Nitric oxide acts as a retrograde messenger during long-term potentiation in cultured hippocampal neurons

We examined long-term potentiation (LTP) at synapses between hippocampal neurons in dissociated cell culture following presynaptic, postsynaptic, or extracellular application of a nitric oxide (NO) scavenger, an inhibitor of NO synthase, and a membrane-impermeant NO donor that releases NO only upon photolysis with UV light. Our results indicate that NO is produced in the postsynaptic neuron, travels through the extracellular space, and acts directly in the presynaptic neuron to produce long-term potentiation, supporting the hypothesis that NO acts as a retrograde messenger during LTP.     

Nitric oxide, a neuronal messenger. Its role in the hippocampus neuronal plasticity

Nitric oxide (NO), a free radical gas, has recently been recognized as an important messenger molecule having a neurotransmitter-like function. Studies on the localization of the enzyme synthesizing NO (NO synthase-NOS) have indicated its presence in almost all parts of the brain with a prevalence in the cerebellum. From recent experimental investigations it is apparent that NO might meet the essential criteria to function as a retrograde messenger for Long-term potentiation in hippocampal cells, a process known to be involved in mammalian learning and memory. However, within the hippocampus NO is present in a few cell types which probably form the local neuronal circuit. Thus NO might function as a paracrine factor rather than a retrograde messenger in the hippocampal neurons.     

Nitric oxide as a regulatory factor in sleep-wakefulness mechanisms

Most screws used in fracture fixation necessitate a separate step for tapping of the screw hole. Titanium screw systems have been developed in which the screws can be inserted directly after a drill hole is made. These self-tapping screws thereby eliminate an operative step. A retrospective study was conducted that evaluated all wrist and hand procedures performed between January 1992 and December 1994 by 1 surgeon using screw fixation. The results of 39 cases treated with standard tapped titanium screws were compared with 28 cases treated with self-tapping titanium screws. Nearly identical union and complication rates were obtained in each group. Comparable results can be obtained with self-tapping screw fixation, which limits the number of instruments needed, eliminates an operative step, and thereby may diminish operative risk and shorten operative time.     

Nitric oxide as S-nitrosoproteins in rheumatoid arthritis

OBJECTIVE: Nitric oxide (NO) is a free radical involved in inflammation and immune reactions. The presence of NO is usually assessed by assaying its degradation products, nitrite and nitrate. NO binds to thiol-containing proteins to form S-nitrosoproteins (S-NP). The aim of this study was to investigate the presence of S-NP, together with nitrite and nitrate, in patients with rheumatoid arthritis (RA). METHODS: Forty patients with RA were studied and compared with 24 patients with osteoarthritis (OA) and 21 control subjects. Fourteen patients were treated with 3 consecutive pulses of methylprednisolone for flares of RA. Nitrite was measured by the Griess reaction, and nitrate by a spectrophotometric assay using nitrate reductase. Spectrofluorometry coupled with the inner filter effect was used for the measurement of S-NP. RESULTS: S-NP was detected in all RA samples, both in serum and synovial fluid (SF). Serum and articular S-NP concentrations were correlated (P < 0.03). In RA, nitrite and S-NP levels were higher in SF than in serum; higher SF levels of the 3 compounds were observed in RA than in OA. S-NP levels in RA patients decreased significantly (P < 0.03) after pulse methylprednisolone treatment, in parallel with the clinical improvement. CONCLUSION: S-NP, a biologically active form of NO, was consistently present in RA, with higher concentrations within the arthritic joint. S-NP assays should be added to nitrite and nitrate assays for the evaluation of NO metabolism. S-NP could be a stable storage form of active NO in RA, and its measurement could be useful in evaluating pharmacologic interventions that modulate NO generation.     

Nitric oxide as a peripheral and central mediator in temperature regulation

In animals including humans nitric oxide (NO) serves as a biological messenger both peripherally at neuroeffector junctions and in the central nervous system where it modulates neuronal activity. Evidence for the involvement of NO in homeostatic control is accumulating also for temperature regulation in homeotherms. In the periphery an auxiliary role in the vasomotor control of convective heat transfer to heat dissipating surfaces and modulation of thermoregulatory heat generation, especially in brown adipose tissue as the site of nonshivering thermogenesis, are discussed as NO actions. At the central level a thermolytic role of NO in thermoregulation as well as in fever is assumed, however, experimental data opposing this view suggest that topical specificity may be important. At the level of single neurons, the observed interrelationships between thermosensitivity and responsiveness to NO are still not consistent enough to reconcile these data with the effects of NO-donors and inhibitors of NO-synthase on temperature regulation.     

Nitric oxide mediates the formation of synaptic connections in developing and regenerating olfactory receptor neurons

Nitric oxide (NO) is a diffusible free radical that functions as a second messenger and neurotransmitter. NO synthase (NOS) is highly and transiently expressed in neurons of the developing olfactory epithelium during migration and establishment of primary synapses in the olfactory bulb. NOS is first expressed at E11 in cells of the presumptive nervous layer of the olfactory placode. NOS immunoreactivity persists in the descendants of these cells that differentiate into embryonic olfactory receptor neurons (ORNs). Olfactory NOS expression in the ORN and in its afferents rapidly declines after birth and is undetectable by P7. Following bulbectomy, NOS expression is rapidly induced in the regenerating ORN and is particularly enriched in their outgrowing axons. Immunoblot and Northern blot analyses similarly demonstrate an induction of NOS protein and mRNA expression, respectively, the highest levels of which coincide with peaks of ORN regeneration. These data argue against a role for NO in odorant-sensitive signal transduction, but suggest a prominent function for NO in activity-dependent establishment of connections in both developing and regenerating olfactory neurons.     

Nitric oxide in invertebrates

Nitric oxide (NO) is considered an important signaling molecule implied in different physiological processes, including nervous transmission, vascular regulation, immune defense, and in the pathogenesis of several diseases. The presence of NO is well demonstrated in all vertebrates. The recent data on the presence and roles of NO in the main invertebrate groups are reviewed here, showing the widespread diffusion of this signaling molecule throughout the animal kingdom, from higher invertebrates down to coelenterates and even to prokaryotic cells. In invertebrates, the main functional roles described for mammals have been demonstrated, whereas experimental evidence suggests the presence of new NOS isoforms different from those known for higher organisms. Noteworthy is the early appearance of NO throughout evolution and striking is the role played by the nitrergic pathway in the sensorial functions, from coelenterates up to mammals, mainly in olfactory-like systems. All literature data here reported suggest that future research on the biological roles of early signaling molecules in lower living forms could be important for the understanding of the nervous-system evolution.     

Nitric oxide in the stress axis

Calcitonin gene-related peptide in sensory primary afferent neurons has an excitatory effect on postsynaptic neurons and potentiates the effect of substance P in the rat spinal dorsal horn. It has been established that calcitonin gene-related peptide expression in dorsal root ganglion neurons is depressed, and the effect of calcitonin gene-related peptide on dorsal horn neurons is attenuated, following peripheral nerve injury. We report here that a subpopulation of injured dorsal root ganglion neurons show increased expression of calcitonin gene-related peptide. Using in situ hybridization and the retrograde tracer, FluoroGold, we detected an increased number of medium- to large-sized rat dorsal root ganglion neurons projecting to the gracile nucleus that expressed alpha-calcitonin gene-related peptide messenger RNA following spinal nerve transection. Immunohistochemistry revealed a significant increase in calcitonin gene-related peptide immunoreactivity in the gracile nucleus and in laminae III-IV of the spinal dorsal horn. These results indicate that a subpopulation of dorsal root ganglion neurons express alpha-calcitonin gene-related peptide messenger RNA in response to peripheral nerve injury, and transport this peptide to the gracile nucleus and to laminae III-IV of the spinal dorsal horn. The increase of the excitatory neuropeptide, calcitonin gene-related peptide, in sites of primary afferent termination may affect the excitability of postsynaptic neurons, and have a role in neuronal plasticity following peripheral nerve injury.     

Nitric oxide as a regulator of prostacyclin synthesis in cultured rat heart endothelial cells

The effects of nitric oxide (NO) and its second messenger cyclic guanosine monophosphate (cGMT) on prostacyclin (PGI2) synthesis were studied in cultured rat heart endothelial cells using three different non-enzymatic nitric oxide releasing substances as well as inhibitors of nitric oxide synthase and of soluble guanylate cyclase. Production of prostacyclin, measured as 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), was stimulated up to 1.7 fold in endothelial cells treated with the NO donors SIN-1 (3-morpholino sydnonimine), GEA 3162 (3-aryl-substituted oxatriazole imine) and GEA 3175 (3-aryl-substituted oxatriazole sulfonyl), chloride). In each case the synthesis of cGMP increase as much as 40-100 fold. An inhibitor of NO synthase, NG-nitro-L-arginine methyl ester (L-NAME), decreased the basal production of 6-keto-PGF1 alpha in non-stimulated endothelial cells, an effect that could be reversed by the NO donors SIN-1, GEA 3162 and GEA 3175. cGMP formation in the L-NAME treated endothelial cells was unaltered. The guanylate cyclase inhibitors, methylene blue (100 mumol/l) and LY83583 (100 mumol/l), caused a 1.5-10 fold increase in 6-keto-PGF1 alpha production while NO-donor-stimulated endothelial cGMP production was decreased by 10 to 90%. However, when SIN-1 was used as a stimulant, LY83583 had no significant effect on the production of cGMP. These findings support the hypothesis that NO stimulates prostacyclin production directly by activating cyclooxygenase. The results also suggest that NO could have an indirect effect on prostacyclin production via cGMP.     

Nitric oxide in vascular remodeling

Vascular remodeling is a series of structural changes in blood vessels. Therefore, it may be conceivable that any humoral factors and physical forces acting on the vascular wall are involved in the remodeling processes. Cells in the vascular wall respond to the humoral and physical factors and may induce extracellular matrix, cell adhesion molecules and other humoral factors. They even grow so that cellular and noncellular components deviate from the normal population. We discuss the relationship among nitric oxide (NO), pressure and growth of smooth muscles. Decreased NO may be a consequence as well as a cause of high pressure. Similarly, high pressure is a cause as well as a consequence of decreased NO. Remodeling could be a consequence of both high pressure and decreased NO. Thus, vascular remodeling is a complex dynamic state, where any causes and results are influenced by each other. Interaction of NO and pressure is one such complexity.     

Nitric oxide in respiratory diseases

Recent reports have described a pathogenic role of nitric oxide in several respiratory disease. It is specially useful in the adult respiratory distress syndrome, where it acts as a selective vasodilator and improves gas exchange, decreasing pulmonary shunting. Although it has a proven bronchodilator effect, its therapeutic role in diseases such as asthma and chronic limitation of airway flow is not well defined. This article review the metabolism, mechanisms of action, potential uses and adverse effects of nitric oxide in respiratory disease.     

Nitric oxide: a new area in intensive care

The relaxing effects of nitric oxide on smooth muscles, first identified in 1987, inaugurated a new area of therapeutic efficacity in intensive care. Nitric oxide is synthesized by endothelial cells, macrophages, brain cells and other cells following immunological activation and plays a role in normal blood pressure homeostasis, neuromodulation, cytotoxicity and intracellular message transmission. Since inappropriate vasodilatation or shock may result from cytokine- or endotoxin-induced overproduction of nitric oxide, experiments have been conducted on the effect of nitric oxide synthase inhibitors on shock-induced hypotension. In animal models, results have demonstrated a new method for treating septic shock since infusing nitric oxide inhibitors can rapidly re-establish haemodynamics. Nevertheless, due to possible interference with the immune defense system further studies on the physiological, pharmacological and metabolic effects are required before routine antishock therapy can be used in the intensive care unit. Inversely, in pulmonary hypertension there may be an insufficient production of endogenous nitric oxide. Thus administration via inhalation would represent a promising replacement therapy. In addition, since nitric oxide is rapidly inactivated by haemoglobin, its vasodilatory effect is restricted to the pulmonary vasculature resulting in lowered pulmonary artery pressure without systemic vasodilatation. Effective protocols have been developed for primary pulmonary hypertension of the newborn and acute respiratory distress syndrome. The bronchodilatory effect of nitric oxide is another area suggesting an alternative approach to treating different causes of bronchoconstriction including asthma. The results of early clinical trials are awaited. When used in low concentrations under continuous monitoring, nitric oxide is a safe new therapeutic option for the treatment of pulmonary hypertension and nitric oxide inhibitors may have an important role to play in the management of septic shock.     

Nitric oxide as an autocrine regulator of sodium currents in baroreceptor neurons

Arterial baroreceptors are mechanosensitive nerve endings in the aortic arch and carotid sinus that play a critical role in acute regulation of arterial blood pressure. A previous study has shown that nitric oxide (NO) or NO-related species suppress action potential discharge of baroreceptors. In the present study, we investigated the effects of NO on Na+ currents of isolated baroreceptor neurons in culture. Exogenous NO donors inhibited both tetrodotoxin (TTX) -sensitive and -insensitive Na+ currents. The inhibition was not mediated by cGMP but by NO interaction with channel thiols. Acute inhibition of NO synthase increased the Na+ currents. NO scavengers (hemoglobin and ferrous diethyldithiocarbamate) increased Na+ currents before but not after inhibition of NO synthase. Furthermore, NO production in the neuronal cultures was detected by chemiluminescence and immunoreactivity to the neuronal isoform of NO synthase was identified in fluorescently identified baroreceptor neurons. These results indicate that NO/NO-related species function as autocrine regulators of Na+ currents in baroreceptor neurons. Modulation of Na+ channels may represent a novel response to NO.     

Nitric oxide in learning and memory

The role of nitric oxide in the central nervous system is described. The main part of this article concerns the problem of learning and memory.