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

Nitric oxide (NO) plays a complex role in the pathophysiology of cerebral ischemia. In this study, mutant mice with disrupted type I (neuronal) NO synthase (nNOS) were compared with wild-type littermates after permanent focal ischemia. Cerebral blood flow in the central and peripheral zones of the ischemic distribution were measured with laser doppler flowmetry. Simultaneously, microdialysis electrodes were used to measure extracellular amino acid concentrations and DC potential in these same locations. Blood flow was reduced to <25 and 60% of baseline levels in the central and peripheral zones, respectively; there were no differences in nNOS mutants versus wild-type mice. Within the central ischemic zone, DC potentials rapidly shifted to -20 mV in all mice. In the ischemic periphery, spreading depression (SD)-like waves of depolarization were observed. SD-like events were significantly fewer in the nNOS mutant mice. Concurrent with these hemodynamic and electrophysiological perturbations, extracellular elevations in amino acids occurred after ischemia. There were no detectable differences between wild-type and mutant mice in the ischemic periphery. However, in the central zone of ischemia, elevations in glutamate and GABA were significantly lower in the nNOS mutants. Twenty-four hour infarct volumes in the nNOS mutant mice were significantly smaller than in their wild-type littermates. Overall, the number of SD-like depolarizations and the integrated efflux of glutamate were significantly correlated with infarct size. These results suggest that NO derived from the nNOS isoform contributes to tissue damage after focal ischemia by amplifying excitotoxic amino acid release in the core and deleterious waves of SD-like depolarizations in the periphery.
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PMID:Attenuated neurotransmitter release and spreading depression-like depolarizations after focal ischemia in mutant mice with disrupted type I nitric oxide synthase gene. 980 93

The selective serotonin reuptake inhibitors (SSRIs), citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline, are the result of rational research to find drugs that were as effective as the tricyclic antidepressants but with fewer safety and tolerability problems. The SSRIs selectively and powerfully inhibit serotonin reuptake and result in a potentiation of serotonergic neurotransmission. The property of potent serotonin reuptake appears to give a broad spectrum of therapeutic activity in depression, anxiety, obsessional and impulse control disorders. However, despite the sharing of the same principal mechanism of action, SSRIs are structurally diverse with clear variations in their pharmacodynamic and pharmacokinetic profiles. The potency for serotonin reuptake inhibition varies amongst this group, as does the selectivity for serotonin relative to noradrenaline and dopamine reuptake inhibition. The relative potency of sertraline for dopamine reuptake inhibition differentiates it pharmacologically from other SSRIs. Affinity for neuroreceptors, such as sigma1, muscarinic and 5-HT2c, also differs widely. Furthermore, the inhibition of nitric oxide synthetase by paroxetine, and possibly other SSRIs, may have significant pharmacodynamic effects. Citalopram and fluoxetine are racemic mixtures of different chiral forms that possess varying pharmacokinetic and pharmacological profiles. Fluoxetine has a long acting and pharmacologically active metabolite. There are important clinical differences among the SSRIs in their pharmacokinetic characteristics. These include differences in their half-lives, linear versus non-linear pharmacokinetics, effect of age on their clearance and their potential to inhibit drug metabolising cytochrome P450 (CYP) isoenzymes. These pharmacological and pharmacokinetic differences underly the increasingly apparent important clinical differences amongst the SSRIs.
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PMID:Selective serotonin reuptake inhibitors in affective disorders--I. Basic pharmacology. 980 77

Nitric oxide (NO) is an excitatory neurotransmitter in the hypoxic ventilatory response (HVR). Furthermore, neuronal NO synthase (nNOS) activity in the developing rat correlates with the magnitude of late hypoxic ventilatory depression. To test the hypothesis that repeated short exposures to hypoxia may modify late HVR characteristics in young rats, we conducted 30-min hypoxic challenges in 2- to 3-day-old rat pups, before (Pre) and 6 h after (Post) they completed a series of eight cycles consisting of 5 min of hypoxia and 10 min of normoxia (Hyp-Norm) or normoxia throughout (Norm-Norm). In an additional group, similar challenges were performed after administration of either intraperitoneal vehicle or 25 mg/kg 7-nitroindazole (7-NI). Ventilation (VE) was measured using whole body plethysmography. Although no changes in peak VE responses occurred with episodic hypoxia (Pre vs. Post, P = not significant), late VE reductions were markedly attenuated in Post (DeltaVE from early to late: 7.2 +/- 1.5 ml/min in Pre vs. 4.5 +/- 1.1 ml/min in Post; P < 0.002). Furthermore, 7-NI treatment of Post animals was associated with late VE reductions to Pre levels in Hyp-Norm-exposed animals. Western blots of protein equivalents from the caudal brain stem revealed increased nNOS expression in Hyp-Norm compared with Norm-Norm (P < 0.01). Current findings suggest that repeated short hypoxic exposures improve the ability to sustain VE, which appears to be mediated by increased nNOS expression and activity in brain stem respiratory regions. We postulate that changes in nNOS may play a role in respiratory control plasticity.
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PMID:Episodic hypoxia enhances late hypoxic ventilation in developing rat: putative role of neuronal NO synthase. 988 73

Ischemic preconditioning (IPC) in the heart may reduce myocardial energy demand. The present study was undertaken to examine changes in myocardial oxygen consumption (MVO2) during ischemia by IPC in Langendorff perfused rat hearts. We assessed MVO2 during ischemia from the measurement of mitochondrial cyt. aa3 redox state by a two-wavelength reflectance spectrophotometry where T(1/2), the time from the onset of ischemia to the point for half reduction of cyt. aa3, was assumed to represent MVO2. The heart was preconditioned by three cycles of 5 min ischemia plus 5 min reperfusion and then subjected to 30 min global ischemia followed by reperfusion for 30 min. The T(1/2) was significantly longer in the preconditioned heart (30 +/- 6 s, n = 10) than the control heart (14 +/- 5 s, n = 9, P<0.001), indicating a reduction of MVO2 during ischemic period by IPC. The prolongation of T(1/2) was evident after only one IPC episode. When the heart was perfused with high K+ solution to abolish MVO2 for contractions, we still found the prolongation of T1(1/2) in the preconditioned heart (116 +/- 12 s, n = 6) compared to the control heart (86 +/- 10 s, n = 6, P<0.01), suggesting that decrease in contractile activity may be, in part but not completely, responsible for the reduction of MVO2. In contrast, the prolongation of T(1/2) was completely abolished by administration of a NO synthase inhibitor N omega-nitro-L-arginine in the high K+ arrested heart, demonstrating involvement of NO in the reduction of MVO2, presumably by suppression of mitochondrial respiratory chain. In conclusion, IPC reduces MVO2 during ischemia. The reduction of MVO2 in the preconditioned heart may be accounted for by decreased contractile activity and by depression of respiratory chain by NO.
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PMID:Effect of ischemic preconditioning on myocardial oxygen consumption during ischemia. 992 54

Nitric oxide synthase (NOS) and the nicotinic acetylcholine receptor (nAChR) immunoreactivity of the cerebral cortex was studied in adult Macaca fascicularis monkeys at light- and electron microscopic levels. NOS was located by means of the polyclonal antibodies developed by Transduction Laboratories (Lexington, KY, USA), as primary serum, in a dilution of 1:1000, and nAChR was located by means of biotinylated alpha-bungarotoxin (BTX) obtained from Molecular probes (Eugene, Oregon, USA) in a dilution of 1:2000. While endothelial eNOS outlined blood vessels in the brain, brain-derived (neural) bNOS labelled three well-defined cell types in area 46 of the prefrontal cortex, viz. (a) bipolar cells, scattered through layers III to V, equipped with long dendrites which pass over the thickness of the cortex in a right angle to the pial surface, establishing dendritic bundles closely reminiscent of a columnar organization; (b) large multipolar cells, located mainly in layers V and VI, with axons which interconnect dendritic bundles of the bipolar cells and establish synapses with dendritic shafts and spines of the former; and (c) stellate cells, located in lamina II and III, which establish an axonal network in lamina zonalis (lamina I). This arrangement is most characteristic in area 46 of the prefrontal cortex; areas 10 and 12 display similar features. In contrast, the primary visual cortex (area 17), is lacking any sign of columnar organization. Localization of bNOS immunoreactivity is at marked variance to that of NADPH-diaphorase which labels large pyramidal cells in the primate cortex. Binding of alpha-bungarotoxin (BTX) which labels the alpha 7 subunit of nAChR is located in somata, dendrites and axons of interneurons scattered over the entire width of the prefrontal cortex; on the other hand, the monoclonal antibody mAb 35 which labels subunits alpha 1, alpha 3 and alpha 5 in the main immunogenic region of the receptor, visualizes apical dendritic shafts similar to those like bNOS. Strategic localization of bNOS in the primate prefrontal cortex fulfills criteria of producing a freely diffusing retrograde messenger molecule operative in signal transduction routes subserving topography and columnar organization of the cortex, as well as long-term potentiation and long-term depression phenomena underlying mnemonic and gnostic functions. Common occurrence of bNOS and nAChR in identical or similar structures in the prefrontal cortex suggests that interactions between nitrogen oxide and presynaptically released acetylcholine might be involved in the metasynaptic organization of the cerebral cortex, operating in a non-synaptic manner in maintaining optimal performance on cognitive tasks.
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PMID:Nitric oxide synthase and the acetylcholine receptor in the prefrontal cortex: metasynaptic organization of the brain. 1022 Jul 75

If, only 20 years ago, anyone had postulated that the absence of nitric oxide gas (NO) would lead to severe hypertension and destruction of the vascular bed of the kidney within weeks, it is not unlikely that smiles of pity would have appeared on the faces of fellow researchers. By now, this has become common knowledge, and hundreds of reports have appeared on the regulation of vascular and renal function by nitric oxide. The amount of information complicates the design of a concept on how NO participates in control of extracellular fluid volume (ECFV) by the kidney. This review analyzes the function of endothelial and macula densa NO synthase (NOS) in the regulation of renal function. From this analysis, endothelial NOS (eNOS)-derived NO is considered a modulator of vascular responses and of renal autoregulation in particular. Increases in renal perfusion pressure and sodium loading will increase eNOS activity, resulting in vasodilatation and depression of tubuloglomerular feedback system responsiveness. Endothelium-derived NO seems important to buffer minute-to-minute variations in perfusion pressure and rapid changes in ANG II activity. In contrast, macula densa NOS is proposed to drive adaptations to long-term changes in distal delivery and is considered a mediator of renin formation. Increases in perfusion pressure and distal delivery will depress the activity and expression of the enzyme that coincides with, and possibly mediates, diminished renin activity. Together, the opposite responses of eNOS and macula densa NOS-derived NO to changes in ECFV lead to an appropriate response to restore sodium balance. The concept that the two enzymes with different localizations in the kidney and in the cell are producing the same product, displaying contrasting responses to the same stimulus but nevertheless exhibiting an integrated response to perturbation of the most important regulated variable by the kidney, i.e., the ECFV, may be applicable to other tissues.
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PMID:Renal endothelial and macula densa NOS: integrated response to changes in extracellular fluid volume. 1036 31

Down-regulation of cortical beta-adrenoceptors is observed in rodents following chronic treatment with many clinically effective antidepressant therapies. [3H]dihydroalprenolol binding to cortical beta-adrenoceptors was examined in mice treated with the nitric oxide (NO) synthase antagonist N(G)-nitro-L-arginine (L-NNA). Administration of L-NNA (0.1, 0.3 mg/kg) for 21 days produced a significant reduction (28%, 31%, respectively, P<0.05) in [3H]dihydroalprenolol binding to cortical membranes without affecting Kd. Dose 1 mg/kg of L-NNA given chronically also produced a 20% decrease in beta-adrenoceptor density, but this effect was not statistically significant. While chronic treatment with imipramine (15 and 30 mg/kg) produced respectively a 30% and 25% (P<0.05) reduction in the density of [3H]dihydroalpenolol, single injection of either imipramine (15 and 30 mg/kg) or L-NNA (0.1, 0.3, and 1 mg/kg) had no effect on [3H]dihydroalprenolol binding. These findings are consistent with the hypothesis that drugs which can affect the Ca2+ -calmodulin/nitric oxide synthase/guanylyl cyclase signaling pathway may represent a novel approach to the treatment of depression and are congruent with our previous observation, which has demonstrated the antidepressant-like properties of NO synthase inhibitors in the forced swim test.
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PMID:Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 2. Chronic treatment results in downregulation of cortical beta-adrenoceptors. 1039 14

Repetitive activation of corticostriatal fibers produces long-term depression (LTD) of excitatory synaptic potentials recorded from striatal spiny neurons. This form of synaptic plasticity might be considered the possible neural basis of some forms of motor learning and memory. In the present study, intracellular recordings were performed from rat corticostriatal slice preparations to study the role of glutamate and other critical factors underlying striatal LTD. In current-clamp, but not in voltage-clamp experiments, brief focal applications of glutamate, as well as high-frequency stimulation (HFS) of corticostriatal fibers, induced LTD. This pharmacological LTD and the HFS-induced LTD were mutually occlusive, suggesting that both forms of synaptic plasticity share common induction mechanisms. Isolated activation of either non-NMDA-ionotropic glutamate receptors (iGluRs) or metabotropic glutamate receptors (mGluRs), respectively by AMPA and t-ACPD failed to produce significant long-term changes of corticostriatal synaptic transmission. Conversely, LTD was obtained after the simultaneous application of AMPA plus t-ACPD. Moreover, also quisqualate, a compound that activates both iGluRs and group I mGluRs, was able to induce this form of pharmacological LTD. Electrical depolarization of the recorded neurons either alone or in the presence of t-ACPD and dopamine (DA) failed to mimic the effects of the activation of glutamate receptors in inducing LTD. However, electrical depolarization was able to induce LTD when preceded by coadministration of t-ACPD, DA, and a low dose of hydroxylamine, a compound generating nitric oxide (NO) in the tissue. None of these compounds alone produced LTD. Glutamate-induced LTD, as well as the HFS-induced LTD, was blocked by L-sulpiride, a D2 DA receptor antagonist, and by 7-nitroindazole monosodium salt, a NO synthase inhibitor. The present study indicates that four main factors are required to induce corticostriatal LTD: (1) membrane depolarization of the postsynaptic neuron; (2) activation of mGluRs; (3) activation of DA receptors; and (4) release of NO from striatal interneurons.
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PMID:Glutamate-triggered events inducing corticostriatal long-term depression. 1040 46

Estrogen promotes neurons growth, prevents neuronal cell atrophy and regulates synaptic plasticity. Administration of estrogen protects neurons against oxidative stress, excitotoxins, and beta-amyloid-induced toxicity in cell culture. It has been shown that estrogen treatment reduces the serum monoamino oxidase levels and might regulate learning and memory. Nitric oxide (NO) is a retrograde messenger and long-term potentiation can be block using NO-synthase inhibitors or can be prevent with NO-scavengers. NO synthase is widespread in the central nervous system and acts as neurotransmitter/neuromodulator. The actions of serotonin, bradykinin, endothelin, acetylcholine and noradrenaline might be linked to NO formation. Estrogen induces activity of constitutive NO synthase and estrogen replacement therapy in postmenopausal women increases significantly circulating nitrite plus nitrate levels. The effect of estrogen on NO synthesis is rapid and is maintained with repeated administration. We demonstrated the effects of estrogen replacement therapy in Andean postmenopausal women were associated with a significantly increase in plasma levels of nitrite plus nitrate. Our hypothesis is that beneficial effect of estrogen replacement therapy on involutive depression in postmenopausal women is mediated by increase in NO production by central nervous system.
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PMID:Improvement in functions of the central nervous system by estrogen replacement therapy might be related with an increased nitric oxide production. 1047 89

Nitric oxide (NO) is a cotransmitter of inhibitory motor neurons of the enteric nervous system. This study examined the effect of 7-nitroindazole (7-NI), an inhibitor of neuronal NO synthase (NOS), on intestinal peristalsis and muscle activity and compared 7-NI with N(G)-nitro-L-arginine methyl ester (L-NAME), a nonselective inhibitor of NOS isoforms. Peristalsis in isolated segments of the guinea pig small intestine was triggered by a perfusion-induced rise of the intraluminal pressure. While L-NAME (10-300 micromol/l) lowered the peristaltic pressure threshold (PPT) at which propulsive muscle contractions were elicited, 7-NI (10-300 micromol/l) caused a concentration-related increase in PPT. L-Arginine (1-3 mmol/l) failed to reverse peristaltic motor depression evoked by 7-NI but annulled the L-NAME-evoked stimulation of peristalsis. Drugs which stimulated peristalsis, such as L-NAME, naloxone, apamin and suramin plus pyridoxal phosphate-6-azophenyl-2'-4'-disulphonic acid counteracted the inhibitory effect of submaximally effective concentrations of 7-NI on peristalsis. 7-NI (100-300 micromol/l) inhibited circular muscle contractions evoked by cholecystokinin octapeptide, the NK(1) receptor agonist GR-73,632 and indomethacin whereas L-NAME (100-300 micromol/l) failed to inhibit any drug-evoked contraction. These data show that 7-NI, unlike L-NAME, inhibits circular muscle contractions of the gut and depresses intestinal peristalsis. It is concluded that the inhibitory motor action of 7-NI is unrelated to inhibition of neuronal NOS and arises from depression of smooth muscle activity.
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PMID:Intestinal motor depression by 7-nitroindazole through an action unrelated to nitric oxide synthase inhibition. 1057 25


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