Gaseous Oxides and Olfactory Computation

The gaseous neurotransmitters nitric oxide (NO) and carbon monoxide(CO) are prominent and universal components of the array ofneurotransmitters found in olfactory information processingsystems. These highly mobile communication compounds have effectson both second messenger signaling and directly on ion channelgating in olfactory receptors and central synaptic processingof receptor input. Olfactory systems are notable for the plasticityof their synaptic connections, revealed both in higher-orderassociative learning mechanisms using odor cues and developmentalplasticity operating to maintain function during addition ofnew olfactory receptors and new central olfactory interneurons.We use the macrosmatic terrestrial mollusk Limax maximus toinvestigate the role of NO and CO in the dynamics of centralodor processing and odor learning. The major central site ofodor processing in the Limax CNS is the procerebral (PC) lobeof the cerebral ganglion, which displays oscillatory dynamicsof its local field potential and periodic activity waves modulatedby odor input. The bursting neurons in the PC lobe are dependenton local NO synthesis for maintenance of bursting activity andwave propagation. New data show that these bursting PC interneuronsare also stimulated by carbon monoxide. The synthesizing enzymefor carbon monoxide, heme oxygenase 2, is present in the neuropilof the PC lobe. Since the PC lobe exhibits two forms of synapticplasticity related to both associative odor learning and continualconnection of new receptors and interneurons, the use of multiplegaseous neurotransmitters may be required to enable these multipleforms of synaptic plasticity.     

Heme oxygenase-2 and nitric oxide synthase immunoreactivity of bovine olfactory receptor neurons and a comparison with the distribution of NADPH-diaphorase staining

It has recently been suggested that, in addition to nitric oxide (NO), carbon monoxide (CO) is an important gaseous messenger which might be involved in vertebrate olfactory transduction because its effects include activation of guanylyl cyclase and the formation of cGMP. As there is no information regarding the presence of heme oxygenase-2 – the constitutive isoform of the heme oxygenase system – in olfactory neurons of non-rodent species, we have investigated the distribution pattern of heme oxygenase-2 in the olfactory epithelium of the bovine, a representative of macrosmatics. Localization of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) activity of the olfactory epithelium was compared with heme oxygenase-2 and NO synthase (NOS) immunoreactivities in order to obtain possible hints at functional significance. NADPH-d activity was particularly intense in apical dendrites of receptor neurons. It was also found in Bowman glands and intraepithelial duct cells. Less intense, discrete NADPH-d activity was present also at intermediate and basal levels of the olfactory epithelium, corresponding to the layer of receptor neuron somata and basal cells. While heme oxygenase-2 activity mainly occured in neuronal perikarya, a very intense NOS immunoreactivity, exclusively for the inducible isoform, was detected in the apical dendrites. Ultrastructurally, NADPH-d histochemistry showed distinct labelling of membranes, in particular of endoplasmic reticulum, mitochondria and nucleus. The coincident localization of the moderate NADPH-d activity and heme oxygenase-2 immunoreactivity in receptor cell perikarya suggest a functional association between NADPH-cytochrome P450 reductase and heme oxygenase-2. In contrast, dendritic localization of NADPH-d activity is topically and possibly functionally related to the presence of the inducible isoform of NOS. The results suggest that both CO and NO may be generated in bovine receptor neurons and thus involved in odorant stimulation. Based on immunocytochemical localization of synthesizing enzymes, NO might be regarded as a direct regulator of transduction related processes while CO might act as a modulator of the initial signal.     

Cardiovascular and renal control in NOS-deficient mouse models

Nitric oxide (NO) plays an essential role in the maintenance of cardiovascular and renal homeostasis. Endogenous NO is produced by three different NO synthase (NOS) isoforms: endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS). To investigate which NOS is responsible for NO production in different tissues, NOS knockout (-/-) mice have been generated for the three isoforms. This review focuses on the regulation of cardiovascular and renal function in relation to blood pressure homeostasis in the different NOS-/- mice. Although regulation of vascular tone and cardiac function in eNOS-/- has been extensively studied, far less is known about renal function in these mice. eNOS-/- mice are hypertensive, but the mechanism responsible for their high blood pressure is still not clear. Less is known about cardiovascular and renal control in nNOS-/- mice, probably because their blood pressure is normal. Recent data suggest that nNOS plays important roles in cardiac function, renal homeostasis, and regulation of vascular tone under certain conditions, but these are only now beginning to be studied. Inasmuch as iNOS is absent from the cardiovascular system under physiological conditions, it may become important to blood pressure regulation only during pathological conditions related to inflammatory processes. However, iNOS is constitutively expressed in the kidney, where its function is largely unknown. Overall, the study of NOS knockout mice has been very useful and produced many answers, but it has also raised new questions. The appearance of compensatory mechanisms suggests the importance of the different isoforms to specific processes, but it also complicates interpretation of the data. In addition, deletion of a single gene may have physiologically significant effects in addition to those being studied. Thus the presence or absence of a specific phenotype may not reflect the most important physiological function of the absent gene.     

Modulation of growth cone filopodial length by carbon monoxide

Carbon monoxide (CO) is physiologically produced via heme degradation by heme oxygenase enzymes. Whereas CO has been identified as an important physiological signaling molecule, the roles it plays in neuronal development and regeneration are poorly understood. During these events, growth cones guide axons through a rich cellular environment to locate target cells and establish synaptic connections. Previously, we have shown that another gaseous signaling molecule, nitric oxide (NO), has potent effects on growth cone motility. With NO and CO sharing similar cellular targets, we wanted to determine whether CO affected growth cone motility as well. We assessed how CO affected growth cone filopodial length and determined the signaling pathway by which this effect was mediated. Using two well‐characterized neurons from the freshwater snail, Helisoma trivolvis , it was found that the CO donor, carbon monoxide releasing molecule‐2 (CORM‐2), increased filopodial length. CO utilized a signaling pathway that involved the activation of soluble guanylyl cyclase, protein kinase G, and ryanodine receptors. While increases in filopodial length often occur from robust increases in intracellular calcium levels, the timing in which CO increased filopodial length corresponded with low basal calcium levels in growth cones. Taken together with findings of a heme oxygenase‐like protein in the Helisoma nervous system, these results provide evidence for CO as a modulator of growth cone motility and implicate CO as a neuromodulatory signal during neuronal development and/or regeneration. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 677–690, 2017     

Mechanisms of microRNA-mediated gene regulation in animal cells

MicroRNAs are a large family of regulatory molecules found in all multicellular organisms. Even though their functions are only beginning to be understood, it is evident that microRNAs have important roles in a wide range of biological processes, including developmental timing, growth control, and differentiation. Indeed, recent bioinformatic and experimental evidence suggests that a remarkably large proportion of genes (>30%) are subject to microRNA-mediated regulation. Although it is clear that microRNAs function by suppressing protein production from targeted mRNAs, there is, at present, no consensus about how such downregulation is accomplished. In this review, I describe the evidence that there are multiple mechanisms of microRNA-mediated repression and discuss the possible connections between these mechanisms.     

Olfactory receptors: G protein-coupled receptors and beyond

Sensing the chemical environment is critical for all organisms. Diverse animals from insects to mammals utilize highly organized olfactory system to detect, encode, and process chemostimuli that may carry important information critical for health, survival, social interactions and reproduction. Therefore, for animals to properly interpret and react to their environment it is imperative that the olfactory system recognizes chemical stimuli with appropriate selectivity and sensitivity. Because olfactory receptor proteins play such an essential role in the specific recognition of diverse stimuli, understanding how they interact with and transduce their cognate ligands is a high priority. In the nearly two decades since the discovery that the mammalian odorant receptor gene family constitutes the largest group of G protein-coupled receptor (GPCR) genes, much attention has been focused on the roles of GPCRs in vertebrate and invertebrate olfaction. However, is has become clear that the 'family' of olfactory receptors is highly diverse, with roles for enzymes and ligand-gated ion channels as well as GPCRs in the primary detection of olfactory stimuli.     

Prostaglandin E2 synthases in neurologic homeostasis and disease

Prostaglandin E₂ synthases (PGES) currently comprise a group of three structurally and biologically distinct molecules. These enzymes are part of an important and complex paracrine signaling system involved in a wide range of biological processes. This review focuses on the normal physiological and pathological roles of these enzymes in the nervous system. Specific topics include the role of PGES(s) in fever and sickness behavior, inflammatory pain, and neural disease. Although the field is in its early stages, ongoing development of selective PGES inhibitors for possible use in people creates a significant need for more fully understanding the biological roles of these important enzymes.     

昆虫气味认知的嗅觉神经结构及分子机制

大多数昆虫主要通过气味认知感知外界环境的变化,维持生命活动。探究昆虫气味认知的嗅觉系统神经结构及分子机制,对于完善气味认知神经生物学理论及利用其原理进行仿生学研究等有重要的科学意义。近年,关于昆虫气味认知科学研究有了很大的进展。本文从昆虫神经生物学的视角详细综述了近年关于昆虫气味认知的嗅觉神经结构、分子机制及气味信号的神经传导途径等方面的基本理论及最新研究成果。综述结果显示:昆虫对气味的认知是通过嗅觉神经系统的触角感器、触角叶(AL)、蕈形体(MB)等脑内多层信号处理神经结构来实现的。当外界气味分子进入触角感器内后,由感器内特定的气味识别蛋白(OBP)将气味分子运载到达嗅觉感受神经元(ORN)树突膜上的受体位点,气味分子与表达特定气味的受体(OR)结合产生电信号,并以动作电位的形式通过ORN的轴突传到脑内的触角叶。在触角叶经过嗅觉纤维球对气味信息选择性加工处理,再由投射神经元(PNs)将初步的识别和分类的气味信息传到蕈形体和外侧角(LH)等神经中枢,实现对气味的识别和认知。虽然,近年昆虫气味认知神经生物学的研究有了很大的进步,但是,我们认为目前的研究成果还不能完全阐明昆虫气味认知的神经机制,还有很多问题,例如,触角叶上众多的嗅觉纤维球是如何对嗅觉感受神经元传入的气味信息进行编码处理的?等有待进一步深入研究。为了搞清这些疑难问题,我们认为需要提高现有的实验技术水平,加强电生理学和分子神经生物学相结合的实验研究,从分子水平探究气味认知的神经机制可能是未来研究的热点。     

Regulation and function of axon guidance and adhesion molecules during olfactory map formation

The olfactory system presents a practical model for investigating basic mechanisms involved in patterning connections between peripheral sensory neurons and central targets. Our understanding of olfactory map formation was advanced greatly by the discovery of cAMP signaling as an important determinant of glomerular positioning in the olfactory bulb. Additionally, several cell adhesion molecules have been identified recently that are proposed to regulate homotypic interactions among projecting axons. From these studies a model has emerged to partially explain the wiring of axons from widely dispersed neuron populations in the nasal cavity to relatively stereotyped glomerular positions. These advances have revitalized interest in axon guidance molecules in establishing olfactory topography, but also open new questions regarding how these patterns of guidance cues are established and function, and what other pathways, such as glycosylation, might be involved. This review summarizes the current state of this field and the important molecules that impact on cAMP-dependent mechanism in olfactory axon guidance.     

Oscillations and gaseous oxides in invertebrate olfaction

Olfactory systems combine an extraordinary molecular sensitivity with robust synaptic plasticity. Central neuronal circuits that perform pattern recognition in olfaction typically discriminate between hundreds of molecular species and form associations between odor onsets and behavioral contingencies that can last a lifetime. Two design features in the olfactory system of the terrestrial mollusk Limax maximus may be common elements of olfactory systems that display the twin features of broad molecular sensitivity and rapid odor learning: spatially coherent oscillations in the second-order circuitry that receives sensory input; and involvement of the interneuronal messengers nitric oxide (NO) and carbon monoxide (CO) in sensory responses and circuit dynamics of the oscillating olfactory network. The principal odor processing center in Limax, the procerebrum (PC) of the cerebral ganglion, contains on the order of 10⁵ local interneurons and receives both direct and processed input from olfactory receptors. Field potential recordings in the PC show an oscillation at approximately 0.7 Hz that is altered by odor input. Optical recordings of voltage changes in local regions of the PC show waves of depolarization that originate at the distal pole and propagate to the base of the PC. Weak odor stimulation transiently switches PC activity from a propagating mode to a spatially uniform mode. The field potential oscillation in the PC lobe depends on intercellular communication via NO, based on opposing effects of reagents that decrease or increase NO levels in the PC. Inhibition of NO synthase slows the field potential oscillation, while application of exogenous NO increases the oscillation frequency. A role for CO in PC dynamics is suggested by experiments in which CO liberation increases the PC oscillation frequency. These design features of the Limax PC lobe odor processing circuitry may relate to synaptic plasticity that subserves both connection of new receptors throughout the life of the slug and its highly developed odor learning ability. © 1996 John Wiley & Sons, Inc.     

Role of heme oxygenase in preserving vascular bioactive NO

Beyond its vasodilator role, vascular nitric oxide (NO), which is synthesized by endothelial NO synthase (eNOS) via its activation, has been shown to play a number of other beneficial roles in the vascular system; it inhibits proliferation of vascular smooth muscle cells, prevents platelet aggregation, and regulates endothelial apoptosis. Such beneficial roles have been shown to be implicated in the regulation of endothelial functions. A loss of NO bioavailability that may result either from decreased eNOS expression and activity or from increased NO degradation is associated with endothelial dysfunction, a key factor in the development of vascular diseases. Heme oxygenase-1 (HO-1), an inducible enzyme, catalyzes the oxidative degradation of heme to free iron, carbon monoxide, and biliverdin, the latter being subsequently converted into bilirubin. In the vascular system, HO-1 and heme degradation products perform important physiological functions, which are ultimately linked to the protection of vascular cells. Studies have shown that HO-1 and heme degradation products exert vasodilatory, antioxidant, anti-inflammatory, antiproliferative and anti-apoptotic effects on vascular cells. Interestingly, these effects of HO-1 and its by-products are similar, at least in part, to those of eNOS-derived NO; this similarity may prompt investigators to study a possible relationship between eNOS-derived NO and HO-1 pathways. Many studies have been reported, and accumulating evidence suggests that HO-1 and heme degradation products can improve vascular function, at least in part, by compensating for the loss of NO bioavailability. This paper will provide the possible pathway explaining how HO-1 and heme degradation products can preserve vascular NO.     

From molecule to mind: the role of experience in shaping olfactory function

The olfactory system is faced with a particular problem – the high dimensionality and inherent unpredictability of the chemical world. Most natural odorants encountered in everyday life are complex mixtures of many different volatiles. This means that from the outset the olfactory system has to contend with a great and often unpredictable diversity of molecules, making it difficult for stable primary features of the chemical world to be mapped onto the sensory surface. One solution to such unpredictability is provided by learning. Learning confers flexibility, enabling individuals of a given species to acquire and make use of the most appropriate information in a particular environment. Two examples of this are presented: learning of maternal odors in neonatal rabbits, including evidence that the sensory surface itself may be influenced by environmental conditions so as to enhance sensitivity to molecules of particular ecological relevance, and cross-cultural human studies suggesting that experience with everyday odors influences not only the way these are evaluated, but also their perceived intensity. It is concluded that an adequate understanding of odor coding and olfactory function will not be possible without taking such experience-dependent factors into account. Accepted: 11 May 1999     

Sex Pheromones of C. elegans Males Prime the Female Reproductive System and Ameliorate the Effects of Heat Stress

Pheromones are secreted molecules that mediate animal communications. These olfactory signals can have substantial effects on physiology and likely play important roles in organismal survival in natural habitats. Here we show that a blend of two ascaroside pheromones produced by C. elegans males primes the female reproductive system in part by improving sperm guidance toward oocytes. Worms have different physiological responses to different ratios of the same two molecules, revealing an efficient mechanism for increasing coding potential of a limited repertoire of molecular signals. The endogenous function of the male sex pheromones has an important side benefit. It substantially ameliorates the detrimental effects of prolonged heat stress on hermaphrodite reproduction because it increases the effectiveness with which surviving gametes are used following stress. Hermaphroditic species are expected to lose female-specific traits in the course of evolution. Our results suggest that some of these traits could have serendipitous utility due to their ability to counter the effects of stress. We propose that this is a general mechanism by which some mating-related functions could be retained in hermaphroditic species, despite their expected decay.     

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.     

Odorant-Dependent Generation of Nitric Oxide in Mammalian Olfactory Sensory Neurons

The gaseous signalling molecule nitric oxide (NO) is involved in various physiological processes including regulation of blood pressure, immunocytotoxicity and neurotransmission. In the mammalian olfactory bulb (OB), NO plays a role in the formation of olfactory memory evoked by pheromones as well as conventional odorants. While NO generated by the neuronal isoform of NO synthase (nNOS) regulates neurogenesis in the olfactory epithelium, NO has not been implicated in olfactory signal transduction. We now show the expression and function of the endothelial isoform of NO synthase (eNOS) in mature olfactory sensory neurons (OSNs) of adult mice. Using NO-sensitive micro electrodes, we show that stimulation liberates NO from isolated wild-type OSNs, but not from OSNs of eNOS deficient mice. Integrated electrophysiological recordings (electro-olfactograms or EOGs) from the olfactory epithelium of these mice show that NO plays a significant role in modulating adaptation. Evidence for the presence of eNOS in mature mammalian OSNs and its involvement in odorant adaptation implicates NO as an important new element involved in olfactory signal transduction. As a diffusible messenger, NO could also have additional functions related to cross adaptation, regeneration, and maintenance of MOE homeostasis.     

嗅觉受体在非嗅觉组织和细胞中的作用及其机制

嗅觉受体(olfactory receptor)不仅表达在鼻腔中,还广泛表达在全身其他部位,起着重要的生理作用.本文综述了非嗅觉组织和细胞中表达的嗅觉受体及其功能,这些嗅觉受体通过调控细胞周围的内源性化学物质,维持正常的生理功能,并且能在选定的外源性配体刺激下,表现出特定的功能.在医药领域,大约有40%上市药物的作用靶点都来自于G蛋白偶联受体(GPCR)家族,而嗅觉受体是GPCR中最大的基因家族,鉴于其表现出的重要作用,我们推测这些嗅觉受体可能成为未来重要的药物靶标.本文对非嗅觉组织和细胞中嗅觉受体功能的综述,一方面有利于将其作为潜在药物靶点,开发新的药物,另一方面也为中药中挥发性单体的药理作用提供了新的研究思路.     

Nitric oxide and cardiovascular effects: new insights in the role of nitric oxide for the management of osteoarthritis

Nitric oxide (NO) is an important mediator in both health and disease. In addition to its effects on vascular tone and platelet function, it plays roles in inflammation and pain perception that may be of relevance in osteoarthritis. Many patients with osteoarthritis take nonsteroidal anti-inflammatory drugs (NSAIDs) long term for pain control. Over recent years concern has been raised about the possible cardiovascular side effects of NSAIDs. The reasons for this possible increased cardiovascular risk with NSAIDs are not yet entirely clear, although changes in blood pressure, renal salt handling and platelet function may contribute. Recently, drugs that chemically link a NSAID with a NO donating moiety (cyclo-oxygenase-inhibiting NO-donating drugs [CINODs]) were developed. NO is an important mediator of endothelial function, acting as a vasodilator and an inhibitor of platelet aggregation, and having anti-inflammatory properties. The potential benefits of CINODs include the combination of effective analgesic and anti-inflammatory actions with NO release, which might counterbalance any adverse cardiovascular effects of NSAIDs. Effects of CINODs in animal studies include inhibition of vasopressor responses, blood pressure reduction in hypertensive rats and inhibition of platelet aggregation. CINODs may also reduce ischemic damage to compromised myocardial tissue. In addition, endothelial dysfunction is a recognized feature of inflammatory arthritides, and therefore a drug that might provide slow release of NO to the vasculature while treating pain is an attractive prospect in these conditions. Further studies of the effects of CINODs in humans are required, but these agents represent a potential exciting advance in the management of osteoarthritis.     

Roles of NO Signaling in Long-Term Memory Formation in Visual Learning in an Insect

Many insects exhibit excellent capability of visual learning, but the molecular and neural mechanisms are poorly understood. This is in contrast to accumulation of information on molecular and neural mechanisms of olfactory learning in insects. In olfactory learning in insects, it has been shown that cyclic AMP (cAMP) signaling critically participates in the formation of protein synthesis-dependent long-term memory (LTM) and, in some insects, nitric oxide (NO)-cyclic GMP (cGMP) signaling also plays roles in LTM formation. In this study, we examined the possible contribution of NO-cGMP signaling and cAMP signaling to LTM formation in visual pattern learning in crickets. Crickets that had been subjected to 8-trial conditioning to associate a visual pattern with water reward exhibited memory retention 1 day after conditioning, whereas those subjected to 4-trial conditioning exhibited 30-min memory retention but not 1-day retention. Injection of cycloheximide, a protein synthesis inhibitor, into the hemolymph prior to 8-trial conditioning blocked formation of 1-day memory, whereas it had no effect on 30-min memory formation, indicating that 1-day memory can be characterized as protein synthesis-dependent long-term memory (LTM). Injection of an inhibitor of the enzyme producing an NO or cAMP prior to 8-trial visual conditioning blocked LTM formation, whereas it had no effect on 30-min memory formation. Moreover, injection of an NO donor, cGMP analogue or cAMP analogue prior to 4-trial conditioning induced LTM. Induction of LTM by an NO donor was blocked by DDA, an inhibitor of adenylyl cyclase, an enzyme producing cAMP, but LTM induction by a cAMP analogue was not impaired by L-NAME, an inhibitor of NO synthase. The results indicate that cAMP signaling is downstream of NO signaling for visual LTM formation. We conclude that visual learning and olfactory learning share common biochemical cascades for LTM formation.     

A cell-based nitric oxide reporter assay useful for the identification and characterization of modulators of the nitric oxide/guanosine 3',5'-cyclic monophosphate pathway

Nitric oxide (NO) plays an important role in protection against the onset and progression of various cardiovascular disorders. Therefore, the NO/guanosine 3',5'-cyclic monophosphate (cGMP) pathway has gained considerable attention and has become a target for new drug development. We have established a rapid, homogeneous, cell-based, and highly sensitive reporter assay for NO generated by endothelial nitric oxide synthase (eNOS). In a coculture system, NO production is indirectly monitored in living cells via soluble guanylyl cyclase (sGC) activation and calcium influx mediated by the olfactory cyclic nucleotide-gated (CNG) cation channel CNGA2, acting as the intracellular cGMP sensor. Using this NO reporter assay, we performed a fully automated high-throughput screening campaign for stimulators of NO synthesis. The coculture system reflects most aspects of the natural NO/cGMP pathway, namely, Ca(2+)-dependent and Ca(2+)-independent regulation of eNOS activity by G protein-coupled receptor agonists, oxidative stress, phosphorylation, and cofactor availability as well as NO-mediated stimulation of cGMP synthesis by sGC activation. The NO reporter assay allows the real-time detection of NO synthesis within living cells and makes it possible to identify and characterize activators and inhibitors of enzymes involved in the NO/cGMP signaling pathway.     

Cross-talk between NO and oxyradicals,a supersystem that regulates energy metabolism and survival of animals

Mammalian tissues have large amounts of available ATP which are generated by oxidative phosphorylation in mitochondria. For the maintenance of the human body, a large amount of oxygen is required to regenerate these ATP molecules. A small fraction of the inspired oxygen is converted to superoxide radical and related metabolites even under physiological conditions. Most reactive oxygen species react rapidly with a variety of molecules thereby interfering with cellular functions and induce various diseases.

Nitric oxide (NO) is an unstable gaseous radical with high affinity for various molecules, such as hemeproteins, thiols, and related radicals. NO easily penetrates through cell membrane/lipid bilayers, forms dissociable complexes with these molecules and modulates cellular metabolism and functions. Because NO has an extremely high affinity for the superoxide radical, the occurrence of the latter might decrease the biological function of NO. Thus, superoxide radicals in and around vascular endothelial cells play critical roles in the pathogenesis of hypertension and vasogenic tissue injury. Because NO also reacts with molecular oxygen, it rapidly loses its biological activity, particularly under ambient atmospheric conditions where the oxygen tension is unphysiologically high. Thus, biological functions of NO are determined by the local concentrations of molecular oxygen and superoxide radicals.

NO also inhibits electron transfer reaction and ATP synthesis in mitochondria and aerobic bacteria, such as E. coli; the inhibitory effects are also enhanced by hypoxia. Thus, the cross-talk between NO, molecular oxygen and oxyradicals play critical roles in the regulation of energy metabolism, fates and the survival of aerobic organisms. The present work describes the pathophysiological significance of the supersystem driven by the cross-talk between NO and oxyradicals.