Nitric oxide and inflammation

There are several pre-clinical studies on the involvement of NO in inflammation. From this large amount of information it is clear that virtually every cell and many immunological parameters are modulated by NO. Thus, the final outcome is that NO cannot be rigidly classified as an anti-inflammatory or pro-inflammatory molecule. This peculiar aspect of the pathophysiology of NO has hampered the development of new drugs based on the concepts developed. Recent therapeutic approach are targeted to increase endogenous NO by activating the gene and some promising early data are available. At the present stage one of the most promising approach in the inflammation field is represented by a new class of NO-releasing compounds namely NO-NSAIDs that have recently enrolled in phase 2 clinical studies.     

Nitric oxide and the CABG patient

The post surgery success of coronary artery bypass grafting (CABG) is counteracted by thrombosis and de-endothelialization, intimal hyperplasia and, over the long term, atherosclerosis. There are many reasons to assume that in CABG patients vascular bioavailability of NO generated by the endothelium plays an important role for graft function. This holds true for factors such as graft type, harvesting and storage, the type of surgery, non-pharmacologic prevention of risk factors, for example, regular physical activity (if feasible), and drug therapy. Although the precise role of graft endothelial NO bioavailability for graft patency and clinical endpoints is still uncertain, current data rather speak in favor of NO indicating that the potential of vasoprotective activities of NO in the CABG patient deserves further investigation.     

Nitric oxide and brain hyperexcitability

Nitric oxide (NO) is a gaseous messenger involved in atypical forms of intercellular communications, able to exert a strong functional modulation of several neurotransmitter systems. In particular, NO heavily influences the excitatory neurotransmitter glutamate, mainly through NMDA receptors, and the inhibitory neurotransmitter GABA, mainly through GABA A receptors. Due to the involvement of glutamate and GABA in a delicate balance conditioning the functional status of the neural cells, this interaction suggests a role for NO in regulating neuronal excitability and its transition towards hyperexcitability phenomena. This article reviews the main knowledge about the relationships existing between the activity of the NO system and the experimental aspects of epilepsy, focusing on the somewhat antithetic findings about the proconvulsant or the anticonvulsant roles exerted by nitric oxide.     

Nitric oxide synthase inhibitors

This patent application claims the identification and preparation of novel amidino compounds and the use of these compounds for the treatment of conditions where there is a need to inhibit nitric oxide (NO) synthase (NOS). More specifically, claims are made for use in arthritis, asthma, ileus and migraine.     

Nitric oxide in atherosclerosis

*NO is produced endogenously from L-arginine by NOSs. Among its multiple activities, the homeostatic control of the vascular endothelium is crucial for atherosclerosis, a pathogenic condition connected with elevated levels of LDL, the main plasma cholesterol carrier. Oxidised LDL is proatheromatic, and toxic peroxidation products contribute to further endothelial damage. *NO controls vascular tone, inhibits LDL oxidation and has hypocholesterolaemic activity. This review is referred to the chemistry, biology and role of *NO on atherosclerosis and its treatment by *NO donors or modulators.     

Nitric oxide and endothelial cell aging

Nitric oxide (NO) is a crucial factor for the integrity and function of the endothelium. Besides its role in blood pressure regulation, NO acts antithrombotically and antiapoptotically. The laminar flow in the blood vessel, called shear stress, is the most potent endogenous protective force against endothelial cell apoptosis, mostly by increasing the expression of the endothelial NO synthase (eNOS) and thereby increasing NO bioavailability in endothelial cells. However, during the process of endothelial cell aging, shear stress is unable to induce eNOS expression and protect against apoptosis induction. Moreover, apoptosis induction is correlated with aging in vivo, suggesting a link between NO bioavailability, aging, and apoptosis. Moreover, cellular aging is accompanied with an increase in reactive oxygen species (ROS), which results in an imbalance of the redox status of the cell. Thioredoxin is an important redox regulator in endothelial cells and can “bind” NO. S-nitrosylation of thioredoxin increases its enzymatic activity, which in turn leads to reduced intracellular ROS and apoptosis, suggesting that thioredoxin may play an important role in NO bioavailability. One crucial step in the process of cellular aging is the telomerase activity that is reduced in aged endothelial cells. NO can inhibit the decrease in telomerase activity and thereby delay the onset of replicative senescence. Thus, the reduction in NO bioavailability is a crucial factor for endothelial cell aging and apoptosis.

     

一氧化氮与索曼中毒

目的：探索索曼中毒机制是否有ＮＯ参与，方法：预先侧脑室注射Ａｒｇ、ＮＡＭＥ，观察索曼中毒小鼠惊厥潜伏期、死亡率及脑中ＮＯＳ活性变化。结果：Ａｒｇ预处理时，潜伏期从５．２ｍｉｎ（对照组）缩短到４．３ｍｉｎ（Ａｒｇ１６０ｎｍｏｌ），死亡率由５０％（对照组）增加至８１％（Ａｒｇ１６０ｎｍｏｌ）。ＮＡＭＥ预处理时，潜伏期从４．０ｍｉｎ延长到１４．５ｍｉｎ（ＮＡＭＥ２．２０μｍｏｌ），死亡率由８７％（对照组     

一氧化氮供体与心血管病治疗药

目的介绍一氧化氮供体药物的研究进展。方法根据相关文献 ,进行分析整理和归纳。结果与结论为一氧化氮供体药物的研究和开发提供了参考     

雄激素对大鼠主动脉一氧化氮合酶/一氧化氮体系的调节

目的：研究雄激素对大鼠主动脉一氧化氮合酶／一氧化氮(NOS／NO)体系的影响，以探讨雄激素对心血管系统的作用。方法：将30只雄性大鼠随机分为三个组，每组10只，去卵巢组(A组)、去卵巢 雄激素组(B组)、假手术组(C组)。正常饮食2个月后处死大鼠，测血清雄激素、主动脉匀浆一氧化氮合酶活性及一氧化氮含量。结果：同假手术组相比。去势大鼠主动脉匀浆NOS活性及NO含量显著降低，在补充适量的雄激素后．主动脉匀浆NOS活性及NO含量显著上升。结论：雄激素可以调节大鼠动脉内一氧化氮合酶／一氧化氮体系，可能是其调节血管张力的作用机制。     

Nitric oxide and gall-bladder motor function

Background:

The L-arginine: nitric oxide (NO) pathway has been shown to be important in the regulation of intestinal motility and NO may be the mediator for nonadrenergic noncholinergic (NANC) neurotransmission.

Aim:

To determine the role of the L-arginine: NO pathway in gall-bladder motor function.

Methods:

Strips of fresh bovine and human gall-bladders were stimulated with cholecystokinin (CCK). The effects of glyceryl trinitrate (GTN), sodium nitroprusside and Kreb’s solution upon CCK-stimulated muscle contraction were examined. The effect of the NO synthase inhibitor, L-N^G-monomethyl-arginine (L-NMMA) upon basal muscle tone was also examined. Ten human gall-bladders were immunohistochemically stained for nitric oxide synthase (NOS) and product 9.5 to identify neurones. Postprandial gall-bladder emptying was measured on separate occasions in six healthy volunteers during systemic intravenous infusion of normal saline; glyceryl trinitrate; sodium nitroprusside (SNP), hydralazine and L-NMMA.

Results:

In the in vitro study, GTN and SNP significantly reduced the tension of CCK-stimulated muscle contraction whilst Kreb’s solution had no effect. L-NMMA increased tonic and phasic muscle contractions. Immunohistochemical staining for NOS was consistently absent in human gall-bladders. In the in vivo study, both GTN and SNP caused significant impairment of gall-bladder emptying; the ejection fraction was only 50% at the end of the study period involving these infusates, this contrasted with ejection fractions in excess of 80% during infusions with hydralazine, saline and L-NMMA.

Conclusion:

Pharmacological doses of NO donors impair postprandial gall-bladder emptying in vivo and relax gall-bladder smooth muscle in vitro. However, negative immunohistochemical staining suggest NOS is unlikely to be the neurotransmitter for NANC innervation regulating gall-bladder motility.

     

Nitric oxide in asthma therapy

The discovery of the delicate role of endogenous nitric oxide in the homeostasis of various cellular functions and the dynamic behaviour of the airways, has led to a new, rapidly progressing area of physiological science, that has direct bearing for our understanding of multiple airway diseases. The potentially protective effects of nitric oxide include: neuromodulation by mediating inhibitory non-cholinergic non-adrenergic nerve activity; smooth muscle relaxation, attenuating airway hyperresponsiveness to bronchoconstrictor stimuli and immune-suppression. NO itself or SNO can be administered directly to the airways, and the development of gene transfer therapy seems to become a realistic approach in the treatment of airway diseases. However, NO has also harmful effects, especially when it interacts with other molecules. At present, there are novel opportunities to modulate nitric oxide-synthesis aimed to restore the balance between the protective and deleterious effects of nitric oxide. This is potentially beneficial in both airway and alveolar diseases. Such interventions might be targeted in various ways, e.g. by using selective reactive nitrogen- and oxygen- scavengers, selective NO donors and selective nitric oxide synthase inhibitors. The possible therapeutical opportunities are reviewed in this paper. Nitric oxide has already made it from the bench to the bedside, and it is likely that new developments in this area will drastically change respiratory medicine during the coming 5-10 years.     

Nitric oxide in parasitic infections

Nitric oxide (NO) is implicated as an integral component of the host armament against invading parasites. Strongest evidence has come from laboratory models of protozoan infections. During malaria, toxoplasmosis and leishmaniasis, to name just a few, the preferential production of pro-inflammatory cytokines predisposes to the increased synthesis of NO, which mediates host protection through either direct parasite killing or by limiting parasite growth. More recently, evidence has been put forward for a beneficial role of NO during helminthic infections. In the case of Schistosomiasis mansoni, for example, NO plays a role in regulation of egg-induced inflammation, preventing hepatocyte death and widespread tissue damage. In spite of these findings, rather than being the ultimate panacea, NO production requires tight control to limit cytotoxic damage to the host's own cells. Unregulated production may lead to a variety of damaging effects including alterations to normal neurological functions during cerebral malaria and intestinal pathology during trichinosis. In this review, I will summarize the role of NO during a number of parasitic infections, drawing on specific examples of disease caused by protozoan and metazoan parasites.     

一氧化氮在急性胰腺炎中的作用

目的：探讨一氧化氮（ＮＯ）和肿瘤坏死因子（ＴＮＦ）在急性胰腺炎中的作用。方法采用比色法和平衡法分析对急性水肿型胰腺炎（ＡＥＰ）患者３０例和急性坏死型胰腺炎（ＡＮＰ）患者２０例以及正常人对照组３０例外周血进行ＮＯ和ＴＮＦ水平检测。结果ＡＥＰ和ＡＮＰ组患者ＮＯ和ＴＮＦ水平显著高于对照组（Ｐ〈０．０５）；ＡＮＰ组ＮＯ和ＴＮＦ水平显著高于ＡＥＰ组。结论ＮＯ和ＴＮＦ在急性胰腺炎的发生、发展中起重要作用。     

Nitric oxide and cardiovascular dysfunction in sepsis

Sepsis and septic shock are the major causes of morbidity and mortality in critically ill patients. During the onset of sepsis, a massive inflammatory reaction involving chemical mediators such as cytokines and chemokines and inflammatory cells such as the polymorphonuclear neutrophil and macrophage takes place. In addition to this systemic inflammatory process, sepsis and septic shocks cause a profound decrease in the peripheral vasomotor tone leading to a great decrease in the peripheral resistance. This event is central to derangement of hemodynamic and perfusion parameters. Nitric oxide (NO) is produced by several cell types and has been implicated in a wide range of physiological and pathological processes, with both detrimental and beneficial effects. There is a wealth of data implicating NO as a key player in all cardiac, vascular, renal and pulmonary derangements of sepsis and septic shock. Clinical assays trying to improve sepsis by inhibiting NO formation by NO synthases have met with failure, probably due to the lack of selectivity of inhibitors towards NOS isoforms. Notwithstanding the search for selective inhibitors, a better understanding of the NO molecular effector mechanisms may provide new opportunities for therapy development. Some of these NO effector mechanisms are discussed, including guanylate cyclase, nitrosothiols, potassium channels, reactive oxygen species and gene expression in the context of sepsis. Thus, more research on the relationship between NO and sepsis is clearly needed and warranted and may provide new therapeutic targets to treat sepsis and septic shock.     

Nitric oxide and T helper cell immunity

In this article, the controversial role of nitric oxide (NO) in T helper (Th) cell activation and T-cell-dependent immunity will be discussed with an emphasis on immunosuppression by NO. NO is generated by antigen-presenting cells (APC) during the process of antigen presentation to T cells. In mouse models, activation of the inducible NO synthase (iNOS) in APC is triggered by Th1-cell-derived IFN-gamma, in combination with other soluble or membrane-associated T-cell factors. The NO so-produced inhibits T-cell proliferation, while it does not inhibit T cell cytokine production. NO blocks T-cell proliferation during G1/S transition. In mouse models of T-cell-mediated autoimmunity such as myelin antigen-induced EAE, the disease is exacerbated by genetic deletion of iNOS, indicating that NO suppresses T-cell-mediated immunity in vivo. Recent studies reveal that interaction with superoxide diminishes the T-cell regulatory activity of NO. The role for NADPH oxidase as a source for NO-inhibiting superoxide is discussed. In conclusion, NO plays an important regulatory role in the induction phase of T-cell-mediated immunity. Superoxide may enhance T-cell-mediated immunity by preventing the immunosuppressive activity of NO.     

一氧化氮合酶抑制剂与脑缺血

随着对一氧化氮、一氧化氮合酶在脑缺血中作用的深入研究，一氧化氮合酶抑制剂也在不断被开发，并成为保护缺血脑损伤的热点研究之一。本文综述了一氧化氮合酶抑制剂尤其是nNOS和iNOS抑制剂在脑缺血损伤中的作用，为缺血性脑损伤疾病的治疗提供新的途径。