Nitric oxide and regulators of its synthesis in chronic obstructive pulmonary disease

ABSTRACT The clinical picture and long-term prognosis of chronic obstructive pulmonary disease (COPD) largely depend on comorbid conditions, thereby prompting a relevant search for predictive and preventive methods in the pathogenesis of the disease. Cardiovascular diseases are highly prevalent among patients with COPD. Cardiovascular risks in patients with COPD are associated with changes in the activity of vasoactive mediators, with nitric oxide (NO) being the most important. The important role of nitric oxide in the body prompts it being studied as a biomarker of many diseases; however, its short half-life and rapid clearance prevent its direct assessment in the blood. In the body, nitric oxide is formed from L-arginine with the help of enzymes of NO-synthase group. NO oxide synthesis depends on the concentration of L-arginine, arginase and asymmetric dimethylarginine (inhibitory effect on NO-synthase). The presented literature review highlights modern views on the importance of nitric oxide and regulators of its synthesis in the pathogenesis of chronic obstructive pulmonary disease. It also indicates their role in the formation of comorbid conditions, and highlights processes of NO formation in the body. CONCLUSION: The components of the nitric oxide system (nitric oxide metabolites, L-arginine, arginase, dimethylarginine dimethylaminohydrolase, asymmetric and symmetric dimethylarginine) can be considered as potential biomarkers of COPD, especially in conditions of cardiovascular comorbidity. Further studies on the nitric oxide system are recommended for assessing the prognosis of the course of diseases and the effectiveness of the current therapy.

The biochemical estimation of the nitric oxide system in prenatally stressed rats

Introduction. Pregnancy development following unfavorable conditions could facilitate disorders of nitric oxide (NO) production during offspring’s postnatal life and «program» offspring’s cardiovascular diseases. Investigation of particular features and mechanisms of nitric oxide synthesis and action disorders following prenatal stress will promote expansion of considerations about pathogenesis of different cardiovascular diseases and propose new approaches to their prevention and management.The aim of the investigation is to assess the nature of nitric oxide synthesis and action in mature rats whose mothers were exposed to chronic «unpredictable» stress during pregnancy. Materials and methods. Pregnant rats were subdivided into the «control» and «stress» groups (in 20 animals). The rats from the «stress» group were exposed to multiple different stressors at various intervals, such as 1-day famine; 20-min. immobilization in the water at room temperature; 1-day contact with cats’ excrements. In the blood serum of 3-mo offspring (n=96, including «control» males – 24, «control» females – 26, «stress» males – 22, «stress» females – 24) concentration of the stable products of NO degradation – nitrates/nitrites (NO3–/NO2–), endothelial (eNOS) and inducible (iNOS) isoforms of the NO-synthase, inhibitor of NO-synthase asymmetric dimethylargininne (ADMA), cyclic guanosine monophosphate (cGMP), lipid peroxidation products – diene conjugates (DC) and malonic dialdehyde (MDA) and C-reactive protein (hsCRP) was detected. Results. The decrease of eNOS and cGMP concentration (by 12.9 and 31.9 %, respectively), increase of iNOS, hsCRP and ADMA concentration (by 49.9, 20.3 и 63.1 %, respectively) without statistically significant fluctuation in the NO3–/NO2– level and accumulation of DC and MDA by 21.1 % and 1.5 times in a prenatally stressed male rats’ blood serum were found (as compared with «control» male rats). In a blood serum of female rats, whose mothers were exposed to chronic «unpredictable» stress during pregnancy, a tendency to eNOS concentration decreasing, and increase of iNOS by 30.6 %, hsCRP by 23.9 % and MDA by 2.3 times without statistically significant changes in cGMP, ADMA, NO3–/NO2–, and DC concentration were detected (as compared with «control» female rats). Conclusion. Identified changes of the nitric oxide system synthesis and action in the prenatally stressed male rats could argue the high risk of their cardiovascular system lesion.

The Role Of Amino Acid Arginine And Nitric Oxide System In Implementing Cardioprotective Effect Of Non-Opioid Analogue Of Leu-Enkephalin In Newborn Albino Rats After Intrauterine Hypoxia

Objective ― to evaluate the role of the amino acid arginine in the structure of the non-opioid analogue of leu-enkephalin (NALE) and the involvement of the nitric oxide system in the implementation of its cardioprotective effect in newborn albino rats subjected to intrauterine hypoxia. Material and Methods ― Pregnant female rats were subjected daily to 4-hour hypobaric hypoxia (oxygen partial pressure – 65 mm Hg) on days 15-19 of their gestation. The 7-day-old offspring of hypoxified female rats were examined. The progeny of intact animals served the control. We studied body and heart weights; activity of proliferative processes and autophagy in the myocardium of subendocardial parts of the left ventricle, expressed via the immunohistochemical detection of Ki-67 and Beclin-1 proteins, respectively; karyometric and nucleolometric indicators of cardiomyocytes (CMC); intensity of free radical processes in the tissues of the heart by chemiluminescence parameters. Correction of post-hypoxic changes in newborn rats was carried out by intraperitoneal injection of two peptides (Phe–D-Ala–Gly–Phe–Leu–Arg – non-opioid analogue of leu-enkephalin, or NALE, and Phe–D-Ala–Gly–Phe–Leu–Gly – G peptide) daily from day 2 through day 6 of their lives at a dose of 100 μg/kg. To assess the involvement of the nitric oxide system in the implementation of the NALE effects, the NO synthase inhibitor – N-nitro-L-arginine methyl ester (L-NAME) was additionally administered at a dose of 50 mg/kg. Results ― Intrauterine hypoxia led to a decrease in body weights of 7-day-old animals, an increase in the number of CMC expressing the Beclin-1 protein, reduction in the size of CMC nuclei, activation of free radial oxidation, and a decrease in antiradical protection in the heart tissues. The administration of NALE to newborn animals, subjected to intrauterine hypoxia (IUH), normalized their body weight and size of the CMC nuclei, and partially corrected changes in Beclin-1 expression and in chemiluminescence parameters. In 7-day-old animals, subjected to IUH and neonatal administration of NALE and L-NAME, a lower body weight was observed than in the control. Against the background of nitric oxide blockade, the antioxidant effect of NALE diminished, but the corrective effect of NALE on the karyometric index and Beclin-1 expression remained. G peptide, which differs from NALE by the substitution of the C-terminal amino acid Arg for the amino acid Gly, exhibited a corrective effect similar to NALE on the consequences of IUH. Conclusion ― Administration of NALE and G peptides to newborn albino rats after IUH has a pronounced cardioprotective effect. The mechanisms of the NALE peptide effects are, in part, associated with the activation of the NOS-NO system. However, the affinity of this peptide for opioid-like receptors may be of greater importance.

EXAMINING THE ROLE OF THE NITRIC OXID SYSTEM AS THE ESSENTIAL PATHOGENETIC LINK IN STEVENS-JOHNSON SYNDROME

, , , , The aim: To determine a possible role of nitric oxide system as one of the pathogenesis links in Stevens-Johnson syndrome depending on the severity of disease progression. Material and methods: We examined 11 patients with Stevens-Johnson syndrome. The function of nitric oxide system (NO - NOS) in blood serum was examined. Results: During the study of nitric oxide system (NO-NOS) in patients with SJS, it was observed that NO2¯ level was increased by 1.53 times, NO3¯ level – by 3.33 times, activity of total NOS – by 5.78 times, constitutive (cNOS) – by 1.81 times and inducible (iNOS) – by 13.36 times. Conclusions: The intensity of nitric oxide system function was studied in patients with Stevens-Johnson syndrome and dependence of changes of its parameters from the clinical signs of disease was detected. It was found that the determination of nitrite and nitrate anion levels in blood serum can be used for the purpose of predicting the disease course and choosing the therapy methods for the patients with SJS.