[Show abstract][Hide abstract] ABSTRACT: Nitric oxide (NO) effects in airways are influenced by the activity of NO-synthase isoforms and NO metabolism. Inducible NO-synthase (iNOS), which produces large amounts of NO, is active during the inflammatory process. NO quickly reacts, producing reactive oxygen species (ROS). In this study we attemepted to detect the expression of iNOS and markers of ROS in the airway hyperreactivity (AHR) condition. The study was performed in guinea pigs, divided into four groups. Two groups were treated with the non-selective inhibitor of NO-synthase L-NAME. The other two groups were used as controls. Exhaled NO was monitored in vivo, AHR was assessed both in vivo and in vitro, and the expression of iNOS in lung homogenate, and oxidative stress markers were measured in the venous blood. L-NAME significantly affected the AHR only in in vitro condition, blocked the expression of iNOS in control but not in sensitized animals, and decreased the level of exhaled NO. The results concerning the oxidative stress markers are equivocal. The study confirmed that NO is involved in the regulation of AHR; the effects being mediated via iNOS and ROS activity.
Full-text · Article · Sep 2014 · Advances in Experimental Medicine and Biology
[Show abstract][Hide abstract] ABSTRACT: Background:
Glutamatergic and nitrergic system participate in the control of respiratory system functions. It is only little information regarding a possible interaction of both systems in the airways hyperractivity. We investigated the effect of agents modulating the activity of these systems on the experimental ovalbumin-induced airways hyperreactivity as well as on the changes of exhaled nitric oxide (eNO) levels.
We used the agonists of NMDA receptors - N-methyl-D-aspartic acid (NMDA) and monosodium glutamate (MSG), selective competitive antagonist (DL-2-amino-5-phosphonovaleric acid - AP-5) and selective non-competitive antagonist (dizocilpine - MK-801) of these receptors. We used also non-specific inhibitor of NO synthases N(ω)-nitro-L-arginine methyl ester (L-NAME). The airways responsiveness to histamine or acetylcholine was evaluated under in vitro conditions.
NMDA administration caused the increase of tracheal smooth muscle response in ovalbumin-induced hyperreactivity to acetylcholine. The effect of MSG was less pronounced. MK-801 as well as AP-5 provoked the decrease of reactivity mainly to acetylcholine in tracheal smooth muscle. We recorded the changes in eNO levels. The activation of NMDA receptor with NMDA or MSG increased eNO levels. The inhibition of NO synthase with L-NAME caused the fall of eNO levels. MK-801 shows (within the group) the more expressive effect in the eNO levels during sensitization than AP-5 group.
The results confirm the possibility of NMDA receptors participation in the experimental airways hyperreactivity.
No preview · Article · May 2013 · Pharmacological reports: PR
[Show abstract][Hide abstract] ABSTRACT: The interest in L-arginine metabolism was triggered primarily by the discovery of nitric oxide (NO) synthesis in mammals and its remarkable biological roles. The real role of L-arginine in the airway hyperreactivity (AHR) has not been established yet. Therefore, we studied whether supplementation of L-arginine can influence the experimental AHR evoked by two different triggers - allergen and exogenous irritant (toluene vapours). Male TRIK strain guinea pigs were used in the study. We used two patterns of pretreatment with L-arginine in vivo, short- and long-term, in a dose of 300 mg/kg administered i.p., after which we studied reactivity of airway smooth muscles in vitro. Pretreatment with L-arginine for 3 days decreased the airway smooth muscle reactivity induced by toluene vapour, whereas pretreatment for 17 days was without any additional effect on smooth muscle reactivity. The short-term pretreatment in ovalbumin-induced hyperreactivity caused an increase in airway smooth muscle reactivity to lower concentrations of both bronchoconstrictors. On the other side, this pretreatment significantly decreased smooth muscle reactivity to high concentrations of both bronchoconstrictors. Supplementation of L-arginine resulted in a modification of the airway smooth muscle response. The effect of supplementation was different depending on the AHR trigger, airway region and pretreatment duration. The results also underscore the importance of an optimal L-arginine level for the control of bronchial tone.
No preview · Article · Jan 2013 · Advances in Experimental Medicine and Biology
[Show abstract][Hide abstract] ABSTRACT: It is proposed the link between the hyperactivity of NMDA receptors and airway hyperresponsiveness. We investigated the effect of agents modulating the activity of NMDA receptors in the ovalbumin-induced airway hyperreactivity in guinea pigs. The airways hyperreactivity was influenced by the agonist (NMDA) and selective antagonist - competitive (AP-5) and non-competitive (MK-801) of NMDA receptors. Airway responsiveness to histamine or acetylcholine was evaluated in in vitro conditions. NMDA administration caused the increase of tracheal smooth muscle response in ovalbumin-induced hyperreactivity to acetylcholine. MK 801 as well as AP-5 provoked the decrease of reactivity mainly to acetylcholine in tracheal smooth muscle, while the former, non-competitive antagonist was more effective. We recorded more pronounced response in tracheal than in lung tissue smooth muscle with more considerable response to acetylcholine than to histamine. The results of experiments show the modification of airway smooth muscles responses by agents modulating the activity of NMDA receptors. They confirm the possibility of NMDA receptors participation in experimental airway hyperreactivity. The results enlarge information regarding the link of the inflammatory diseases and glutamatergic system.
Preview · Article · Mar 2012 · General Physiology and Biophysics
[Show abstract][Hide abstract] ABSTRACT: General idea of this comprehensive review is to sum-marize information about the role of nitric oxide in the human body—cardiovascular, respiratory, urge-nital, gut, NO and immune system, however, NO sig-naling has a role also in musculoskeletal system, even in bones. NO in the past had been recognized as a molecule relevant to air pollution. In 1980 Furchgott and Zawadzki identified new messenger molecule within the endothelial cells with vasodilating potential and they named it endothelium derived relaxing fac-tor (EDRF). Seven years later the role of NO as a re-laxing factor was definitely proven. The fact of gas, being produced by cells, crossing membranes of neighboring cells and having a character of signal brought a brand new insight to the signaling physiol-ogy. The breakthrough in the NO history was in 1992, when it was assigned as "molecule of the year". Role of NO was defined mainly in the cardiovascular sys-tem, but as the research expanded, the ultimate func-tion, and mechanism of action, dual effect of NO had been identified in all systems of human body. NO in low concentrations considerably regulates the physio-logical functions, but in high concentration may con-tribute to the pathogenetic process. Knowledge the physiology of NO signaling cascades could have clini-cal application, mainly considering therapeutic poten-tial of NO donors, or antagonists of NO-synthases. This molecule has undoubtedly huge future potential.
Full-text · Article · Jan 2012 · Open Journal of Molecular and Integrative Physiology
[Show abstract][Hide abstract] ABSTRACT: This review is written to summarize and critically analyze pathogenesis of bronchial hyperreactivity (BHR) as an underlying outcome for suitable treat-ment options. It describes and discusses the role of genetic predisposition, inflammatory mediators and other endogenous factors (growth factors, nuclear transcription factors), neural regulation and pro-
inflammatory neurotransmitter in the pathogenesis of BHR. Based on these data it provides brief insight into the treatment options, which could be applied to minimize symptoms of respiratory diseases charac-terized by BHR and successfully diminish the patho-genesis pathways involved.
Full-text · Article · Oct 2011 · Open Journal of Molecular and Integrative Physiology
[Show abstract][Hide abstract] ABSTRACT: The competition between arginases and NO synthases (NOS) for their common substrate L-arginine can be important in the airways hyperreactivity. We investigated the effect of the simultaneous modulation of arginase and NOS activities in allergen-induced airways hyperreactivity. We analysed the response of tracheal and lung tissue smooth muscle to histamine or acetylcholine after administration N(ω)-nitro-L-arginine methyl ester (L-NAME), aminoguanidine (AG) and N(ω)-hydroxy-L-arginine (NOHA) in the combinations in in vitro conditions. The results show the decrease of ovalbumin-induced hyperreactivity after inhibition of arginase activity with NOHA. A supplementation of L-arginine caused favourable effect on the airway smooth muscle response. We found the airway reactivity decrease on the whole if we used the combination of NOS and arginase inhibitors. The inhibition of both types of enzymes caused more expressive effect in tracheal smooth muscles. We recorded the difference in the response to histamine or acetylcholine. The simultaneous inhibition of iNOS (with AG) and arginase (with NOHA) evoked the most expressive effect. Results show the importance of competition of both types enzymes - NOS and arginase for the balance of theirs activities in the control of airways bronchomotoric tone in the conditions of the airways hyperreactivity.
No preview · Article · Mar 2011 · General Physiology and Biophysics
[Show abstract][Hide abstract] ABSTRACT: Allergic asthma is the most frequent disease of the respiratory tract. The aim of the current experimental and clinical studies was to find new sources of drugs able to control asthmatic inflammation and airway hyperresponsiveness. Our experimental studies were focused on efficiency evaluation of substances able to influence activities of ion channels, phosphodiesterase (PDE) isoforms, substances from the group of polyphenols and NO metabolism modulators during experimentally induced allergic asthma.
Full-text · Article · Mar 2011 · Interdisciplinary toxicology
[Show abstract][Hide abstract] ABSTRACT: The airway hyperreactivity (AHR) is a symptom occurring in various diseases of the respiratory system. It is defined as an abnormal bronchoconstriction response to a different spectrum of biological, chemical and pharmacological stimuli. Pathogenesis of airway hyperreactivity is not well understood. The available literature data shows that in the AHR pathogenesis is important not only genetic predisposition or influence of combination environmental and genetic factors, but also the presence and activity of various inflammatory mediators and other endogenous factors (growth factors, nuclear transcription factors). In this process is also important role of neural regulation and release of pro-inflammatory neurotransmitters. Our aim was to provide a comprehensive overview of knowledge about the symptoms--from the risk factors and pathogenesis through the clinical importance to the need for better understanding new options in therapeutic interventions.
No preview · Article · Jan 2011 · Ceskoslovenska fysiologie / Ustredni ustav biologicky
[Show abstract][Hide abstract] ABSTRACT: A significant role In the pathogenesis of asthma may be played by obesity, through adipocytokines produced by adipose tissue, of which one of the most important is leptin. A parallel increase in the prevalence of obesity and asthma suggests a potential association between them, with leptin being considered a link connecting these two conditions. The article aimed at presenting the current view of and opinions on the potential causal relationship between obesity and asthma.
No preview · Article · Jan 2011 · Studia Pneumologica et Phthiseologica
[Show abstract][Hide abstract] ABSTRACT: The interest of arginase action is increasing because limitation of L-arginine bioavailability by arginase for NO synthesis via constitutive NOS can contribute to airway hyperreactivity.
We investigated the effect of intervention in the arginase activity in guinea pig model of experimental ovalbumin-induced airway hyperreactivity.
We analysed the response of tracheal and lung tissue smooth muscle strips to histamine or acetylcholine after in vitro administration of arginase in a dose of 75 UI or after administration of the non-selective inhibitor of arginase N(omega)-hydroxy-L-arginine (NOHA) in a dose of 5 and 10 micromol. We used as well as the incubation of strips with the precursor of NO synthesis L-arginine in a dose of 10(-4) mol/l together with NOHA.
We did not find any significant differences in the reactivity of tracheal and lung tissue smooth muscle if we applied arginase in a dose of 75 UI in vitro. NOHA in a dose of 5 a 10 micromol induced the decrease of tracheal and lung tissue smooth muscle reactivity overall. The decrease of the contraction amplitude was dose-dependent. The supplementation of NO synthesis precursor L-arginine in a dose of 10(-4) mol/l together with NOHA intensified the decrease of the airways reactivity induced by an arginase inhibition.
The results suggest that arginase is involved in the control of airways bronchomotoric tone and therefore modulation of arginase activity could be a useful tool for airway smooth muscle tone control in clinical conditions (Fig. 7, Ref. 33). Full Text (Free, PDF) www.bmj.sk.
Full-text · Article · Jan 2009 · Bratislavske lekarske listy
[Show abstract][Hide abstract] ABSTRACT: The majority of nitric oxide (NO) effects in the respiratory system are caused by stimulation of soluble guanylyl cyclase (sGC) with subsequent increase of cyclic guanosine monophosphate (cGMP) production. The importance of this mechanism of NO action in airway hyperreactivity (AHR) pathogenesis is unknown. Therefore, the aim of our experiment was to examine the changes of airway reactivity enhanced by toluene vapor exposure in the presence or inhibition of sGC activity in guinea pigs. Animals were treated with a nonspecific sGC inhibitor, methylene blue, in a dose of 50 or 100 mg/kg body weight, administered by intraperitoneal injection 30 min before or after exposure to toluene vapors. The toluene exposure lasted 2 hr in each of 3 consecutive days under in vivo conditions. Thereafter, the tracheal and lung tissue smooth muscle response to cumulative doses of mediators (histamine or acetylcholine) was recorded under in vitro conditions. The exposure to toluene vapors significantly increased the airway reactivity to both mediators in comparison with the healthy animal group. The administration of methylene blue decreased the amplitude of airway smooth muscle contraction in toluene-induced hyperreactivity. The decreases were dependent on the inhibitor doses, on a regimen of administration (before or after toluene inhalation), the level of the respiratory system (trachea, lung), and the bronchoconstrictor mediators. Our results suggest that the interaction between NO and sGC may be important for airway reactivity changes, but other mechanisms of NO action are important in AHR pathogenesis, too.
No preview · Article · Nov 2008 · Biological Research for Nursing
[Show abstract][Hide abstract] ABSTRACT: The deficiency or the decrease in the bioavailability in basic substrate for nitric oxide synthesis - L-arginine can be one of factors contributing to the airway hyperreactivity. We studied the influence of L-arginine supplementation on the experimental airway hyperreactivity induced in guinea pigs by exposure to toluene vapours. L-arginine was administered before exposure in a dose of 300 mg/kg b.w. intraperitoneally during 3 or 17 days. After that the airway reactivity changes to histamine or acetylcholine were studied in in vitro conditions. In addition to that the tissue strips from exposed animals were incubated with L-arginine in concentration 10(-4) mol/l. The administration of L-arginine during 3 days decreased the airway reactivity increased by irritant exposure. We recorded the decrease in the airway reactivity in animals with bronchial hyperreactivity after incubation of tissue strips with L-arginine, too. The pre-treatment of animals with L-arginine during 17 days did not affect the airway smooth muscle reactivity in larger extent. The exogenous administration of L-arginine resulted in a protective effect under the conditions of experimental airway hyperreactivity. The effect of supplementation was different depending on airway level and pre-treatment duration. The results refer to the importance of optimal L-arginine level for the control of bronchomotoric tone.
No preview · Article · Jun 2008 · General Physiology and Biophysics
[Show abstract][Hide abstract] ABSTRACT: The decreased L-arginine bioavailability, the basic substrate for nitric oxide synthesis, can be one of the factors contributing to the airways hyperreactivity.
We investigated the effect of various inhibitors of the enzyme activities utilizing L-arginine in a guinea pig model of experimental ovalbumin-induced airway hyperreactivity.
We used the in vivo pre-treatment with non-specific inhibitor of NO synthase No-nitro-L-arginine metylester (L-NAME) and relatively specific inhibitor of inducible NO synthase--aminoguanidine. Inhibitors were administered in one-shot (on the 14th day, 30 minutes before the inhalation of ovalbumin) or in a long-time regime (during the whole period of sensibilization by ovalbumin--14 days). We administered the inhibitor of arginase Nomega-hydroxy-L-arginine (NOHA) to the tracheal and lung tissue smooth muscle strips from sensibilized animals.
We observed an increase in the tracheal smooth muscle response to histamine in animals that received an inhalation dose of L-NAME (40 mg/kg b.w.) or aminoguanidine (50 mg/kg b.w.) 30 minutes before the inhalation of ovalbumin but did not evoke any significant difference in the reactivity of lung tissue smooth muscle. Tracheal smooth muscle responded with enhanced contraction amplitude to histamine after chronic pre-treatment with L-NAME or aminoguanidine. The inhibition of arginase with NOHA in vitro decreased the tracheal and lung tissue smooth muscle reactivity to histamine.
The results suggest that NO-synthase isoforms as well as arginase are involved in the production of NO and in the control of bronchomotoric tonus (Fig. 4, Tab. 2, Ref. 31). Full Text (Free, PDF) www.bmj.sk.
No preview · Article · Jan 2008 · Bratislavske lekarske listy
[Show abstract][Hide abstract] ABSTRACT: Rational pharmacotherapy of respiratory diseases represents an important factor in improving the care of patients suffering especially from their chronic forms. Most drugs used in the therapy of mainly inflammatory diseases act via various receptor and enzyme systems. If these are affected, disease manifestations decrease or disappear and the patients' quality of life improves. In the text, the authors characterize mechanisms of action of the most important groups of drugs (bronchodilators, antiinflammatory agents) and present perspective options and new alternatives for treating respiratory diseases.
No preview · Article · Jan 2007 · Studia Pneumologica et Phthiseologica
[Show abstract][Hide abstract] ABSTRACT: Nitric oxide (NO) is an important endogenous mediator involved in many biological functions in both physiological and pathological conditions. Many of studies suggest that high level of NO may play a role in the pathogenesis of various diseases including respiratory diseases with bronchial hyper-reactivity (BHR). The aim of our study was to examine the relationship between NO production and BHR. The reactivity of tracheal and lung tissue smooth muscle to histamine and acetylcholine was measured in vitro in male guinea pigs pre-treated with NO synthase (NOS) inhibitors. The drugs were administered in vivo during either 3 or 17 days. Furthermore, the animals were exposed in vivo to the toluene vapours after administration of agents. NOS inhibitors showed mainly beneficial effect in the presented study. They decreased the hyper-reactivity of the tracheal and lung tissue smooth muscle evoked by toluene. The decrease was dependent on the duration of their administration and on the type of inhibitor. Short-term administration of inhibitors was more effective than long-term one. A more significant effect was recorded after the pre-treatment with non-selective inhibitor L-NAME. The results showed possible participation of constitutive forms of NOS in the BHR.
Full-text · Article · Jul 2006 · General Physiology and Biophysics
[Show abstract][Hide abstract] ABSTRACT: Prostaglandins and nitric oxide are important mediators of different physiological and pathophysiological processes. So far, is not characterized clearly their relationship in the conditions of airways hyperreactivity.
We tried to detect the relationship of interaction NOS-COX in conditions of exogenous irritant-induced experimental bronchial hyperreactivity.
Male guinea pigs were used in the experiment. Animals received agent that inhibits COX activity--diclofenac in a dose of 10 mg/kg i.m. or direct NO donor--molsidomine in a dose of 2 mg/kg i.p. Agents were administered singly (10 days) or in combination (last 3 days). Then animals were exposed to the toluene vapours for two hours over each of three consecutive days to provoke hyperreactivity. Then we recorded the reactivity changes to cumulative doses of histamine or acetylcholine (10(-8)-10(-3) mol/I).
The administration of NO donor (10 days) and consecutive COX inhibition (3 days) increased the reactivity of both observed preparations in comparison to agents administered single. COX inhibition during 10 days and consecutive treatment with NO donor (3 days) evoked different changes of tracheal smooth muscle and lung tissue smooth muscle response but had more beneficial effect on the airways reactivity on the whole.
It is possible to suppose some participation of both followed enzymatic systems and theirs interaction in our experimental conditions since airways reactivity was affected the by used agents (Fig. 7, Ref. 32).
Preview · Article · Feb 2006 · Bratislavske lekarske listy
[Show abstract][Hide abstract] ABSTRACT: The majority of nitric oxide (NO) effects in the respiratory system are mediated via the stimulation of soluble guanylyl cyclase with subsequent generation of the second messenger--cyclic guanosine monophosphate (cGMP).
We were interested in the effect of non-selective soluble guanylyl cyclase inhibitor--methylene blue on the exogenous irritant-induced bronchial hyperreactivity.
Male guinea pigs were used in the experiment. The animals received non-selective soluble guanylyl cyclase inhibitor--methylene blue in a dose of 50 or 100 mg/kg b.w. 30 minutes before inhalation of the exogenous irritant--toluene vapours. The toluene exposition lasted three consecutive days during two hours in in vivo conditions. The monitoring of tracheal and lung tissue strips reactivity changes was carried out in in vitro conditions. The brochoconstrictor mediators histamine and acetylcholine in the cumulative doses (10(-8)-10(-3) mol/l) were used in the experiment.
The methylene blue pretreatment induced the decrease of tracheal and lung tissue smooth muscle contraction amplitude increased by exogenous irritant--toluene. We recorded different smooth muscle response depending on the doses of inhibitor. Methylene blue in a dose of 50 mg/kg b.w. affected mainly tracheal smooth muscle, in a dose of 100 mg/kg b.w. mainly the lung tissue.
The interaction between nitric oxide and soluble guanylyl cyclase can be important for bronchial reactivity changes. The changes depended on the dose of inhibitor and on the type of respiratory system tissue (trachea, lung). We can summarise that changes of the airways reactivity are not only evoked by NO/cGMP pathway but probably by any other mechanisms (Fig. 5, Ref. 26).
Full-text · Article · Feb 2005 · Bratislavske lekarske listy
[Show abstract][Hide abstract] ABSTRACT: Time course of oxidative modification of forebrain neural proteins was investigated in the rat model of global and partial cerebral ischemia/reperfusion. Animals were subjected to 4-vessel occlusion for 15 min (global ischemia). After the end of ischemia and at different reperfusion times (2, 24 and 48 h), lipoperoxidation-dependent and direct oxidative modification neural protein markers were measured in the forebrain total membrane fraction (tissue homogenate). Ischemia itself causes significant changes only in levels of tryptophan and bityrosine fluorescence when compared to controls. All tested parameters of protein modification altered significantly and were maximal at later reperfusion stage. Content of carbonyl group in re-flow period steadily increased and culminated at 48 h of reperfusion. The highest increase in the fluorescence of bityrosines was detected after 24 h of reperfusion and was statistically significant to both sham operated and ischemic groups. The changes in fluorescence intensity of tryptophan decreased during a reperfusion time dependent manner. Formation of lysine conjugates with lipoperoxidation end-products significantly increased only at later stages of reperfusion. Total forebrain membranes from animals subjected to 3-vessel occlusion model to 15 min (partial ischemia) show no altered content of oxidatively modified proteins compared to controls. Restoration of blood flow for 24 h significantly decreased only fluorescence of aromatic tryptophan. Partial forebrain ischemia/reperfusion resulted in no detectable significant changes in oxidative products formation in extracerebral tissues (liver and kidney) homogenates. Our results suggest that global ischemia/reperfusion initiates both the lipoperoxidation-dependent and direct oxidative modifications of neural proteins. The findings support the view that spatial and temporal injury at later stages of ischemic insult at least partially involves oxidative stress-induced amino acid modification. The results might have important implications for the prospective post-ischemic antioxidant therapy.
Full-text · Article · Jan 2005 · General Physiology and Biophysics
[Show abstract][Hide abstract] ABSTRACT: Nitric oxide acts as neurotransmitter of the nonadrenergic noncholinergic mediation in respiratory system and participates in the physiological functions regulation. Most important pharmacological activities of nitric oxide are manifested in the area of vessels and bronchial smooth muscle, mucous secretion, mucociliary transport, activity in the conditions of the inflammation, hyperreactivity and defensive reaction of the organism. It plays the important role in the pathogenesis of different respiratory diseases what demonstrate various concentrations of nitric oxide in the exhaled air mainly in the inflammatory diseases. The estimation of the possibility of the correlation of this marker value to the eosinophilic inflammation or atopy is the topic of the interest. The utilization of this small radical molecule as well as of agents influencing its synthesis, transmission and modulating nitric oxide effects in the diagnosis and therapy is other area of the following that can render another pharmacotherapeutic alternatives in pneumology.