UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Among the multiple biological activities of nitric oxide (NO) an immunoregulatory role consisting of the mediation of macrophage suppressive activity, has recently been evidenced. In the present work, we investigated whether NO was implicated in immunosuppression following burn injury. Thermal injury affecting 20-25% of the total body surface area in Wistar rats, provoked a biphasic depression of spleen cell proliferative responses to phytohemagglutinin (PHA) and concanavalin A (Con A). We show that these responses are fully restored on day 4 after burn and only by 55% on day 10 when spleen cells were stimulated in the presence of NG-monomethyl-L-arginine (NMMA), a potent inhibitor of the macrophage inducible NO synthase. Nitrite content in culture supernatant, as an indicator of NO release (in the absence of NMMA), was significantly augmented in Con A-stimulated spleen cells from burned rats as compared to normal spleen cells. These results show for the first time that NO is implicated, at least in part, in an immunosuppression state which is not linked to an infectious disease.
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PMID:Nitric oxide mediates the depression of lymphoproliferative responses following burn injury in rats. 130 64

1. We have investigated whether the myocardium and isolated cardiac myocytes can express a Ca(2+)-independent NO synthase after treatment with endotoxin or cytokines. Nitric oxide synthesis was measured in cytosols from the left ventricular wall from rats treated with endotoxin, or from freshly isolated myocytes from adult rats treated in vitro with cytokines. 2. Cytosols from the ventricle of saline-treated control animals showed only Ca(2+)-dependent NO synthesis. After treatment with endotoxin, the expression of an inducible, Ca(2+)-independent NO synthase was observed. The activity of this enzyme was maximal at 6 h and returned towards control levels by 18 h; no alterations occurred in the Ca(2+)-dependent NO synthase activity. Parallel to this enzyme induction there was an increase in myocardial guanosine 3':5'-cyclic monophosphate (cyclic GMP) and plasma nitrite and nitrate (NOx-). All these changes were prevented by pretreatment of the rats with dexamethasone. 3. Myocytes possessed Ca(2+)-dependent NO synthase activity and expressed, after treatment with tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta), a Ca(2+)-independent NO synthase, the induction of which was prevented by dexamethasone and cycloheximide. 4. Since increases in cyclic GMP levels in the heart are associated with reduced myocardial contractility, it is possible that the enhanced production of NO by a Ca(2+)-independent enzyme accounts, at least in part, for the depression of myocardial contractility seen in septic shock, cardiomyopathies, allograft rejection, burn trauma, as well as during anti-tumour therapy with cytokines.
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PMID:Induction and potential biological relevance of a Ca(2+)-independent nitric oxide synthase in the myocardium. 137 38

We investigated whether increased nitric oxide (NO) synthase activity within cardiac myocytes contributes to the depressed cardiac contractility observed in endotoxic shock. Isolated ventricular myocytes were studied to examine the effects of substrates and inhibitors of NO synthase on myocyte contractility. When stimulated electrically, the resting length of myocytes from control animals shortened by 5.3 +/- 0.3% (means +/- SE, n = 32). Baseline contraction of myocytes from endotoxin-treated animals was reduced to 3.0 +/- 0.3% (n = 17, P < 0.001). The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) had no effect on myocytes from control animals, but it increased the contraction of myocytes from endotoxin-treated animals by 40% (fractional shortening increased to 4.3 +/- 0.4%, P < 0.01). Similar results were obtained with NG-methyl-L-arginine. The effect of L-NAME could be reversed by excess L-arginine, but not D-arginine. The effect of endotoxin was abolished by dexamethasone pretreatment. Methylene blue also reversed the effects of endotoxin but had toxic effects on myocytes. Agents that either prevent synthesis or the effects of NO reverse the depression of myocyte contraction seen following endotoxin treatment.
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PMID:Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. 148 19

The tone of vascular smooth muscle is influenced by factors released from the endothelium, including endothelin (ET)-1 and endothelium-derived relaxing factor (EDRF). To better understand the interactions between these two mediators, we examined the release of both immunoreactive ET-1 (ir-ET-1) and EDRF from bovine aortic intact endothelium. Bovine aortas were opened longitudinally, washed, and clamped with the endothelium uppermost between two plates. The upper plate contained six openings forming identical and independent wells of endothelial cell monolayer. In experiments examining the release of EDRF, measured as accumulated NO2- and NO3- (NO chi -), we found that ET-3, calcium ionophore A23187 (A23187), acetylcholine (ACh), or ADP caused significant increase in NO chi- release, whereas ET-1 did not. These were significantly reduced in the presence of the EDRF/NO synthase inhibitor, NG-methyl-L-arginine (L-NMA). In a parallel series of experiments measuring EDRF release by stimulation of guanosine 3',5'-cyclic monophosphate (cGMP) accumulation in rat fetal lung (RFL)-6 cells, ET-3 but not ET-1 was also found to be active as a releaser of EDRF. A23187 caused an increase of ir-ET-1 release, whereas ACh, ADP, or the NO-containing compound sodium nitroprusside decreased the release of ir-ET-1. The depression in ir-ET-1 release in the presence of ACh or ADP was not seen when the endothelium was treated with L-NMA. When the cells were pretreated with 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP), the release of ir-ET-1 in response to A23187 was significantly depressed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interactions of endothelins and EDRF in bovine native endothelial cells: selective effects of endothelin-3. 159 Apr 65

1. Isolated rings of rabbit external jugular vein (RbJV) and rat thoracic aorta (RA) were used to study the effect of the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) on muscarinic and 5-hydroxytryptamine (5-HT) receptor-stimulated, endothelium-dependent vascular relaxations. 2. In RbJV relaxations produced by the endothelial 5-HT receptor agonist alpha-methyl-5-HT were potently and non-surmountably inhibited by L-NAME (10 microM), whereas acetylcholine relaxations in this tissue were unaffected by this concentration of inhibitor. By contrast, acetylcholine relaxations in RA were virtually abolished by 10 microM L-NAME. In each case an equivalent concentration of D-NAME was without effect on agonist-induced relaxations. 3. The different effect of L-NAME on acetylcholine relaxations in RbJV and RA was not due to muscarinic receptor differences. Affinity estimates for acetylcholine (pKA = 6.12 +/- 0.09; 6.09 +/- 0.08 respectively) and for 4-diphenyl-acetoxy-N-methylpiperidine methobromide (4-DAMP, pKB = 9.01 +2- 0.012; 9.24 +/- 0.16 respectively) indicated that the receptors in both tissues belong to the same M3 class. Tissue differences resulting from the release of a cyclo-oxygenase product or a glibenclamide-sensitive K(+)-channel-linked hyperpolarizing factor were also ruled out by selective inhibition of these pathways. 4. When phenoxybenzamine was used to reduce the efficacy of acetylcholine in RbJV so that it behaved as a partial agonist in this tissue, L-NAME (10 microM) now produced non-surmountable inhibition of relaxation responses. In untreated tissues the same concentration of L-NAME also profoundly inhibited responses produced by butyrylcholine and pilocarpine, both of which behave as partial agonists at the M3 receptor in RbJV. 5. A simple model was developed which describes the theoretical behaviour of receptor-stimulated synthesis and release of NO. The model predicts that competitive inhibition of NO formation results in parallel displacements of the agonist response curve in the case of high efficacy agonist, but right-shift with concomitant depression of the curve maximum in the case of low efficacy agonists. Simulations based on the model showed reasonable agreement with the experimental data. 6. It is concluded that analogues of L-arginine demonstrate tissue- and agonist-dependence in terms of their ability to inhibit receptor-mediated events involving the liberation of NO. This behaviour can reflect differences in agonist efficacy in the receptor systems being studied, a possibility that should be ruled out before apparent resistance to inhibition is taken as evidence for the involvement of heterogeneous endothelium-derived relaxing factors (EDRFs).
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PMID:Inhibition of endothelium-dependent vasorelaxation by arginine analogues: a pharmacological analysis of agonist and tissue dependence. 162 52

Conjunctive stimulation of climbing and parallel fibres in the cerebellum evokes a long-term depression of parallel-fibre Purkinje-cell transmission, a phenomenon implicated as the cellular mechanism for cerebellar motor learning. It is suspected that the increase in cyclic GMP concentration that occurs after activation of climbing fibres is required to evoke long-term depression. Excitatory amino acids are known to cause the release of nitric oxide (NO), resulting in elevation of the cGMP level in the cerebellum. Here we report that endogenous NO is released after stimulation of climbing fibres, that long-term depression evoked by conjunctive stimulation of parallel and climbing fibres is blocked by haemoglobin (which strongly binds NO) or L-NG-monomethyl-arginine (an inhibitor of NO synthase), and that exogenous NO or cGMP can substitute for the stimulation of climbing fibres to cause long-term depression in rat cerebellar slices. These results demonstrate that the release of endogenous NO is essential for the induction of synaptic plasticity in the cerebellum.
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PMID:Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum. 170 79

In addition to its role in blood vessel and macrophage function, nitric oxide (NO) is a neurotransmitter found in high densities in emotion-regulating brain regions. Mice with targeted disruption of neuronal NO synthase (nNOS) display grossly normal appearance, locomotor activity, breeding, long-term potentiation and long-term depression. The nNOS- mice are resistant to neural stroke damage following middle cerebral artery ligation. Although CO2-induced cerebral vasodilatation in wild-type mice is NO-dependent, in nNOS- mice this vasodilation is unaffected by NOS inhibitors. Establishing a behavioural role for NO has, until now, not been feasible, as NOS inhibitor drugs can only be administered acutely and because their pronounced effects on blood pressure and other body functions obfuscate behavioural interpretations. We now report a large increase in aggressive behaviour and excess, inappropriate sexual behaviour in nNOS- mice.
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PMID:Behavioural abnormalities in male mice lacking neuronal nitric oxide synthase. 747 65

The actions of NO synthase inhibitors and indomethacin, a cyclooxygenase inhibitor, on the nonadrenergic noncholinergic (NANC) mechanical responses of cat distal colon were studied in vitro using muscle strips orientated in the axis of the longitudinal muscle layer with pelvic nerves attached. Electrical field stimulation (EFS) or pelvic nerve stimulation (PNS) caused inhibition of spontaneous contractions followed by off-contractions. Indomethacin (10-30 microM) caused concentration-dependent reductions in amplitude and duration of EFS- and PNS-evoked off-contractions but not latency. The NO synthase inhibitors, N omega-nitro-L-arginine (L-NNA), N omega-nitro-L-arginine methyl ester (L-NAME) and NG-monomethyl-L-arginine (L-NMMA) (each at 100 microM) significantly reduced latency, amplitude, and duration of off-contractions evoked by EFS and PNS. This inhibition was partially reversed by L-arginine (120 microM) but not by D-arginine. Incubation of colonic strips with alpha-chymotrypsin (2 U/ml) decreased latency, amplitude, and duration of NANC off-contractions. L-NNA reduced amplitude, duration, and latency of off-contractions in preparations pretreated with alpha-chymotrypsin. Hydroquinone (10-30 microM), a generator of superoxide anions, caused significant depression of amplitude, duration, and latency of off-contractions which was completely reversed by superoxide dismutase (200 U/ml). These data suggest that the components of NANC off-contractions evoked by EFS and PNS involve peptides, NO, and prostaglandins.
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PMID:A nitric oxide and prostaglandin-dependent component of NANC off-contractions in cat colon. 750 99

The mammalian cerebellum is built around an array of parasagittal bands of Purkinje cells that can be demonstrated by immunocytochemical staining for the differentiation antigen zebrin II. Climbing and mossy fiber afferents also terminate in bands, and the afferent terminal fields and the Purkinje cell bands are aligned. The convergence of mossy and climbing fiber pathways onto the Purkinje cells, which are the sole output of the cerebellar cortex, is a characteristic feature of cerebellar circuitry. Previous studies showed that when both afferent pathways are activated synchronously there develops a long-term depression of synaptic efficacy at the parallel fiber-Purkinje cell synapse. Two second messenger pathways mediate long-term depression: one involves diacylglycerol and protein kinase C, and the other involves nitric oxide that is generated by a nitric oxide synthase. We have studied the distribution of nitric oxide synthase in the adult mouse cerebellum by using nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry. NADPH-diaphorase activity is found mainly in the granule and basket cells. Within the granular layer NADPH-diaphorase activity is expressed nonuniformly by patches of granular cells and synaptic glomeruli. The patches are seen in all lobules, are reproducible from individual to individual, and are topographically ordered with respect to the Purkinje cell compartments as revealed by using anti-zebrin II immunocytochemistry. These data imply that nitric oxide-dependent, long-term depression may only involve a subset of mossy fiber/granule cell projections, and that one role for nitric oxide may be to refine cerebellar receptive fields.
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PMID:Compartmentation of NADPH-diaphorase activity in the mouse cerebellar cortex. 752 60

1. Myocardial dysfunction during septic shock is associated with enhanced production of cytokines such as interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha). These cytokines depress cardiac mechanical function by a mechanism which is not well defined. 2. Bacterial endotoxin or cytokines cause the expression of Ca(2+)-independent nitric oxide (NO) synthase in cardiac myocytes, vascular endothelial cells and endocardial endothelial cells, causing enhanced production of NO. As NO has negative inotropic actions on cardiac muscle, we tested the sum effects of IL-1 beta plus TNF-alpha in the intact heart to determine whether enhanced expression of NO synthase activity in the cells that comprise the heart is involved in cardiac depression associated with cytokine stimulation. 3. Rat isolated working hearts perfused with IL-1 beta plus TNF-alpha showed a markedly greater depression in contractile function, measured as cardiac work, after 2 h of perfusion compared with time-matched control hearts. The depressant action of IL-1 beta plus TNF-alpha was first apparent after 1 h of perfusion; no early (15 min) cardiac depressant actions were seen. 4. The competitive inhibitor of Ca(2+)-dependent and Ca(2+)-independent NO synthases, NG-nitro-L-arginine methyl ester (L-NAME, 3 microM) when given concurrently with IL-1 beta plus TNF-alpha prevented the loss in contractile function such that these hearts after 2 h of perfusion had similar function to time-matched controls. L-NAME did not acutely reverse the loss of contractile function in hearts exposed for 2 h to IL-1 beta plus TNF-alpha. The protective action of L-NAME in the presence of cytokines was concentration-dependent and was not seen at a higher concentration (10 micro M) due to the significant reduction in coronary flow observed at this concentration.5. In contrast, when L-NAME (3 micro M) was given in the absence of IL-l beta plus TNF-alpha it depressed contractile function over the 2 h perfusion period by significantly reducing coronary flow.6. Inhibition of protein synthesis with cycloheximide (Cx) abolished the loss in function that occurred over 2h in both control and IL-1 beta plus TNF-a-treated hearts.7. Inducible, Ca2+-independent NO synthase activity was not observed in freshly isolated hearts but was observed in control hearts perfused for 2 h in vitro and was doubled in hearts perfused with IL-1 beta plus TNF-a. Cx prevented the expression of Ca2+-independent NO synthase in both control and cytokine-treated hearts.8. In summary, these results suggest that the depression of myocardial function by IL-l beta plus TNF-alpha is mediated, at least in part, by induction of Ca2+-independent NO synthase activity in the heart.
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PMID:The role of nitric oxide in cardiac depression induced by interleukin-1 beta and tumour necrosis factor-alpha. 753 96

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