Brain hypoxia-ischemia has been considered as critical factors in many human central nervous system diseases, including stroke and neonatal hypoxic-ischemic encephalopathy. In brain hypoxia-ischemia processes, inducible NO synthase (iNOS) is induced to produce excessive nitric oxide (NO) which leads to cascade reactions of inflammation and neuronal death, deteriorating primary brain injury. Inhibiting iNOS expression has opened new perspectives in the treatment of brain hypoxia-ischemia because iNOS inhibitor has been shown as a potent therapeutic agent. This reviews focus on recent research achievements regarding the relationship between iNOS and ischemic-hypoxic brain damage and the perspective of using iNOS inhibitors as therapeutic strategies for brain ischemic-hypoxic brain damage.
Animals ; Humans ; Hypoxia-Ischemia, Brain ; drug therapy ; metabolism ; Nitric Oxide Synthase Type II ; antagonists & inhibitors ; genetics ; physiology

Animals ; Brain ; metabolism ; Brain Injuries ; metabolism ; Enzyme Inhibitors ; pharmacology ; Guanidines ; pharmacology ; Neuroprotective Agents ; pharmacology ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type II ; antagonists & inhibitors ; Rats

OBJECTIVETo explore the effects of intrathecal injection of neuronal nitric oxide synthase (nNOS) inhibitors 7-Nitroindazole (7-Ni) and inducible nitric oxide synthase(iNOS) inhibitors aminoguanidine (AG) on the behavioral changes of morphine-induced dependent and withdrawal rats; the expression of Fos, nNOS and iNOS in spinal cord.

METHODSTo set up morphine dependence model, rats were subcutaneously injected with morphine (twice a day, for 5 d). The dose of morphine was 10 mg/kg in the first day and was increased by 10 mg/ kg every day. On day 6, 4 h after the injection of morphine (50 mg/kg), morphine withdrawal syndrome was precipitated by an injection of naloxone (4 mg/kg ip). 7-Ni, an nNOS inhibitor or iNOS inhibitors AG were intrathecally injected 30 min before the administration of naloxone respectively. The scores of morphine withdrawal symptom and morphine withdrawal-induced allodynia were observed. One hour after naloxone-precipitated withdrawal, Fos protein expression was assessed by immunohistochemical analysis and Western blot was used to detect the expression of nNOS and iNOS in the rat spinal cord.

RESULTSIntrathecal administration of nNOS inhibitor 7-Ni and iNOS inhibitors AG decreased the scores of morphine withdrawal, attenuated morphine withdrawal-induced allodynia and also inhibited the increase of Fos protein expression in the spinal cord of morphine withdrawal rats. nNOS and iNOS positive neurons in dorsal horn in nNOS group and iNOS group were significantly lower than that in withdrawal group. Compared with withdrawal group, level of nNOS and iNOS protein in spinal cord in nNOS group and iNOS group were significantly lower.

CONCLUSIONIt is suggested that nNOS and iNOS in the spinal cord may contribute to naloxone-precipitated withdrawal in rats and may play different roles in the above-mentioned effect.

Animals ; Guanidines ; pharmacology ; Indazoles ; pharmacology ; Male ; Morphine Dependence ; metabolism ; Naloxone ; pharmacology ; Nitric Oxide Synthase Type I ; antagonists & inhibitors ; metabolism ; Nitric Oxide Synthase Type II ; antagonists & inhibitors ; metabolism ; Rats ; Rats, Sprague-Dawley ; Spinal Cord ; drug effects ; metabolism ; Substance Withdrawal Syndrome ; metabolism

AIMTo investigate the causative role of nitric oxide synthase (NOS) and nitric oxide (NO) in neurotoxicity of beta-amyloid (Abeta) and the pathogenesis of Alzheimer's disease (AD).

METHODSUsing behavioral and neuropathological methods, we observed the effects of Abeta(1-40) injection into hippocampi on rats learning and memory in Y maze and on the neuropathology in hippocampi. The intervention by intraperitoneal administration of aminoguanidine (AG), a selective inducible NOS (iNOS) inhibitor, and 7-nitroindazole (7-NI), a selective neuronal NOS (nNOS) inhibitor, in the neurotoxicity of Abeta(1-40) was studied then.

RESULTSThe capability of acquisition and retrieval in Y maze and local neurons in hippocampus of the rats were impaired significantly after Abeta(1-40) injection. Intraperitoneal administration of AG, but not 7-NI, could prevent the damages caused by Abeta(1-40) injection above-mentioned.

CONCLUSIONiNOS/NO participates in the mechanisms of Abeta-induced neurotoxicity and may play an important role in the pathogenesis of AD.

Alzheimer Disease ; metabolism ; pathology ; Amyloid beta-Peptides ; metabolism ; toxicity ; Animals ; Guanidines ; pharmacology ; Indazoles ; pharmacology ; Male ; Maze Learning ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase ; antagonists & inhibitors ; Nitric Oxide Synthase Type II ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo study the effects of inducible NOS inhibitor aminoguanidine on the expression of NOS in facial nerve and surrounding tissue of traumatic facial paralysis rats.

METHODSA small dose of aminoguanidine were intraperitoneally injected into rats before and after facial paralysis. The facial nerve and surrounding tissues were cut at different time point. Immunohistochemical ABC method was used to study the changes of NOS expression in facial nerve and surrounding tissues.

RESULTSThe inducible NOS immunoreactivity was obvious inhibited in the facial nerve and surrounding tissues in aminoguanidine group.

CONCLUSIONAminoguanidine chronic treatment can obvious inhibit the inducible NOS expression in the facial nerve and surrounding tissues. Aminoguanidine can improve the regeneration of facial nerve and the recovery of traumatic tissues.

Animals ; Facial Nerve ; enzymology ; Facial Nerve Injuries ; enzymology ; Facial Paralysis ; enzymology ; Guanidines ; pharmacology ; Male ; Muscles ; enzymology ; Nerve Regeneration ; Nitric Oxide Synthase ; antagonists & inhibitors ; metabolism ; Nitric Oxide Synthase Type II ; Random Allocation ; Rats ; Rats, Sprague-Dawley

Clinical epidemiologic data and animal experimental studies regard estrogen as being protective against the development of cardiovascular diseases. The mechanisms by which estrogen affects the development of vascular diseases are not clear. Recent studies demonstrated that the cardiovascular protective effects of estrogen are closely related to nitric oxide (NO) pathway. Our previous study proved that estrogen inhibited the proliferation and oncogene expression of vascular smooth muscle cells (VSMCs) induced by endothlin 1 (ET-1) and serum,this effect was mediated by NO release. In the present study, we investigated the role of inducible nitric oxide synthase (iNOS) in the VSMCs cycle arrest induced by 17 beta-estradiol (E(2)). The effects of E(2) on iNOS activity and protein expression in cultured rat VSMCs and the influence of NOS inhibitor N(G)-nitro-L-arginine methylester (L-NAME) on the inhibitory effect of E(2) on cell cycle were investigated. NOS assay kit was used to measure the activity of iNOS and protein expression of iNOS was determined by Western-blot. Cell cycle analysis was accessed by flow cytometry. The results obtained showed that E(2) increased iNOS activity of VSMCs but not in a dose-dependent manner. E(2) 10 nmol/L increased the iNOS activity of VSMCs distinctly at two time points: 30 min and 12 h. These effects were significantly inhibited by estrogen receptor (ER) antagonist Tamoxifen (0.1 micromol/L) and NOS inhibitor L-NAME (1 micromol/L). E(2) increased iNOS protein expression of VSMCs in a dose-dependent manner. The effect of E(2) on iNOS protein expression of VSMCs started at 3 h, distinctly increased at 12 h and then decreased. Tamoxifen significantly inhibited the E(2)-induced iNOS protein expression of VSMCs. ET-1 increased cell percentage of S phase and G(2)+S/G(1). This effect was inhibited by E(2). L-NAME significantly attenuated the inhibitory effect of E(2) on cell cycle of VSMCs. The results suggest that E(2) induced G(1) arrest of VSMCs, which was associated with an increase in iNOS activity and protein expression of VSMCs. These effects were at least mediated by estrogen receptor partly.
Animals ; Cell Cycle ; drug effects ; Cell Division ; drug effects ; Cells, Cultured ; Endothelin-1 ; metabolism ; Estradiol ; pharmacology ; Estrogen Antagonists ; pharmacology ; Female ; Muscle, Smooth, Vascular ; cytology ; Nitric Oxide Synthase ; metabolism ; physiology ; Nitric Oxide Synthase Type II ; Rats ; Tamoxifen ; pharmacology

AIMTo determine the protective effect and influence on NOS expression of Montelukast sodium--a leukotriene antagonist on myocardial necrosis in rats.

METHODSMyocardial ischemia and necrosis were induced in rats by isoproterenol (2 mg.kg-1, s.c., qd for 2 d). Serum activity of LDH, CK, MDA, NO content in myocardium and scope of myocardial necrosis were measured. nNOS, iNOS and eNOS were investigated by immunohistochemical evaluation.

RESULTSDecreased serum level of LDH, CK, MDA and attenuated myocardial necrosis area were found in rats pretreated with Montelukast sodium 10 and 30 mg.kg-1. Montelukast sodium 30 mg.kg-1 also enhanced NO content in myocardium. Montelukast sodium activated the eNOS expression and reduced the iNOS expression.

CONCLUSIONMontelukast sodium is cardioprotective during myocardial injury in rats by halting the leukotrienes-induced inflammatory response and upregulating the eNOS expression as well as downregulating the iNOS expression. This may represent an approach to the treatment of myocardial ischemia with leukotriene antagonists.

Acetates ; pharmacology ; Animals ; Cardiotonic Agents ; pharmacology ; Female ; Isoproterenol ; Leukotriene Antagonists ; pharmacology ; Male ; Myocardial Ischemia ; chemically induced ; enzymology ; pathology ; Myocardium ; metabolism ; pathology ; Necrosis ; Nitric Oxide Synthase ; metabolism ; Nitric Oxide Synthase Type II ; Nitric Oxide Synthase Type III ; Quinolines ; pharmacology ; Rats ; Rats, Sprague-Dawley

The inducible form of nitric oxide synthase (iNOS) is expressed in hepatic cells in pathological conditions. Its induction is involved in the development of liver fibrosis, and thus iNOS could be a therapeutic target for liver fibrosis. This review summarizes the role of iNOS in liver fibrosis, focusing on 1) iNOS biology, 2) iNOS-expressing liver cells, 3) iNOS-related therapeutic strategies, and 4) future directions.
Endothelial Cells/metabolism ; Hepatic Stellate Cells/metabolism ; Humans ; Kupffer Cells/metabolism ; Liver Cirrhosis/metabolism/*pathology ; Nitric Oxide/*metabolism ; Nitric Oxide Synthase Type II/antagonists & inhibitors/genetics/*metabolism ; Polymorphism, Single Nucleotide ; RNA, Untranslated/metabolism

To explore the effective ingredients and mechanism of Ligusticum wallichii in treating brain ischemia. Four brain ischemia-related target proteins were selected in the joint screening for the 45 component in L. wallichii reported in literatures based on molecular docking by reference to the corresponding drugs in the market. According to the docking results, multiple components in L. wallichii, such as phthalides, were superior to the corresponding drugs in the market, suggesting that they may be the major effective components in L. wallichii for treating brain ischemia. The method can be used to study the material base and molecular mechanism of traditional Chinese medicines.
Brain Ischemia ; drug therapy ; Ligusticum ; chemistry ; Medicine, Chinese Traditional ; Molecular Docking Simulation ; Nitric Oxide Synthase Type II ; antagonists & inhibitors ; Peroxidase ; antagonists & inhibitors ; Phytotherapy ; Tumor Necrosis Factor-alpha ; antagonists & inhibitors

PURPOSE: Oxidative stress during CO2 pneumoperitoneum is reported to be associated with decreased bioactivity of nitric oxide (NO). However, the changes in endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and arginase during CO2 pneumoperitoneum have not been elucidated. MATERIALS AND METHODS: Thirty male Sprague-Dawley rats were randomized into three groups. After anesthesia induction, the abdominal cavities of the rats of groups intra-abdominal pressure (IAP)-10 and IAP-20 were insufflated with CO2 at pressures of 10 mm Hg and 20 mm Hg, respectively, for 2 hours. The rats of group IAP-0 were not insufflated. After deflation, plasma NO was measured, while protein expression levels and activity of eNOS, iNOS, arginase (Arg) I, and Arg II were analyzed with aorta and lung tissue samples. RESULTS: Plasma nitrite concentration and eNOS expression were significantly suppressed in groups IAP-10 and IAP-20 compared to IAP-0. While expression of iNOS and Arg I were comparable between the three groups, Arg II expression was significantly greater in group IAP-20 than in group IAP-0. Activity of eNOS was significantly lower in groups IAP-10 and IAP-20 than in group IAP-0, while iNOS activity was significantly greater in group IAP-20 than in groups IAP-0 and IAP-10. Arginase activity was significantly greater in group IAP-20 than in groups IAP-0 and IAP-10. CONCLUSION: The activity of eNOS decreases during CO2 pneumoperitoneum, while iNOS activity is significantly increased, a change that contributes to increased oxidative stress and inflammation. Moreover, arginase expression and activity is increased during CO2 pneumoperitoneum, which seems to act inversely to the NO system.
Animals ; Aorta/*physiology ; Arginase/*antagonists & inhibitors ; Enzyme Inhibitors/administration & dosage/pharmacology ; Inflammation/etiology/*prevention & control ; Injections, Subcutaneous ; Lung Injury/etiology/prevention & control ; Male ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/*metabolism ; Nitric Oxide Synthase Type III/*metabolism ; Oxidative Stress/*drug effects ; Pneumoperitoneum/*complications/drug therapy ; Rats ; Rats, Sprague-Dawley