Role Of Nitric Oxide Synthase Research Articles

Role of Nitric Oxide Synthases in Respiratory Health and Disease: Insights from Triple Nitric Oxide Synthases Knockout Mice.

The system of nitric oxide synthases (NOSs) is comprised of three isoforms: nNOS, iNOS, and eNOS. The roles of NOSs in respiratory diseases in vivo have been studied by using inhibitors of NOSs and NOS-knockout mice. Their exact roles remain uncertain, however, because of the non-specificity of inhibitors of NOSs and compensatory up-regulation of other NOSs in NOS-KO mice. We addressed this point in our triple-n/i/eNOSs-KO mice. Triple-n/i/eNOSs-KO mice spontaneously developed pulmonary emphysema and displayed exacerbation of bleomycin-induced pulmonary fibrosis as compared with wild-type (WT) mice. Triple-n/i/eNOSs-KO mice exhibited worsening of hypoxic pulmonary hypertension (PH), which was reversed by treatment with sodium nitrate, and WT mice that underwent triple-n/i/eNOSs-KO bone marrow transplantation (BMT) also showed aggravation of hypoxic PH compared with those that underwent WT BMT. Conversely, ovalbumin-evoked asthma was milder in triple-n/i/eNOSs-KO than WT mice. These results suggest that the roles of NOSs are different in different pathologic states, even in the same respiratory diseases, indicating the diversity of the roles of NOSs. In this review, we describe these previous studies and discuss the roles of NOSs in respiratory health and disease. We also explain the current state of development of inorganic nitrate as a new drug for respiratory diseases.

Evaluation of serum nitric oxide synthase levels in patients with coronary slow flow based on corrected TIMI frame count.

The coronary slow flow phenomenon (CSFP) finding in angiography is characterized by the delayed filling of the terminal vessels without significant epicardial coronary disease. The endothelium performs a vital role in cardiovascular homeostasis by releasing vasoactive substances. Endothelial cells produce nitric oxide (NO) as one of these essential compounds. Three isoforms of nitric oxide synthase (NOS) are endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and induced nitric oxide synthase (iNOS). We aimed to determine the role of NOS in the development of CSFP as the first human study. A total of 129 patients who met the inclusion criteria were enrolled in the study. The patients were classified into five groups based on the results of coronary angiography: Group 1 without coronary artery disease (CAD) and without CSF, group 2 without CAD and with CSF, group 3 with CAD (< 50%) and without CSF, group 4 with CAD (50-90%) and without CSF, and group 5 with CAD and CSF. The serum level of NOS was determined in the participants. Coronary flow was quantified in patients with CSFP using the corrected TIMI frame count (CTFC) method, and the correlation between the levels of this biomarker and CTFC was investigated. In this study, the NOS serum levels were not significantly correlated with the mean CTFC. Since the total amount of NOS was measured as a result of 3 isoforms of this enzyme, the lack of correlation could be related to increased iNOS level and decreased eNOS concentration. These results should be confirmed by more human studies.

Chronic Inhibition of Nitric Oxide Synthases Impairs Spatiotemporal Learning and Memory to a Similar Extent in C57BL/6 and hAPP23+/− Mice

Due to global population growth, age-related disorders like cardiovascular disease and dementia are anticipated to increase. Recent data suggests a connection between cardiovascular disease and neurodegeneration, especially focusing on arterial stiffness (AS) and Alzheimer’s disease (AD). In light of this, we conducted a study to explore the impact of long-term nitric oxide synthase (NOS) isoform inhibition, which leads to AS, on neurobehavioral performance. We also compared these effects in an AD model and control mice. C57BL/6 and hAPP23+/− mice (an established AD model) were given 0.5 mg/mL N(G)-Nitro-L-Arginine Methyl Ester (L-NAME) in their drinking water for 16 weeks. Our findings indicate that chronic non-selective NOS inhibition increased AS and reduced spatiotemporal learning and memory in both C57BL/6 and hAPP23+/− mice. These effects were consistent across both groups, emphasizing the role of neuronal NOS (nNOS) in cognitive aging, regardless of genetic predisposition to AD.

An oral glucose tolerance test does not affect cerebral blood flow: role of NOS.

Animal data indicate that insulin triggers a robust nitric oxide synthase (NOS)-mediated dilation in cerebral arteries similar to the peripheral tissue vasodilation observed in healthy adults. Insulin's role in regulating cerebral blood flow (CBF) in humans remains unclear but may be important for understanding the links between insulin resistance, diminished CBF, and poor brain health outcomes. We tested the hypothesis that an oral glucose challenge (oral glucose tolerance test, OGTT), which increases systemic insulin and glucose, would acutely increase CBF in healthy adults due to NOS-mediated vasodilation, and that changes in CBF would be greater in anterior regions where NOS expression or activity may be greater. In a randomized, single-blind approach, 18 young healthy adults (24 ± 5 yr) underwent magnetic resonance imaging (MRI) with a placebo before and after an OGTT (75 g glucose), and 11 of these adults also completed an NG-monomethyl-l-arginine (l-NMMA) visit. Four-dimensional (4-D) flow MRI quantified macrovascular CBF and arterial spin labeling (ASL) quantified microvascular perfusion. Subjects completed baseline imaging with a placebo (or l-NMMA), then consumed an OGTT followed by MRI scans and blood sampling every 10-15 min for 90 min. Contrary to our hypothesis, total CBF (P = 0.17) and global perfusion (P > 0.05) did not change at any time point up to 60 min after the OGTT, and no regional changes were detected. l-NMMA did not mediate any effect of OGTT on CBF. These data suggest that insulin-glucose challenge does not acutely alter CBF in healthy adults.

Black Seed (&lt;i&gt;Nigella sativa&lt;/i&gt;) oil restores smoke or nicotine-induced vascular impairment via improvement in endothelium-dependent relaxation: role of nitric oxide synthase and voltage-sensitive potassium channels

Background: Despite the overwhelming evidence linking smoking and nicotine intake with vascular function impairments, the mechanisms involved and the possible ameliorative effect of black seed (Nigella sativa (NS)) oil administration are not clearly understood. This study sought to determine the involvement of nitric oxide synthase and voltage-sensitive potassium channels in the modulation of vascular reactivity in cigarette or nicotine-exposed rats treated with NS oil.&#x0D; Methods: Thirty male Sprague-Dawley rats were divided into 6 groups comprising vehicle control (Control), NS oil only (NS), Smoke only (SMK), Smoke + NS oil (SMKNS), Nicotine only (NCT) and Nicotine + NS oil (NCTNS). Animals were either passively exposed to cigarette smoke or nicotine vapour for 12 weeks, however, NS oil treatment commenced from 9th-12th week orally. At the end of the 12-week experimental period, vascular reactivity to norepinephrine (NE), acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed with or without the presence of L-nitro-arginine (LNA) or 4-Amino-pyridine (4AP).&#x0D; Results: Percent contractile response to NE was higher (p &lt; 0.01) while relaxation response to ACh was lower in the SMK and NCT (p &lt; 0.05) groups. LNA-induced inhibition to ACh was significantly reduced in both SMK and NCT groups. 4AP-induced inhibition to ACh was significantly increased only in the NCT group. 4AP-induced inhibition to SNP was increased in SMK group. NS oil reduced only contractile response to NE in NCT group. It also significantly improved relaxation response to ACh as well as restored LNA-induced inhibition to ACh in the SMK and NCT groups. Interestingly, while NS oil reduced 4AP-induced inhibition in the NCT group, it reduced 4AP-induced inhibition to SNP in the SMK group.&#x0D; Conclusion: NS oil ameliorates vascular dysfunction by reducing contractile response in rats exposed to nicotine vapour while increasing endothelium-dependent relaxation as well as restoring differentially both LNA- and 4AP-induced inhibition in rats exposed to cigarette smoke and nicotine vapour.

The Role of NO Synthase, MPT pore, and Protein Kinase A in the Cardioprotective Effect of the Opioid Receptor Agonist Deltorphin II.

In male Wistar rats, coronary occlusion (45 min) and reperfusion (120 min) were modeled. Selective δ2-opioid receptor agonist (deltorphin II, 0.12 mg/kg) was administered intravenously 5 min before reperfusion; NO synthase inhibitor (L-NAME, 10 mg/kg), MPT pore blocker (atractyloside, 5 mg/kg), and protein kinase A inhibitor (H-89, 10 μg/kg) were administered intravenously 10 min before reperfusion. Deltorphin II administered before reperfusion led to a 2-fold decrease in the infarct size. The infarct-limiting effect of deltorphin II was associated with blockade of MPT pore. Protein kinase A and NO synthase were not involved in the cardioprotective effect of deltorphin II.

The Role of NO Synthase in the Infarct-Limiting Effect of Urgent and Chronic Adaptation to Normobaric Hypoxia.

We studied the role of NO synthase in the infarct-limiting effect of short-term (SNH) and chronic continuous normobaric hypoxia (CNH). In male Wistar rats, SNH (6 sessions of 10-min hypoxia 8% O2 and 10-min reoxygenation) or CNH (12% O2 for 21 days) was modeled. In 30 min after SNH or 24 h after CNH, the rats were subjected to coronary artery occlusion (45 min) and reperfusion (2 h). The following drugs were administered to rats: non-selective NO synthase inhibitor L-NAME (10 mg/kg), inhibitor of inducible NO synthase S-methylthiourea (3 mg/kg), and inhibitor of neuronal NO-synthase 7-nitroindazole (50 mg/kg). NO donor diethylenetriamine was administered intravenously in a dose 2 mg/kg. It was found that L-NAME and S-methylthiourea abolished the infarct-limiting effect of SNH and CNH. Diethylenetriamine increased cardiac tolerance to ischemia/reperfusion. It is believed that inducible NO synthase plays an important role in the cardioprotective effect of normobaric hypoxia.

Role of nitric oxide synthase in mice to protect against Plasmodium berghei malaria

Malaria is the most prevalent parasitic infection that has affected human health over the millennium. Malaria is threatening the lives and affecting the development of over 2.2 billion people in over 100 countries. Presently due to absence of vaccine, chemotherapy is most suitable but due to wide spread drug resistance against commonly used anti-malarial there is an urgent need of new control strategies. For this role of NO in pathogenesis of malaria present study was carried out to measure the baseline or malaria induced NO, nitric oxide products and NOS activity in P. berghei. Since, in vitro cultivation of the blood stage of human parasite P. falciparum is associated with many problems, P. berghei, a murine rodent parasite was used as a practical model. In the present investigation nitric oxide, total nitrite and nitric oxide synthase activity was studied in normal and P. berghei infected tissues at different parasitaemia. P. berghei infected tissue except brain showed the decline in nitric oxide level at maximum parasitaemia. Along with this, in vivo study exhibited partial protection against P. berghei infection suggesting role of NOS in malaria control.

Role of NOS and Inflammatory Markers in the Early Restenosis After the Application of Femoral Arterial Stent.

The objective of this research was to investigate the role of inflammatory markers, including the interleukin-6 (IL-6), matrix metalloprotease 9 (MMP-9), tumor necrotic factor α (TNF-α), endothelin-1 (ET-1) and nitric oxide synthase (NOS) in the early restenosis after the application of femoral arterial stent. According to this, serum samples were collected from the patients who accepted the implantation of arterial stents due to the atherosclerotic occlusive disease in the lower extremities at the following timepoints: 24 h before implantation, 24 h, 1 month, 3 months and 6 months after implantation. With the samples, we detected the levels of IL-6, TNF-α and MMP-9 by using the enzyme-linked immunosorbent assay (ELISA) in serum, levels of ET-1 in plasma by using the non-balanced method of radioimmunity assay and the activity of NOS by using the chemical analysis. Results showed that during the 6-month follow-up, 15 patients (15.31%) reported restenosis; at postoperative 24 h, the level of IL-6 in the restenosis group was much lower than that of the non-restenosis group (P < 0.05), while the level of MMP-9 was higher than that of the non-restenosis group (P < 0.01); besides, at postoperative 24 h, 1, 3, and 6 months after the operation, the average level of ET-1 in the restenosis group was higher than that in the non-restenosis group (P < 0.05 or 0.01). In the restenosis group, the level of NOS in the serum of patients after the implantation of the stent decreased evidently, which was rescued by the treatment of atorvastatin in a dose-dependent manner (P < 0.05). In conclusion, at postoperative 24 h, the levels of IL-6 and MMP-9 increased, while the level of NOS decreased, and the level of ET-1 in the plasma of restenosis patients keeps higher than the baseline.

Iterative analysis of metabolic modulation in the cyanobacterium Aphanizomenon flos-aquae 2012 KM1/D3 upon nitric oxide synthase derived NO induction

Nitric oxide synthase (NOS) in mammals is recognized for its essentialities in several metabolism including blood vascular relaxation and nerves transmission etc. yet their functionalities in prokaryotes are largely unknown. Our study aimed to evaluate the putative role of nitric oxide synthase (NOS) derived nitric oxide (NO) during oxidative burst in the cyanobacterium, Aphanizomenon flos-aquae 2012/KM1/D3. Here, the accumulation of NO was dramatically reduced upon NOS inhibitor L-NG-Nitro arginine methyl ester (L-NAME) supplementation, exhibiting significant NO synthesis by NOS, whereas addition of L-arginine increase NOS derived NO in a dose dependent manner. Moreover, the reduction in the growth and metabolic activities of the cyanobacterium were evident upon L-NAME treatment that possibly pertained to decline in photopigments, PSII efficiency, loss in membrane integrity and DNA damage due to oxidative burst which culminated into cell death. Besides, the increment in carbohydrates and lipid content ensued with a decrease in protein content, indicating gluconeogenesis. Additionally, NOS inhibition disrupted the fatty acid and hydrocarbon profile, suggesting diminished membrane fluidity and cell integrity. However, higher content of flavonoids, phenolics, thiols and proline in L-NAME treated cells was also observed. Furthermore, L-arginine supplementation enhanced pigment content, photosynthetic efficiency, and reduced oxidative stress, thereby enhancing cyanobacterial growth. Further, L-arginine supplementation maintained Asc/DHAsc and GSH/GSSG ratio, conferred redox homeostasis. These results suggest that the NOS activity plays a critical role in protecting cyanobacteria from oxidative burst, maintaining their physiological balance.

The role of nitric oxide synthase and cystatin C in the mechanisms of antimicrobial protection in children with urinary tract infections considering the etiological factor

The aim of the study was to investigate the main etiological factors of urinary tract infections in children, the role of nitric oxide synthase and cystatin C in the mechanisms of antimicrobial protection in children with acute and chronic urinary tract infections. Materials and methods. The study groups consisted of 84 children (mean age – 10.0 ± 1.3 years). The main group was divided into subgroups: the first subgroup – 17 children with acute pyelonephritis, the second subgroup – 21 patients with chronic pyelonephritis, the third subgroup – 16 patients with acute cystitis, the fourth subgroup – 10 patients with unspecified urinary tract infections. The control group consisted of 20 relatively healthy children. The levels of inducible NO-synthase (NOS2) and cystatin C were measured by enzyme-linked immunosorbent assay. The etiological pathogen was identified in the urine of 200 patients with urinary tract infections. Results. Escherichia coli was identified as the dominant pathogen in 46.7 % of cystitis patients and in 66.6 % of chronic pyelonephritis patients. The next most frequently detected etiological agent in children with acute (27.3 % of cases) and chronic (25.6 %) pyelonephritis and unspecified urinary tract infection (32.2 %) was Enterococcus faecium. Proteus mirabilis was found in 26.6 % of patients with cystitis. The level of NOS2 in all the studied subgroups was significantly higher than that in the control group (P &lt; 0.01). A statistically significant increase in the level of cystatin C in the main group (P &lt; 0.05) was determined. The cystatin C-to-NOS2 ratios in the studied subgroups were 1.5–2.0 times lower than those in the control group (P &lt; 0.05). Conclusions. The change in the spectrum of pathogens has been determined, which was a premise of the need for constant bacteriological monitoring. The development of the primary inflammatory process in the urinary tract occurred amidst a certain dysfunction of the immune system, which was manifested in an insufficient quantitative response of cystatin C, as well as high serum levels of inducible NO-synthase in the patients.

Role of Nitric Oxide Synthase in the Infarct-Limiting Effect of Normobaric Hypoxia

Role of Nitric Oxide Synthase in the Infarct-Limiting Effect of Normobaric Hypoxia

The modulation of neuroinflammation by inducible nitric oxide synthase.

The accumulation and propagation of misfolded proteins in the brain is a pathological hallmark shared by many neurodegenerative diseases, such as the depositions of β-amyloid and hyperphosphorylated tau proteins in Alzheimer's disease. Initial evidence shows the role of nitric oxide synthases in the development of neurodegenerative diseases. A recent, in an exciting paper (Bourgognon et al. in Proc Natl Acad Sci USA 118, 1-11, 2021. 10.1073/pnas.2009579118) it was shown that the inducible nitric oxide synthase plays an important role in promoting oxidative and nitrergic stress leading to neuroinflammation and consequently neuronal function impairments and decline in synaptic strength in mouse prion disease. In this context, we reviewed the possible mechanisms of nitric oxide synthase in the generation of neurodegenerative diseases.

Intense orthodontic force induces the three dental pulp nitric oxide synthase isoforms and leads to orofacial discomfort in rats.

The objective of this study was to evaluate the role of nitric oxide synthase (NOS) isoforms influence during tooth movement with different forces. 100 male Wistar rats (n=10/group) were divided into a Sham group (animals not submitted to device installation nor Induced Toot Movement [ITM]), Negative Control Group (NCG) (animals submitted to device installation but not to ITM) and three experimental groups (F1, F2 and F3) (submitted to ITM with forces of 25, 50 and 100gF respectively). A daily count of biting and scratching on the vibrissae and the Grimace scale were applied. After 4 (D4) and 11 (D11) days, the molar diastema was measured, and the animals were euthanized for histological (vascular parameters) and immunohistochemistry (iNOS, eNOS and nNOS) in the dental pulp. On D4, there was significant movement in the F3 group (P=.001) and on D11 in F1, F2 and F3 (P<.001). The number of bites (P<.001) and scratching (P=.006) was higher in F2-F3, and F3 had higher Grimace scores (P<.001) and weight loss (P<.001). At D4, there was an increase in pulp ectasia in F2-F3 (P=.021) and a reduction in the number of vessels in F3 (P=.005). In D4 and D11, there was a significant increase in immunostaining for iNOS and eNOS in F1 (P=.025 and P<.001 respectively) and F2 (P=.007 and P<.001 respectively). At D4, F2 and F3 showed higher immunostaining for nNOS (P=.027). Thus, IDM induced inflammatory changes in the dental pulp reflecting in force-dependent pain/suffering signs.

How do we kNOw the individual contribution of eNOS and nNOS for cerebral blood flow regulation?

How do we kNOw the individual contribution of eNOS and nNOS for cerebral blood flow regulation?

Effects of Remote Ischaemic Preconditioning on the Internal Thoracic Artery Nitric Oxide Synthase Isoforms in Patients Undergoing Coronary Artery Bypass Grafting.

Remote ischaemic preconditioning (RIPC) is a medical procedure that consists of repeated brief periods of transient ischaemia and reperfusion of distant organs (limbs) with the ability to provide internal organ protection from ischaemia. Even though RIPC has been successfully applied in patients with myocardial infarction during coronary revascularization (surgery/percutaneous angioplasty), the underlying molecular mechanisms are yet to be clarified. Thus, our study aimed to determine the role of nitric oxide synthase (NOS) isoforms in RIPC-induced protection (3 × 5 min of forearm ischaemia with 5 min of reperfusion) of arterial graft in patients undergoing urgent coronary artery bypass grafting (CABG). We examined RIPC effects on specific expression and immunolocalization of three NOS isoforms — endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) in patients’ internal thoracic artery (ITA) used as a graft. We found that the application of RIPC protocol leads to an increased protein expression of eNOS, which was further confirmed with strong eNOS immunopositivity, especially in the endothelium and smooth muscle cells of ITA. The same analysis of two other NOS isoforms, iNOS and nNOS, showed no significant differences between patients undergoing CABG with or without RIPC. Our results demonstrate RIPC-induced upregulation of eNOS in human ITA, pointing to its significance in achieving protective phenotype on a systemic level with important implications for graft patency.

The Critical Role of Tetrahydrobiopterin (BH4) Metabolism in Modulating Radiosensitivity: BH4/NOS Axis as an Angel or a Devil.

Ionizing radiation and radioactive materials have been widely used in industry, medicine, science and military. The efficacy of radiotherapy and adverse effects of normal tissues are closed related to cellular radiosensitivity. Molecular mechanisms underlying radiosensitivity are of significance to tumor cell radiosensitization as well as normal tissue radioprotection. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthases (NOS) and aromatic amino acid hydroxylases, and its biosynthesis involves de novo biosynthesis and a pterin salvage pathway. In this review we overview the role of BH4 metabolism in modulating radiosensitivity. BH4 homeostasis determines the role of NOS, affecting the production of nitric oxide (NO) and oxygen free radicals. Under conditions of oxidative stress, such as UV-radiation and ionizing radiation, BH4 availability is diminished due to its oxidation, which subsequently leads to NOS uncoupling and generation of highly oxidative free radicals. On the other hand, BH4/NOS axis facilitates vascular normalization, a process by which antiangiogenic therapy corrects structural and functional flaws of tumor blood vessels, which enhances radiotherapy efficacy. Therefore, BH4/NOS axis may serve as an angel or a devil in regulating cellular radiosensitivity. Finally, we will address future perspectives, not only from the standpoint of perceived advances in treatment, but also from the potential mechanisms. These advances have demonstrated that it is possible to modulate cellular radiosensitivity through BH4 metabolism.

Role of nitric oxide and endothelial NO synthase in carcinogenesis

Introduction. Nitric oxide (NO) produced by NO synthases (NOS) is involved in the regulation of vital physiological functions. At the same time, NO and NOS are involved in events associated with the tumor process: mutagenesis, proliferation, apoptosis, angiogenesis, etc., exerting a multidirectional effect on the tumor.Objectives – analyze and summarize literature data concerning the role of NO and endothelial NOS (eNOS) in the initiation and progression of tumors, as well as in the inhibition of tumor growth.Materials and methods. In preparing the review, publications of information bases of biomedical literature were used: SciVerse Scopus (538), PubMed (1327), Web of Science (905), Russian Science Citation Index (125).Results. The molecular mechanisms of the action of NO and its derivatives on the initiation and progression of carcinogenesis have been explored. Numerous factors and conditions regulating the activity of eNOS in health and tumor growth have been analyzed. The molecular signaling pathways through which the pro-tumor effects of NO and eNOS, stimulating angiogenesis, lymphangiogenesis, are realized, including through the mobilization of stem cells, are considered.Conclusion. Nitric oxide produced by activated eNOS promotes tumor progression by increasing the proliferation of tumor cells, enhancing the action of pro-angiogenic factors, stimulating angiogenesis, lymphangiogenesis, and metastasis. Selective inhibition of increased eNOS activity may be a promising therapeutic approach aimed at reducing metastasis and tumor growth.

Prospects for the Personalized Multimodal Therapy Approach to Pain Management via Action on NO and NOS.

Chronic pain syndromes are an important medical problem generated by various molecular, genetic, and pathophysiologic mechanisms. Back pain, neuropathic pain, and posttraumatic pain are the most important pathological processes associated with chronic pain in adults. Standard approaches to the treatment of them do not solve the problem of pain chronicity. This is the reason for the search for new personalized strategies for the prevention and treatment of chronic pain. The nitric oxide (NO) system can play one of the key roles in the development of peripheral pain and its chronicity. The purpose of the study is to review publications devoted to changes in the NO system in patients with peripheral chronical pain syndromes. We have carried out a search for the articles published in e-Library, PubMed, Oxford Press, Clinical Case, Springer, Elsevier, and Google Scholar databases. The search was carried out using keywords and their combinations. The role of NO and NO synthases (NOS) isoforms in peripheral pain development and chronicity was demonstrated primarily from animal models to humans. The most studied is the neuronal NOS (nNOS). The role of inducible NOS (iNOS) and endothelial NOS (eNOS) is still under investigation. Associative genetic studies have shown that single nucleotide variants (SNVs) of NOS1, NOS2, and NOS3 genes encoding nNOS, iNOS, and eNOS may be associated with acute and chronic peripheral pain. Prospects for the use of NOS inhibitors to modulate the effect of drugs used to treat peripheral pain syndrome are discussed. Associative genetic studies of SNVs NOS1, NOS2, and NOS3 genes are important for understanding genetic predictors of peripheral pain chronicity and development of new personalized pharmacotherapy strategies.

Effects of Lithium Chloride and Nitric Oxide Inhibitor on Orthodontic Tooth Movement in the Rat

Orthodontic tooth movement in a rodent model is reduced by lithium chloride (LiCl), a mood-stabilizing agent with antithyroid effects. Considering the established inhibitory effect of N(omega)-nitro-L-arginine methyl ester (L-NAME) on orthodontic tooth movement and the possible role of nitric oxide synthase in LiCl mechanism of action, the question arises if these two mechanisms are synergistic. To answer this question, 70 male Sprague Dawley rats were randomly divided into seven groups: untreated group without any interventions (i), and the orthodontic tooth movement groups receiving daily saline injection (ii), 300 (iii), and 600 mg/kg (iv) of LiCl per os, 10 mg/kg of L-NAME (v) and the combinations of 300 (vi) and 600 mg/kg LiCl (vii) with L-NAME. The first molar was moved towards the incisor with 60 g of mesial tipping force applied by an activated fixed coil spring for two weeks. The resulted distance between the first and the second molar was measured using a feeler gauge. The serum parameters were also determined. We report here that both concentrations of LiCl significantly decreased tooth movement. Even though L-NAME was capable of reducing orthodontic tooth movement, no synergistic effects with LiCl were observed. Moreover, L-NAME had no impact on the robust and significant increase of thyroid-stimulating hormone (TSH) and decrease of triiodothyronine (T3) and thyroxine (T4) in the LiCl treated rats. These findings suggest LiCl significantly decreases the orthodontic tooth movement in rats; however, this ability seems not to be principally mediated through nitric oxide synthase.