe that low level NO production promotes CLL cell viability and that inhibition of CLL NOS induces CLL cell apoptosis. Importantly, our studies provide direction for the rational design and selection of NOS inhibitors that may be useful as CLL therapeutics.

scholarly journals Tetrahydrobiopterin does not affect end-organ responsiveness to norepinephrine-mediated vasoconstriction in aged skin

2010 ◽  
Vol 299 (6) ◽  
pp. R1651-R1655 ◽  
Author(s):  
James A. Lang ◽  
Lacy A. Holowatz ◽  
W. Larry Kenney
Keyword(s):  
Sympathetic Nerves ◽  
Adrenergic Nerve ◽  
Adrenergic Blockade ◽  
Local Skin ◽  
Forearm Skin ◽  
Aged Skin ◽  
Adrenergic Nerve Terminals ◽  
Doppler Flux ◽  
Cutaneous Vascular Conductance ◽  
Treated Site

We have recently demonstrated that tetrahydrobiopterin (BH4) augments reflex vasoconstriction (VC) in aged skin. Although this appears to occur through its role in norepinephrine (NE) biosynthesis, the extent with which vascular mechanisms are affected are unknown. We hypothesized that localized BH4 supplementation would not affect the VC response to exogenous NE when sympathetic nerves were blocked. Two microdialysis fibers were placed in bretylium tosylate pretreated (presynaptically blocks neurotransmitter release from sympathetic adrenergic nerve terminals; iontophoresis, 200 μA for 20 min) 3-cm2 forearm skin of 10 young (Y) and 10 older (O) subjects for perfusion of 1) Ringer (control) and 2) 5 mM BH4. While local skin temperature was clamped at 34°C, six concentrations of NE (10−12, 10−10, 10−8, 10−6, 10−4, 10−2 M) were infused at each drug-treated site. Cutaneous vascular conductance (CVC) was calculated (CVC = laser Doppler flux/mean arterial pressure) and normalized to baseline (%ΔCVCbase). Despite prejunctional adrenergic blockade, NE-mediated VC was blunted in aged skin at each NE dose (10−12: −12 ± 2 vs. −21 ± 2; 10−10: −15 ± 2 vs. −27 ± 1; 10−8: −22 ± 2 vs. −32 ± 2; 10−6: −27 ± 2 vs. −38 ± 1; 10−4: −52 ± 3 vs. −66 ± 5; 10−2: −62 ± 3 vs. −75 ± 4%ΔCVCbase; P < 0.01), and this response was not affected by pretreatment with BH4 ( P > 0.05). Localized BH4 did not affect end-organ responsiveness to exogenous NE, suggesting that the effects of BH4 on cutaneous VC are primarily isolated to the NE biosynthetic pathway.

Inhibition of nitric oxide synthase attenuates NNMU-induced alveolar injury in vivo

1997 ◽  
Vol 273 (6) ◽  
pp. L1167-L1173 ◽  
Author(s):  
Wilhelm S. Cruz ◽  
Michael A. Moxley ◽  
John A. Corbett ◽  
William J. Longmore
Keyword(s):  
Nitric Oxide ◽  
Acute Lung Injury ◽  
Methyl Ester ◽  
Lung Injury ◽  
Protein Ratio ◽  
Nos Inhibitors ◽  
Elevated Expression ◽  
Nos Inhibitor ◽  
Oxide Synthase

The purpose of this study was to determine if the acute alveolar injury induced by subcutaneous injections of N-nitroso- N-methylurethane (NNMU) in rats is mediated by nitric oxide (NO ⋅). We show that intraperitoneal injections of the NO ⋅ synthase (NOS) inhibitor N ω-nitro-l-arginine methyl ester (l-NAME) or aminoguanidine significantly attenuate the NNMU-induced alveolar injury as assessed by 1) normalization of the alveolar-arterial O2difference, 2) attenuation of the lowered phospholipid-to-protein ratio in the crude surfactant pellet (CSP), 3) attenuation of the elevated minimal surface tension of the CSP, and 4) attenuation of polymorphonuclear neutrophilic infiltration into the alveolar space. Injections of N ω-nitro-d-arginine methyl ester, the inactive stereoisoform ofl-NAME, did not affect the acute lung injury. Western blot analysis of whole lung homogenates demonstrate an elevated expression of transcriptionally inducible, Ca2+-independent NOS (iNOS) in NNMU-injected rats compared with control saline-injected rats. NOS inhibitors did not affect NNMU-induced iNOS expression. These investigations demonstrate that the inhibition of NOS attenuates NNMU-induced acute lung injury, suggesting a role for NO ⋅ in the progression of acute respiratory distress syndrome.

scholarly journals Regulation of cyclooxygenase activity and progesterone production in the rat corpus luteum by inducible nitric oxide synthase

Reproduction ◽  
2002 ◽  
pp. 663-669 ◽  
Author(s):  
A Hurwitz ◽  
Z Finci-Yeheskel ◽  
A Milwidsky ◽  
M Mayer
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Corpus Luteum ◽  
Prostaglandin E ◽  
No Production ◽  
Luteal Cells ◽  
Progesterone Production ◽  
Nos Inhibitors ◽  
Nos Inhibitor ◽  
Oxide Synthase

This study explores interactions between the nitric oxide synthase (NOS) and the cyclooxygenase (COX) pathways in the regulation of progesterone production in early corpus luteum cells of rats. Nitric oxide (NO), prostaglandin E (PGE) and progesterone production was analysed in luteal cells of the rat corpus luteum exposed to inhibitors of non-specific NOS, inhibitors of inducible NOS (iNOS) and inhibitors of COX. Equine chorionic gonadotrophin (eCG)/hCG-primed rat corpus luteum cells produced NO, PGE and progesterone in a linear manner during 66 h of culture. Exposure of the cells to the non-specific NOS inhibitor, N(omega)-nitro-L-arginine (0.15 mmol l(-1)) for 48 h reduced NO, PGE and progesterone production to 21, 32 and 60% of that of the controls, respectively (P < 0.05 to P < 0.01). Another non-specific NOS inhibitor, N(omega)-methyl-L-arginine, produced similar inhibitions. Exposure of the cultured cells to S-ethylisothiourea (1 mmol l(-1)), a selective inhibitor of iNOS, suppressed the production of NO by 63%, PGE by 69% and progesterone by 48%. These findings indicate that production of PGE is regulated partly by iNOS, and that progesterone is probably regulated indirectly by the secondary changes in PGE. The addition of arachidonic acid to N(omega)-methyl-L-arginine-treated cells resulted in a significant increase in PGE and progesterone production (273 and 186%, respectively) without stimulating NO production. In contrast to the regulation exerted by the NO system on COX activity, the COX system does not modulate NO production in this model. This notion stems from the observation that the COX inhibitors acetylsalicylic acid (5 mmol l(-1)) and indomethacin (5 micromol l(-1)) suppressed PGE by 86 and 89%, respectively, and progesterone by 34 and 57%, respectively, but failed to inhibit NO production. The results from the present study indicate that iNOS-mediated NO production is involved in stimulating PGE synthesis in rat luteal cells, which may upregulate progesterone production.

Changes in regional hemodynamics after nitric oxide inhibition during ovine bacteremia

1996 ◽  
Vol 270 (1) ◽  
pp. R207-R216 ◽  
Author(s):  
W. Lingnau ◽  
R. McGuire ◽  
D. J. Dehring ◽  
L. D. Traber ◽  
H. A. Linares ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Continuous Infusion ◽  
Regional Blood Flow ◽  
Recovery Period ◽  
Blood Flows ◽  
Nos Inhibitors ◽  
Regional Hemodynamics ◽  
Live Bacteria ◽  
Nos Inhibitor ◽  
Oxide Synthase

We studied the action of nitric oxide synthase (NOS) inhibition on changes in regional blood flow during a continuous infusion of live bacteria. Eighteen ewes were chronically instrumented. After a 7-day recovery period, an infusion of 10(6) colony-forming units/min Pseudomonas aeruginosa was begun. At 24 h, cardiac output increased significantly above baseline in all groups (5.9 +/- 0.4 vs. 8.2 +/- 0.6 l.min 1.m-2), systemic vascular resistance decreased (1,362 +/- 120 vs. 821 +/- 145 dyn.g.cm-5.m-2), and cerebral, cephalic mesenteric, and hindlimb blood flows increased. The animals were then equally and randomly assigned to a bolus of a NOS inhibitor, either 25 mg/kg N omega-nitro-L-arginine methyl ester (L-NAME) or 20 mg/kg N omega-monomethyl-L-arginine (L-NMMA), followed by a continuous infusion of 7 mg.kg-1.min-1 L-NMMA or saline. After NOS inhibition, cardiac index decreased [5.6 +/- 0.1 (L-NAME) and 5.5 +/- 0.4 l.min-1.m-2 (L-NMMA)] and remained significantly decreased for 12 h. 1-NAME decreased carotid and mesenteric blood flows to 64% of the preseptic baseline, and they remained below baseline for 20 h. L-NMMA decreased blood flows only to preseptic baseline values. NOS inhibitors may affect blood flows independently of their hemodynamic effects.

scholarly journals Anticompulsive-like effect of nitric oxide synthase inhibitors in marble-burying test

2020 ◽  
Vol 1 ◽  
Author(s):  
Karina Montezuma ◽  
Caroline Biojone ◽  
Samia Joca ◽  
Plinio Casarotto ◽  
Francisco Silveira Guimarães
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Current Literature ◽  
Elevated Plus Maze ◽  
Plus Maze ◽  
Marble Burying ◽  
Nos Inhibitors ◽  
Nos Inhibitor ◽  
Nitric Oxide Inhibitors ◽  
Oxide Synthase

Nitric oxide synthase (NOS) inhibitors decrease marble burying behavior (MBB), and the effect of several compounds that also attenuate MBB (such as classical antidepressants) engages the nitrergic system. In the present study, we tested the effect of the NOS inhibitor aminoguanidine (AMG) in attenuating MBB. For comparative reasons, we also tested the effect of selective inhibitors of neuronal (NOS1) and inducible (NOS2) isoforms NPA and 1400W, respectively. Our results indicate that AMG and NPA, but not 1400W, reduced the number of buried marbles in the marble burying test (MBT), which is considered an anticompulsive-like effect. No effect of AMG in the anxiety- or locomotor-related parameters of the elevated plus maze was observed. Taken together, our data is consistent with the current literature that suggests that nitric oxide inhibitors, putatively acting through the neuronal isoform of the synthesis enzyme (NOS1), exhibit anticompulsive-like properties.

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