Role Of Nitric Oxide In Pathophysiology Research Articles

Exhaled breath analysis in evaluation of psychological stress: A short literature review.

Physiological stress is pervasive in today's society. Its detection is normally performed through several unobtrusive methods, driving both caregivers and patients to take measures to reduce the burden of this condition on human health. Among the methods for assessing stress, exhaled breath analysis represents a non-invasive, real-time alternative to classic laboratory tests. Therefore, a literature review was performed to assess the presence of altered parameters, related to psychological stress, in exhaled breath. Most studies in our review measured nitric oxide (NO), whose concentration was often correlated, either positively or negatively, with psychological stress, with reasonable scientific support. Other compounds (isoprene, terpene and so on) were rarely studied and with mixed evidence. Further investigations are needed to elucidate the involvement and the pathophysiological role of NO in stress, possibly including a greater number of individuals, as sample size actually represents the main limitation of the work published to date.

Exhaled Nitric Oxide Measurement in Patients Affected by Nasal Polyposis

Nitric oxide (NO) is produced in the respiratory tract with a major contribution coming from paranasal sinuses and the nose. The pathophysiological role of NO in the airways has been debated. The aims of this study were to measure fraction of exhaled NO (FENO), a validated marker of airway inflammation, in patients affected by nasal polyposis with and without asthma; to assess the importance of FENO measurement in detecting subclinical involvement of lower airways in patients with clinical rhinosinusal symptoms; and to clarify the impact of endoscopic surgical removal of polyps on airway inflammation. The study was conducted at the O.R.L. Clinic and Clinical Pharmacology Unit, University Hospital Agostino Gemelli, Rome, Italy. Prospective study. Concentrations of FENO were measured with the NIOX system (Aerocrine, Stockholm, Sweden) by using a single-breath online method, according to the American Thoracic Society guidelines. Compared with those in healthy subjects (15 [11-19] ppb, n = 15; P < .0001), FENO values were elevated in patients with nasal polyposis (41 [21-77] ppb, n = 43). There was no significant difference in FENO concentrations between asthmatic and nonasthmatic patients with nasal polyposis (P = .73). Concentrations of FENO in patients with nasal polyposis were decreased after surgery (64.2 [30.0-132.7] ppb vs 56.0 [26.4-73.8] ppb, respectively; P = .03). The fraction of exhaled NO is elevated in the inflammatory process involving both the rhinosinusal district and lower airways, supporting the one-airway disease hypothesis.

Nitric Oxide in Asthma Physiopathology

Asthma is a chronic inflammatory airway disease characterized by allergen-induced airway hyperresponsiveness, airway inflammation, and remodeling. Nitric oxide (NO) derived from constitutive and inducible enzymes affects many aspects of asthma physiopathology. Animal in vivo studies have indicated that inhibition of iNOS may play a central role in the modulation of these features, particularly extracellular matrix remodeling. Additionally, increases in iNOS-derived NO, observed in asthmatic patients, may lead to an increase in peroxynitrite and an imbalance of oxidant and antioxidant pathways. In addition, endogenous nitric oxide produced by constitutive enzymes may protect against the remodeling of the lung. Therefore, nitric oxide donors and/or iNOS inhibitors may have therapeutic potential in asthma treatment and can also be used with corticosteroids to counteract airway remodeling. This paper focuses on the pathophysiological role of nitric oxide, mainly derived from inducible isoforms, in the various pathologic mechanisms of allergic asthma and the importance of nitric oxide and/or arginase inhibitors in asthma treatment.

Cerebral blood flow regulation by nitric oxide in neurological disorders

There has been a rapid increase in the amount of information on the physiological and pathophysiological roles of nitric oxide (NO) in the brain. This molecule, which is formed by the constitutive isoforms of NO synthase, endothelial (eNOS) and neuronal (nNOS), plays an obligatory role in the regulation of cerebral blood flow and cell viability and in the protection of nerve cells or fibres against pathogenic factors associated with Alzheimer's disease, Huntington's disease, seizures, and migraine. Cerebral blood flow is impaired by decreased formation of NO from endothelial cells, autonomic nitrergic nerves, or brain neurons and also by increased production of reactive oxygen species (ROS). The NO-ROS interaction is an important topic in discussing blood flow and cell viability in the brain. Excessive production of NO by inducible NOS (iNOS) and nNOS in the brain participates in neurotoxicity. Recent studies on brain circulation have provided useful information about the involvement of impaired NO availability or uncontrolled NO production in cerebral pathogenesis, including Alzheimer's disease, seizures, vascular headaches, and inflammatory disorders. Insight into the role of NO in the brain will contribute to our better understanding of cerebral hemodynamic dysfunction and will aid in developing novel therapeutic measures in diseases of the central nervous system.

Nitric oxide, health and disease

Nitric oxide is a gaseous substance which possesses many important physiological characteristics ranging from its action as a natural immune mechanism to endothelial control of blood pressure. However, it can also generate nitrogen reactive species (peroxynitrite and others), which are involved as a cause of or a consequence of many diseases. This article updates and summarizes the physiological and pathophysiological roles of nitric oxide.

The shy Angeli and his elusive creature: the HNO route to vasodilation

what we now call Angeli's salt (AS) was discovered more than a century ago by the Italian chemist Angelo Angeli (Fig. 1) . He found that “salts of nitroxylaminic acid are readily resolved into the corresponding nitrites and the unsaturated residue nitroxyl” (HNO), proposing their use as suppliers of HNO (3). However, by analogy with the genial but very reclusive personality of the discoverer (17), the physiological properties of HNO didn't draw too much attention until early 1990s. In their seminal work, Fukuto and colleagues (19) reported that HNO elicits vasorelaxation in both the rabbit aorta and bovine intrapulmonary artery by a soluble guanylate cyclase (sGC)- dependent pathway. Later, it was evident that the thiol-donating agent l-cysteine can discriminate the vasodilatative profile of HNO from that of nitric oxide (NO·) or nitrosothiols: AS/HNO action can be blocked by this agent, whereas the NO· effect is potentiated (36). In combination with the suggestion that NO· is the only species able to directly activate sGC (9), these data led to the conclusion that HNO-induced vasorelaxation is due to its intracellular conversion to NO· with subsequent activation of sGC. For several years, this idea has relegated HNO to a mere precursor of the presence and biological activity of NO·, de facto negating to HNO its own right to exist.

Nitric oxide signaling comes of age: 20 years and thriving

The lyrics of a famous tango state that “twenty years time is just nothing”. While this impression may broadly apply to different circumstances, such might not be the case for nitric oxide (NO). In the year 1987 two seminal contributions coming from independent laboratories [1,2] established the identity of the elusive endothelial derived relaxing factor reported by Bob Furchgott seven years earlier [3]. These laboratories showed that the chemical nature of “endothelium-derived relaxing factor” (EDRF) was identical to NO. The idea that NO could act as an activator of soluble guanylate cyclase had been proposed even earlier [4]. These four papers, together with the demonstration of l-arginine as substrate for the generation of NO [5], defined a pathway in endothelial cells which is now considered classical: the l-arginine-NO-cGMP pathway. Of importance, a considerable amount of information had already accumulated almost at the same time and had arrived at the same conclusions in non-vascular cells such as macrophages (see [6] for review). For the past twenty years, we have both witnessed and participated in an explosion of knowledge in the NO field, leading to the comprehension of the physiological and pathophysiological roles of NO in several organs and tissues, among which the cardiovascular system is “primus inter pares”. This Spotlight Issue is devoted to classical and non-classical targets of NO signaling in the cardiovascular system. One of the most cogent analyses of NO signaling in pathways independent from cGMP was published in 1992, in which Loscalzo and colleagues proposed that S -nitrosylation of albumin could represent an effective mechanism to deliver NO at distal sites [7]. Studies from the laboratories of Stamler, Loscalzo and others opened a new perspective related to the potential modification of protein function by S -nitros(yl)ation [8]. In this current … * Corresponding author. Centro de Investigaciones Biologicas-CSIC, Ramiro de Maeztu 9, Madrid, 28040, Spain. Tel.: +34 91 837 3112x4302, +34 64 941 8799 (mobile); fax: +34 91 536 0432. slamas{at}cib.csic.es

Nitric oxide, antioxidant capacity, nitric oxide synthase and xanthine oxidase plasma levels in a cohort of burn patients

Background Nitric oxide (NO) is an important signal molecule in many types of cells and tissues. Efficiently balanced NO production was noted to play an important role in the healing of burns. However, the exact pathophysiological role of NO in burns and its potent relation with clinical and laboratory parameters has not been elucidated. Methods A cohort of 23 burn patients followed for 5 days were enrolled. NO, antioxidant capacity (AC), NO synthase (NOS) activity and xanthine oxidase (XO) activity were indirectly determined by fluorophotometer. Multiple regression against total burn surface area (TBSA), age, weight, height, proximity of septic episode, hemoglobin, white blood cells, percent of neutrophils, platelets, glucose, urea, potassium, sodium and albumin was performed. Results Elevation of NO, XO and AC levels is observed from day 2 ( p < 0.00001), day 4 ( p = 0.005) and day 6 ( p = 0.036), respectively. At the end of follow-up period (day 6), NO production was found to independently correlate with TBSA, glucose levels and percent of neutrophils ( p = 0.0004), AC with age, hemoglobin and glucose levels ( p = 0.012), and NOS with proximity of septic episode and glucose levels ( p = 0.027). Conclusions NO production exerts its prophylactic effect from the first 24 h after burn, and is independently correlated with severe injury, enhanced neutrophil motivation and augmented glucose levels, thus possibly representing a response to stress. This need might trigger induction of XO and salvage of antioxidants, as suggested by their rise at a later stage. These data underline that an effort to compromise stress and to administer antioxidants could be a priority in the treatment of these patients.

Pathophysiological role of nitric oxide (NO) in the preconditioning-induced ischemic tolerance of neurons in neuron/astrocyte co-cultures

Pathophysiological role of nitric oxide (NO) in the preconditioning-induced ischemic tolerance of neurons in neuron/astrocyte co-cultures

Pathophysiological Roles of Nitric Oxide: In the Heart and the Coronary Vasculature

Nitric oxide is a key player among the numerous mediators of endothelial homeostasis and cardiac contractility and is thereby involved in the pathogenic processes leading to vascular and myocardial dysfunctions. Although none of the current paradigms would elevate the influence of NO on cardiac contraction to the level of that of e.g., catecholamines or increased calcium, this unusual signaling molecule can modulate virtually all the regulatory steps of excitationcontraction coupling and influence the course of cardiac decompensation. Not only alterations in spatial confinement or post-translational modifications but also changes in the abundance of one of the three NOS isoforms may result in profound cellular disturbancies that participate in the endothelial and contractile dysfunctions leading to cardiovascular diseases. Keywords: nitric oxide, nitric oxide synthase, heart, endothelium, coronary, ischemia, Infarct, mechanoenergetic uncoupling

Role of nitric oxide in liver injury.

The complex role of nitric oxide (NO) in the liver can be explained by its patterns of regulation and unique biochemical properties. With a broad range of direct and indirect molecular targets, NO acts as an inhibitor or agonist of cell signaling events. In the liver, constitutively generated NO maintains the hepatic microcirculation and endothelial integrity, while inducible NO synthase (iNOS)-governed NO production can be either beneficial or detrimental. For instance, NO potentiates the hepatic oxidative injury in warm ischemia/reperfusion, while iNOS expression protects against hepatic apoptotic cell death seen in models of sepsis and hepatitis. Anti-apoptotic actions are either cyclic nucleotide dependent or independent, including the expression of heat shock proteins, prevention of mitochondrial dysfunction, and inhibition of caspase activity by S-nitrosation. Whether NO protects or injures is probably determined by the type of insult, the abundance of reactive oxygen species (ROS), the source and amount of NO production and the cellular redox status of liver. Through the use of pharmacological NO donors or NOS gene transfer in conjunction with genetically altered knockout animals, the physiological and pathophysiological roles of NO in liver function can be explored in more detail. The purpose of this paper is to review the current understanding of the role of NO in liver injury.

Real-time measurement of nitric oxide by luminol-hydrogen peroxide reaction in crystalloid perfused rat heart

The objective of this study was to develop an assay system that allows continuous monitoring of nitric oxide (NO) released from crystalloid perfused hearts. We utilized chemiluminescence reaction between NO and luminol-H 2O 2 to quantify the NO level in coronary effluent. Isolated rat hearts were subjected to ordinary Langendorff's perfusion, and the right ventricle was cannulated to sample coronary effluent. After equilibration, the coronary flow rate was set constant and the hearts were paced at 300 bpm. Coronary effluent was continuously sampled and mixed with the chemiluminescent probe containing 0.018 mmol/l luminol plus 10 mmol/l H 2O 2. Chemiluminescence from the mixture of coronary effluent and the probe was continuously measured. NO concentration was calibrated by various concentrations (0.5–400 pmol/l) of standard NO solution. The lower detection limit of NO was 1 pmol/l. Basal NO release from isolated perfused rat heart was 0.41 ± 0.17 pmol/min/g of heart weight, and that was significantly suppressed by 0.1 mmol/l of L-NAME to 0.18 ± 0.10 pmol/min/g of heart weight (n = 7). Application of 0.1 and 0.3 μmol/l acetylcholine increased NO level in the coronary effluent, in a concentration-dependent manner, from 6.6 ± 1.7 in a baseline condition to 16.3 ± 7.4 and 30.3 ± 16.1 pmol/l at each peak, respectively. Thrombin at 1 and 10 U/ml also increased NO level from 17.6 ± 4.3 in control to 35.5 ± 10.4 and 48.7 ± 8.7 pmol/l at each peak, respectively (n = 7). Thus, this assay system is applicable to the continuous real-time measurement of NO released from crystalloid perfused hearts, and it may be useful for the study of physiological or pathophysiological role of NO in coronary circulation.

Pathophysiological role of nitric oxide and adrenomedullin in autism.

Several studies indicate that nitric oxide (NO) is involved in the aetiopathogenesis of many neuropsychiatric disorders such as schizophrenia, bipolar disorder, depression, Alzheimer's disease, Hungtington disease and stroke. Although it has not been investigated yet, several recent studies proposed that NO may have a pathophysiological role in autism. Adrenomedullin (AM), a recently discovered 52-amino acid peptide hormone, induces vasorelaxation by activating adenylate cyclase and also by stimulating NO release. AM immune reactivity is present in the brain consistent with a role as a neurotransmitter. It has been stated that NO and AM do function in the regulation of many neurodevelopmental processes. We hypothesized that NO and AM activities have been affected in autistic patients and aimed to examine these molecules. Twenty-six autistic patients and 22 healthy control subjects were included in this study. AM and total nitrite (a metabolite of NO) levels have been measured in plasma. The mean values of plasma total nitrite and AM levels in the autistic group were significantly higher than control values, respectively (p < 0.001, p = 0.028). There is no correlation between total nitrite and AM levels (r = 0.11, p = 0.31). Certainly, this subject needs much further research investigating autistic patients in earlier periods of life and with subtypes of the disorder.

Selective augmenting effects of nitric oxide on antigen-specific IgE response in mice

Here, we report the enhancing effects of nitric oxide (NO) on an IgE antibody response in mice. Anti-trinitrophenyl (TNP) IgE production induced in vitro in TNP keyhole limpet hemocyanin (KLH)-primed spleen cells was inhibited by approximately 70% when an NO synthase (NOS) inhibitor, l-NG-monomethyl-l-arginine, was added at 10−7–10−6 M to the lymphocyte culture. On the other hand, addition of NO-generating agents to the culture resulted in a marked enhancement of the IgE production. In contrast, anti-TNP IgM and IgG1 responses were affected only marginally when the IgE production was either suppressed or augmented by these agents. NO did not directly augment IgE class switching in normal B cells stimulated with lipopolysaccharide and interleukin (IL)-4. NO-mediated augmentation of the IgE response is considered to be of a physiological significance because administration of aminoguanidine (AG), an inhibitor of inducible NOS, to immunized mice resulted in a preferential suppression of anti-TNP IgE production in vivo. This may be explained by the observation that AG-administration increased interferon-γ expression without changing that of IL-4 in the immunized mice. Taken together, these observations suggest a pathophysiological role of NO in the development of IgE-mediated allergic diseases.

A defect of lipopolysaccharide-induced nitric oxide synthase gene expression in the paraventricular nucleus of Lewis rats.

The hypothalamo-pituitary-adrenal (HPA) axis activity of Lewis rats has been reported to be hyporesponsive to immune challenge, and nitric oxide (NO) has been demonstrated to be involved in the regulation of the HPA axis during the response to immune challenge. The present study investigates the effect of systemic injection of lipopolysaccharide (LPS) on NO production within the paraventricular nucleus (PVN) of immature female Fisher-344 (F344) and Lew/N rats (Lew/N), to clarify the pathophysiological role of NO in the dysregulation of the HPA axis in Lewis/N. Intraperitoneal injection of 25 mg/kg LPS significantly increased neuronal NO synthase (nNOS) mRNA expression in the PVN of F344 rats, but did not change nNOS mRNA levels in the PVN of Lew/N rats. CRF mRNA levels in the PVN significantly increased in response to LPS injection only in F344 rats. In contrast, inducible NOS (iNOS) mRNA increased similarly in both strains. These results demonstrated a defect of up-regulation of nNOS gene expression in the PVN of Lew/N rats following immune challenge. The defect appears to be associated with the dysfunction of the HPA axis in this strain. An increase in iNOS mRNA may partially restore NO production in the PVN.

Pathophysiological role of nitric oxide in streptozotocin-induced diabetic neuropathy

Pathophysiological role of nitric oxide in streptozotocin-induced diabetic neuropathy

Chronic Inhibition of Nitric Oxide Ameliorates Splanchnic Hyposensitivity to Glypressin in a Hemorrhage-transfused Rat Model of Portal Hypertension

Background: Vasopressin given during hemorrhage is less effective than when given during a stable state in experimental portal hypertension or patients with cirrhosis (the so-called hyposensitivity phenomenon). This study investigated whether chronic inhibition of nitric oxide (NO) synthesis by NG-nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor, could potentiate the portal-hypotensive effect of glypressin (a long-acting vasopressin analogue) in portal-hypertensive rats during acute bleeding status. Methods: Portal hypertension was induced by partial portal vein ligation (PVL). Rats were divided to receive either L-NAME (~25 mg/kg/day in tap water) or placebo (tap water) treatment orally from 2 days prior to until 14 days after the operation. At the end of treatment, L-NAME-and placebo-treated PVL rats were subdivided into without-bleeding and with-bleeding groups to assess the effects of glypressin (0.07 mg/kg) on systemic and portal hemodynamics. In rats with a hypotensive hemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin. Results: As compared with placebo-treated rats, chronic treatment with L-NAME in PVL rats significantly increased mean arterial pressure (P < 0.001) without modulating portal pressure (P > 0.05). In placebo-treated PVL rats, glypressin resulted in a less decrease in portal pressure in rats with bleeding than in those without bleeding (P < 0.05). For PVL rats with bleeding, the portal-hypotensive effect of glypressin was significantly potentiated after chronic L-NAME treatment (P < 0.05). Conclusions: Chronic inhibition of NO alleviates the splanchnic hyposensitivity to glypressin observed in bleeding PVL rats, suggesting the pathophysiological role of nitric oxide in mediating this splanchnic hyposensitivity.

Measurement by in vivo brain dialysis of nitrite and nitrate levels as indices of nitric oxide production

Nitric oxide (NO) is a free radical gas with a role in signal transduction in diverse processes. In the central nervous system, NO acts as an intercellular signaling molecule as well as a neurotoxic substance. To clarify the role of NO in the brain, we measured nitrite and nitrate levels, as indices of NO production, in the dialysate of brains in conscious rats, by using an in vivo dialysis technique. We have demonstrated that NO production in the cerebellum can be modulated by the activation of glutamate receptors and KCl stimulation. Glial cells appear to be involved in the modulation of NO production by regulating the availability of an NO precursor, L-arginine. We have also demonstrated that NO plays a role in the development of lipopolysaccharide-induced brain dysfunction and pentylenetetrazol-induced kinding. We believe that the in vivo dialysis method to measure nitrite and nitrate levels as indices of NO production is a useful tool for investigating physiological and pathophysiological roles of NO in the brain.

Nitric oxide as a signaling molecule in the vascular system: an overview.

In retrospect, basic research in the fields of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) during the past two decades appears to have followed a logical course, beginning with the findings that NO and cGMP are vascular smooth muscle relaxants, that nitroglycerin relaxes smooth muscle by metabolism to NO, progressing to the discovery that mammalian cells synthesize NO, and finally the revelation that NO is a neurotransmitter mediating vasodilation in specialized vascular beds. A great deal of basic and clinical research on the physiologic and pathophysiologic roles of NO in cardiovascular function has been conducted since the discovery that endothelium-derived relaxing factor (EDRF) is NO. The new knowledge on NO should enable investigators in this field to develop novel and more effective therapeutic strategies for the prevention, diagnosis, and treatment of numerous cardiovascular disorders. The goal of this review was to highlight the early research that led to our current understanding of the pathophysiologic role of NO in cardiovascular medicine. Furthermore, we discussed the possible mechanism of some drugs interfering with NO signaling cascade.

Induction of Neuronal and Inducible Nitric Oxide Synthase in the Motoneurons of Spinal Cord Following Transient Abdominal Aorta Occlusion in Rats

Background. Motoneurons in the spinal cord are especially vulnerable to ischemic injury and selectively destroyed after transient ischemia. Nitric oxide (NO) has been implicated in both neurodegneration and neuroprotection to ischemic insult. To evaluate the role of NO in pathophysiology to spinal cord ischemia, the expression of neuronal and inducible nitric oxide synthase (n-NOS and i-NOS) and nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) in the motoneurons of the lumbosacral spinal cord was examined in a rat model with transient abdominal aorta (TAA) occlusion.Materials and Methods. Male Sprague–Dawley rats were divided into sham-operated (n = 12) and TAA occlusion (n = 24) groups. TAA occlusion was induced by placement of a microvascular clamp around the abdominal aorta for 20 min. Three sham-operated and six TAA occlusion animals were sacrificed at each time interval at 4, 24, and 48 h and 7 days after operation. Tissue sections obtained from the lumbosacral spinal cord were processed for n-NOS, i-NOS, NADPH-d, and hematoxylin–eosin (HE) staining. Histological changes of motoneurons in ventral horn were assessed by HE staining.Results. In sham-operated control animals, n-NOS-, i-NOS-, and NADPH-d-positive neurons were barely detectable in the ventral horn of the spinal cord. At 4 h after TTA occlusion, n-NOS and NADPH-d expression became evident in the motoneurons and was markedly enhanced at 24 and 48 h. i-NOS expression was also induced in the ventral horn motoneurons of the lumbosacral spinal cord at the same time points. Enzymatic expression in the motoneurons was diminished 7 days after operation. Hyperchromatic neurons indicative of cell death were observed in HE-stained specimens 7 days following TAA occlusion.Conclusions. The rapid induction of n-NOS, i-NOS, and NADPH-d in the motoneurons of ventral horn suggests that NO may be involved in the selective and delayed neuronal death in the spinal cord to the ischemic insult.