Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) plays a role in the pathophysiology of septic shock. The depression of cardiac contractility in such situations is mediated by proinflammatory cytokines, including interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha). The effects of two NOS inhibitors with different isoform selectivity were compared in isolated working rat hearts. The depression of contractility by IL-1beta and TNF-alpha was prevented by administration of a nonselective nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) or an inhibitor of inducible nitric oxide synthase, L-canavanine. In contrast, when L-NAME was administered in the absence of IL-1beta and TNF-alpha, it depressed contractility over the 2h perfusion period by significantly reducing coronary flow. These results support current thinking that the depression of myocardial function by IL-1beta and TNF-alpha is mediated, at least in part, by an intracardiac increase in inducible nitric oxide synthase, and that in contrast to L-NAME, the decline in coronary conductance seen in cytokine-treated is not prevented by L-canavanine hearts. L-canavanine shows selective inhibition of inducible nitric oxide synthase unlike the vasopressor action of L-NAME in cytokine-treated hearts.
 ...
PMID:Effect of L-canavanine, an Inhibitor of inducible nitric oxide synthase, on myocardial dysfunction during septic shock. 1184 4

In formalin pain model, the effect of propofol on Fos expression in the spinal cord was examined by means of c -fos oncogene immunohistochemistry and NADPH-d histochemistry. Fos-like immunoreactive (FLI) neurons were mainly found in the ipsilateral dorsal horn after injection of formalin, some of which were FLI/NOS double-labeled neurons. Most of the FLI or FLI/NOS double-labeled neurons were observed in the medial part of lamina and the outer lamina . Before or after injection of formain, i.p. injection of propofol significantly decreased the number of FLI and FLI/NOS double-labeled neurons in all laminae (P<0.05 or P<0.01). By single i.p. injection of propofol or normal saline, few FLI neurons were found in the spinal cord. The results suggest that the antinociceptive function of propofol is possibly involved in the depression of the NOS neurons in the spinal cord.
 ...
PMID:[Propofol depresses c -fos expression of NOS neurons in the spinal cord of rats with inflammatory pain]. 1193 Feb 43

Induction of inducible nitric oxide synthase (iNOS) expression is likely important in the pathogenesis of sepsis. However, the sepsis-mediated induction of iNOS is associated with a decrease in constitutive NO synthase (cNOS) activity (which is reversible following acute but not chronic sepsis). Whether this decreased cNOS activity is due to functional inhibition of cNOS by the high concentrations of NO produced by iNOS or to downregulation of cNOS expression is not clear. Thus, we tested the hypothesis that sepsis produces a reversible iNOS/NO-mediated inhibition of cNOS activity. Using a rat cecal ligation and perforation (CLP) model of sepsis, we examined the time course of the changes in iNOS and cNOS activities in lung and thoracic aortae. Reversibility of the sepsis-induced decrease in cNOS activity was assessed in vitro by enzyme activity determination following selective inhibition of iNOS. iNOS and endothelial cNOS protein concentrations were determined by Western blotting. In all septic tissues, cNOS activity was depressed at 6, 12, 24, and 48 hours post-CLP. Inhibition of the increased iNOS activity with aminoguanidine, in vitro, partially restored cNOS activity following acute (6-12 hours) but not chronic sepsis (24-48 hours post-CLP). Consistent with the irreversible depression of cNOS activities in tissues following chronic sepsis, endothelial NOS protein concentrations declined progressively during the time course of sepsis. We have demonstrated the restoration of cNOS activity following in vitro inhibition of iNOS, early, and the downregulation of endothelial NOS, later, in a rat CLP model of sepsis. This suggests that further study is required before iNOS-selective inhibition can be considered in human sepsis.
 ...
PMID:Functional inhibition of constitutive nitric oxide synthase in a rat model of sepsis. 1201 7

Altered nitric oxide (NO) bioavailability has been ascribed an important role in the pathophysiology of congestive heart failure (CHF). In the peripheral vasculature, we recently demonstrated a depression of L-arginine transport in association with pharmacological evidence of reduced endothelial function. In contrast, increased myocardial NO generation has been proposed to account for a component of the reduced myocardial contractility in CHF, although this remains controversial. We determined the whole body clearance rate and cardiac fractional extraction of L-arginine during a steady-state intravenous infusion of [3H]L-arginine (300 nCi/min) in 9 healthy control subjects and 7 patients with moderate to severe CHF. In patients with CHF, there was a 30% reduction in the transcardiac extraction of [3H]L-arginine compared with controls (P<0.05), which was accompanied by a trend toward reduced [3H]L-citrulline release (P=0.06). In conjunction, the systemic clearance rate of [3H]L-arginine was significantly lower in patients with CHF (778+/-148 versus 1278+/-144 mL/min, P<0.05). In association with these biochemical indices, we observed a 38% reduction (P<0.05) in the mRNA expression of the cationic amino acid transporter CAT-1 in ventricular myocardial samples from patients with CHF compared with healthy unused donor myocardium, whereas myocardial NOS enzymatic activity and NOS protein were unchanged. These data indicate the presence of a significant reduction in the myocardial uptake of L-arginine in patients with CHF. Furthermore, this abnormality seems to be part of a systemic downregulation of L-arginine transport.
 ...
PMID:Reduced myocardial and systemic L-arginine uptake in heart failure. 1248 Aug 22

Nitric oxide (NO) is a retrograde messenger involved in the processes of learning and memory. The role of the endothelial isoform of nitric oxide synthase (eNOS) in striatal synaptic plasticity was investigated in eNOS-deficient (eNOS(-/-)) and wild type (WT) mice. Tetanic stimulation of cortical afferents in WT mice evoked either long-term potentiation (LTP), or long-term depression (LTD) of cortico-striatal transmission. Both these plasticity related phenomena were NMDA-receptor-dependent; LTD was blocked by sulpiride, a dopamine D2-receptor antagonist. LTP occurrence in slices from eNOS(-/-) mice was significantly reduced when compared with WT mice. The NOS inhibitor NL-ARG reduced the occurrence of LTP and increased the occurrence of LTD in WT mice, resembling the balance of LTP/LTD in eNOS(-/-) mice. Impairment of NO-synthesis thus shifts striatal plasticity towards LTD. This indicates a possible involvement of eNOS from endothelia in neuronal modulation.
 ...
PMID:Cortico-striatal synaptic plasticity in endothelial nitric oxide synthase deficient mice. 1257 25

Several studies have shown a relationship between high testosterone and violent aggressive behaviour. The general aim of this study was to gain knowledge of the importance of testosterone in suicide attempters. Testosterone in cerebrospinal fluid (CSF) was analysed in men with a recent suicide attempt, diagnostically subdivided into groups according to DSM-III-R axis I and II diagnosis and mode of suicidal behaviour. In general, our patients had lower CSF testosterone levels than aggressive violent patients in other studies. Patients with depression NOS or dysthymia showed higher CSF testosterone levels than the rest. Significant positive correlation between testosterone and irritability or a negative correlation with social desirability was found in diagnostic subgroup of patients, specifically axis II, cluster B personality disorders. The results suggest that suicide attempts may be mediated by different biological variables than aggression.
 ...
PMID:CSF testosterone in 43 male suicide attempters. 1265 Sep 54

Cortical spreading depression (CSD) is a transient disruption of local ionic homeostasis that may promote migraine attacks and the progression of stroke lesions. We reported previously that the local inhibition of nitric oxide (NO) synthesis with Nomega-nitro-L-arginine methyl ester (L-NAME) delayed markedly the initiation of the recovery of ionic homeostasis from CSD. Here we describe a novel method for selective, controlled generation of exogenous NO in a functioning brain region. It is based on microdialysis perfusion of the NO donor, 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO). As DEA/NO does not generate NO at alkaline pH, and as the brain has a strong acid-base buffering capacity, DEA/NO was perfused in a medium adjusted at alkaline (but unbuffered) pH. Without DEA/NO, such a microdialysis perfusion medium did not alter CSD. DEA/NO (1, 10 and 100 microM) had little effect on CSD by itself, but it reversed in a concentration-dependent manner the effects of NOS inhibition by 1 mM L-NAME. These data demonstrate that increased formation of endogenous NO associated with CSD is critical for subsequent, rapid recovery of cellular ionic homeostasis. In this case, the molecular targets for NO may be located either on brain cells to suppress mechanisms directly involved in CSD genesis, or on local blood vessels to couple flow to the increased energy demand associated with CSD.
 ...
PMID:Effects of the nitric oxide donor, DEA/NO on cortical spreading depression. 1272 26

Nitric oxide (NO) from endothelial or neuronal NO synthases (eNOS or nNOS) may contribute both to the cerebrovascular responses to oxygen and potentially to the peroxynitrite-mediated toxic effects of hyperbaric oxygen (HBO(2)) on the central nervous system (CNS O(2) toxicity). In mice lacking eNOS or nNOS (-/-), regional cerebral blood flow (rCBF) and 3-nitrotyrosine (3-NT), a biochemical marker for peroxynitrite (ONOO(-)) formation, were measured in the brain during HBO(2) exposure. These variables were then correlated with EEG spiking activity related to CNS O(2) toxicity. In wild-type (WT) mice, HBO(2) exposure transiently reduced rCBF, but by 60 min rCBF was restored to baseline levels and above, followed by EEG spikes. Mice lacking nNOS also showed initial depression of rCBF followed by hyperemia but the delay in the onset of EEG discharges was greater. In contrast, in eNOS-deficient mice rCBF did not decrease and hyperemia was less pronounced during HBO(2). EEG spike latency was longer in eNOS(-/-) compared to WT or nNOS(-/-) mice. 3-NT gradually increased in all strains during HBO(2) but accumulation was slower in nNOS(-/-) mice, consistent with less ONOO(-) production. These results indicate that NOS-deficient mice have different cerebrovascular responses and tolerance to HBO(2) depending on which enzyme isoform is affected. The data suggest a key role for eNOS-dependent NO production in cerebral vasoconstriction and in the development of hyperoxic hyperemia preceding O(2) seizures, whereas neuronal NO may mediate toxic effects of HBO(2) mainly by its reaction with superoxide to generate the stronger oxidant, peroxynitrite.
 ...
PMID:Oxygen seizure latency and peroxynitrite formation in mice lacking neuronal or endothelial nitric oxide synthases. 1278 20

The bioassay of nithiazide for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. Nithiazide was administered in the diet, at either of two concentrations, to groups of 50 male and 50 female animals of each species. The high and low concentrations of nithiazide utilized were, respectively, 1,250 and 625 ppm for rats and 5,000 and 2,500 ppm for mice. Dosed rats received feed containing nithiazide for 38 weeks, and as a result of a shortage of nithiazide, the animals were not fed the dosed feed for the next 9 weeks. The dosed feed diet was then resumed and continued for 56 weeks, after which time a 1-week observation period followed. Dosed mice received feed containing nithiazide for 61 weeks and, due to a shortage of nithiazide, the animals were not fed dosed feed for the next 9 weeks. The dosed feed diet was then resumed and continued for 33 weeks, followed by a 1-week observation period. Twenty animals of each sex and species were placed on test as controls. In both species, adequate numbers of animals survived sufficiently long to be at risk from late-developing tumors. There was no significant positive association between dosage and mortality for either rats or mice. Compound-related mean body weight depression occurred in both sexes of each species. Statistically significant incidences of hepatocellular adenomas and carcinomas were found in high dose male mice but not in female mice. Although the increased incidences of these tumors in dosed female mice were not statistically significant, the evidence presented was strongly suggestive of carcinogenicity to the liver in female B6C3F1 mice. Statistically significant increased incidences of a combination of mammary and skin fibroadenomas and cystadenomas NOS were found in the high dose female rats. No unusual tumors were observed in either species. Under the conditions of this bioassay, nithiazide was carcinogenic in male and probably female B6C3F1 mice, causing a combination of hepatocellular carcinomas and hepatocellular adenomas. Nithiazide was also carcinogenic in female Fischer 344 rats, causing an increase in the incidence of mammary neoplasms. The compound was not carcinogenic in male Fischer 344 rats.
 ...
PMID:Bioassay of nithiazide for possible carcinogenicity. 1279 16

Many individuals with cardiovascular diseases undergo periodic exercise conditioning with or without medication. Therefore, the purpose of this study was to examine the effect of exercise training on BP and HR under the condition of NOS inhibition and to clarify the mechanism of the effect in regard to oxidative stress, antioxidant enzyme activity, and NO production in the plasma of the rat. Fisher 344 rats were divided into four groups: (1) sedentary control, (2) exercise training for 8 weeks, (3) nitro-L-arginine methyl ester (L-NAME) (10mg/kg, s.c. for 8 weeks) and (4) ET + L-NAME. Blood pressure (BP) and heart rate (HR) were monitored weekly for 8 weeks. The animals were sacrificed 24h after last treatments, plasma isolated and analyzed. The results show that exercise conditioning resulted in enhanced NO production (120% of control), GSH levels (110% of control), GSH/GSSG ratio (124% of control) and the up-regulation of catalase (CAT) (225% of control), glutathione peroxidase (GSH-Px) (161% of control), glutathione reductase (GR) (142% of control) and glutathione-S-transferase (GST) (189% of control) and depression of malondialdehyde (MDA) (90% of control) and lactate (75% of control) in plasma of the rat. These biochemical changes were accompanied by no significant change in BP but slight increase in HR. Chronic L-NAME administration resulted in depression of NO (84% of control), GSH (90% of control), GSH/GSSG ratio (76% of control), the down-regulation of superoxide dismutase (SOD) (67% of control), GST (74% of control), and GR (90% of control). Plasma CAT and GSH-Px activities, MDA and lactate levels were significantly increased in L-NAME treated rats. The biochemical changes were accompanied by increase in blood pressure and heart rate. Interaction of exercise training and chronic NOS inhibitor treatment resulted in normalization of plasma NO levels, GSH/GSSG ratio, SOD and GST activities, and the up-regulation of, CAT, GSH-Px, and GR activities. The interaction resulted in depletion of plasma MDA levels compared to L-NAME treated group. The biochemical changes were accompanied by decrease in BP and HR compared to L-NAME treated group. The data suggest that the exercise training attenuated the oxidative injury caused by NOS inhibitor by increasing the plasma NO levels, GSH/GSSG ratio and up-regulating the antioxidant enzyme and lowering the BP and HR in the rat.
 ...
PMID:Interaction of exercise training and chronic NOS inhibition on blood pressure, heart rate, NO and antioxidants in plasma of rats. 1464 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>