RESUMEN
The mechanisms of anti-inflammatory action of saturated N-acylethanolamine--N-stearoylethanolamine (NSE) were investigated on the rat model of nonspecific inflammation (thermal burns of the skin). The results showed that the NSE application in a form of aqueous suspension (10 mg/ml) on the damaged skin area during 12 days significantly accelerated the healing process of burned wounds. NSE also prevented the increase of 11-hydroxycorticosteroids content in the blood of rats with burns. There was also found a significant decrease of cytokines (IL-1beta, IL-6 and TNFalpha) levels under the NSE action. This way may be one of the mechanisms of NSE anti-inflammatory action.
Asunto(s)
11-Hidroxicorticoesteroides/sangre , Antiinflamatorios no Esteroideos/farmacología , Quemaduras/tratamiento farmacológico , Etanolaminas/farmacología , Piel/efectos de los fármacos , Ácidos Esteáricos/farmacología , Cicatrización de Heridas/efectos de los fármacos , Administración Cutánea , Animales , Quemaduras/sangre , Quemaduras/inmunología , Quemaduras/patología , Calor , Inflamación/sangre , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Interleucina-1beta/sangre , Interleucina-6/sangre , Masculino , Ratas , Ratas Wistar , Piel/inmunología , Piel/lesiones , Factor de Necrosis Tumoral alfa/sangre , Cicatrización de Heridas/fisiologíaRESUMEN
The influence of N-stearoylethanolamine (NSE) on the content of lipid peroxidation products, activity of antioxidant enzymes and the nitric oxide level in the liver and blood plasma of rats with insulin-resistance (IR) state was investigated. IR state was induced in rats by prolonged high-fat diet (58% of energy derived from fat) for 6 months combined with one injection of streptozotocin (15 mg/kg of body weight). The existence of IR state was estimated by results of glucoso-tolerance test and blood plasma insulin content. The level of lipid peroxides products was shown to be higher in the liver of insulin resistant animals as a result of reduced superoxide dismutase and catalase activity, however, glutathione peroxidase activity was increased. The increase of nitric-oxide content in the liver and blood plasma of high-fat diet rats compared with healthy control animals was also observed. The administration of the NSE suspension per os in a dose of 50 mg/kg during 2 weeks to the rats with induced insulin-resistance state contributed to the increase of superoxide dismutase, catalase and glutathione peroxidase activity. In consequence of antioxidant enzymes activation the intensity of POL process was decreased. The NSE administration caused normalization of nitric oxide level, restoring pro-/antioxidant balance in the liver and blood plasma of rats with IR state. In conclusion, the NSE administration to the rats with insulin-resistance state restored pro-/antioxidant balance and enhanced the content of nitric oxide, therefore, improving insulin sensitivity.
Asunto(s)
Etanolaminas/farmacología , Hiperglucemia/tratamiento farmacológico , Resistencia a la Insulina , Hígado/efectos de los fármacos , Óxido Nítrico/antagonistas & inhibidores , Ácidos Esteáricos/farmacología , Animales , Animales no Consanguíneos , Glucemia/metabolismo , Catalasa/metabolismo , Dieta Alta en Grasa , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Hiperglucemia/inducido químicamente , Hiperglucemia/metabolismo , Insulina/sangre , Peroxidación de Lípido/efectos de los fármacos , Hígado/enzimología , Masculino , Óxido Nítrico/metabolismo , Ratas , Estreptozocina/farmacología , Superóxido Dismutasa/metabolismoRESUMEN
The aim of the study was to evaluate the possibility to reduce the doxorubicin toxic effects by its immobilization with N-stearoylethanolamine (NSE) on nanocarier polyethylene glycol. The studied parameters of the doxorubicin toxicity were: the level of creatinine in the mice blood plasma and activity of alanine aminotransferase and aspartate aminotransferase in the blood plasma of mice. The activity of catalase superoxide dismutase, glutathione peroxidase and intensity of lipid peroxidation was determined in the tissues of the heart, kidneys and liver. Doxorubicin in the content of nanocarrier alone caused an increase of serum creatinine and aspartateaminotrasferase activity in plasma of experimental animals with carcinoma. Nanocomposite which contained doxorubicin and NSE, did not cause an increase of these parameters. It has been shown that the administration of a carrier containing doxorubicin to mice with Lewis lung carcinoma caused the decrease of catalase activity in mice with carcinoma. The combination of NSE and doxorubicin on the carrier led to the normalization of this parameter to the level of intact animals. NSE immobilized on a carrier together with doxorubicin caused a decrease in the activity of superoxide dismutase in the kidney tissue of mice with tumor. The tumor growth caused the increase of the of superoxide dismutase in mice. The administration of a carrier which contained doxorubicin and NSE normalized superoxide dismutase in heart tissue contrary of kidney. The obtained results show the antitoxic and antioxidant effects of N-stearoylethanolamine immobilized in the nanocarrier complex together with doxorubicin.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Antioxidantes/farmacología , Carcinoma Pulmonar de Lewis/tratamiento farmacológico , Doxorrubicina/farmacología , Etanolaminas/farmacología , Ácidos Esteáricos/farmacología , Alanina Transaminasa/sangre , Animales , Antibióticos Antineoplásicos/química , Antioxidantes/química , Aspartato Aminotransferasas/sangre , Carcinoma Pulmonar de Lewis/metabolismo , Catalasa/antagonistas & inhibidores , Catalasa/metabolismo , Creatinina/sangre , Doxorrubicina/química , Etanolaminas/química , Glutatión Peroxidasa/metabolismo , Corazón/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Nanocompuestos , Polietilenglicoles/química , Ácidos Esteáricos/química , Superóxido Dismutasa/antagonistas & inhibidores , Superóxido Dismutasa/metabolismoRESUMEN
The influence of N-stearoylethanolamine was investigated on the activity of enzymes of antioxidant protection and content of stable metabolites of nitric oxide (NO) in the testes and plasma of rats at the early stages of development of streptozotocine-induced diabetes mellitus. It was shown that the activity of superoxide dismutase, catalase is reduced in the plasma and testes of animals with streptozotocin-induced (50 mg/kg) diabetes (blood glucose 8-10 mmol/L). A significant increase in the amount of nitrite and nitrate anions was revealed in the plasma of rats, while only the level of nitrite was significantly changed in the testes of animals. The per os administration of the NSE aqueous suspension in a dose of 50 mg/kg during 10 days to the rats with induced diabetes contributed to the normalization of catalase activity in the testis, which correlated with a decrease in the amount of TBA-reacting products and activity of superoxide dismutase and catalase in the blood plasma of animals; the use of NSE also contributed to the reduction of nitrite content in the gonads and to normalization of both nitrite and nitrate in the blood plasma of rats. The NSE administration to intact animals caused an increase in superoxide dismutase activity and significantly reduced the content of stable NO metabolites in the blood plasma of animals.
Asunto(s)
Antioxidantes/uso terapéutico , Catalasa/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Etanolaminas/uso terapéutico , Óxido Nítrico/sangre , Ácidos Esteáricos/uso terapéutico , Superóxido Dismutasa/sangre , Animales , Glucemia/análisis , Diabetes Mellitus Experimental/metabolismo , Masculino , Nitratos/sangre , Nitritos/sangre , Ratas , Estreptozocina , Testículo/efectos de los fármacos , Testículo/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/análisisRESUMEN
The influence of N-stearoylethanolamine on the alterated antioxidant enzyme activity in the heart tissue and blood plasma of rats under the doxorubicin treatment was investigated. It was shown that doxorubicin administration caused the decrease of antioxidant enzymes activity (superoxide dismutase and glutathione peroxidase) in the heart tissue. Administration of the NSE promoted the partial normalization of these enzymes activity. It was shown that doxorubicin treatment caused the increase of the urea and creatinine level in the blood plasma of experimental animals. The NSE administration normalized the level of the urea and did not affect creatinine level.
Asunto(s)
Doxorrubicina/farmacología , Etanolaminas/farmacología , Corazón/efectos de los fármacos , Miocardio/metabolismo , Plasma/efectos de los fármacos , Ácidos Esteáricos/farmacología , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Creatinina/sangre , Doxorrubicina/sangre , Interacciones Farmacológicas , Etanolaminas/sangre , Glutatión Peroxidasa/metabolismo , Miocardio/enzimología , Oxidación-Reducción , Plasma/química , Ratas , Ácidos Esteáricos/sangre , Superóxido Dismutasa/metabolismo , Urea/sangreRESUMEN
The influence of N-stearoylethanolamine on the nitric oxide system, the state of lipid peroxidation, antioxidant enzyme activity, content of phospholipids and fatty acids were studied under the acute ethanol intoxication (2.5 g/kg) in rats. The results of investigations show that acute ethanol intoxication caused abnormalities of the oxidative homeostasis accompanied by the accumulation of thiobarbituric acid reactive substances (TBARS). High catalase and glutathione peroxidase activity was also shown. The altered content of total and individual fatty acids of phospholipids in the rat liver tissue was found. The content of saturated fatty acids (palmitic, stearic) increased and amount of unsaturated (palmitoleic, oleic, linolenic) acids decreased under acute ethanol intoxication. The changes of nitric oxide content was found in the brain, plasma and red blood cells. N-stearoylethanolamine (NSE) in a dose of 50 mg/kg of body weight shows the pronounced antioxidative and hepatoprotective properties under these conditions. It was found that the preliminary NSE administration to rats inhibited accumulation of TBARS and caused a simultaneous increase of antioxidant enzyme activity. The NSE administration modulated also the content of total and individual fatty acids of phospholipids and the amount of nitric oxide in pathologically altered tissues. These results suggested that NSE protected the structural integrity and functional ability of cell membranes under the acute ethanol intoxication.
Asunto(s)
Intoxicación Alcohólica/prevención & control , Etanol/toxicidad , Etanolaminas/uso terapéutico , Sustancias Protectoras/uso terapéutico , Ácidos Esteáricos/uso terapéutico , Enfermedad Aguda , Intoxicación Alcohólica/sangre , Intoxicación Alcohólica/metabolismo , Animales , Antioxidantes/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Encéfalo/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/enzimología , Membrana Celular/metabolismo , Modelos Animales de Enfermedad , Etanolaminas/administración & dosificación , Ácidos Grasos/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Óxido Nítrico/sangre , Óxido Nítrico/metabolismo , Sustancias Protectoras/administración & dosificación , Ratas , Ácidos Esteáricos/administración & dosificación , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
The influence of N-stearoylethanolamine (NSE) on total 11-hydroxycorticosteroids (11-HCS) and testosterone level in the blood of male rats in normal conditions and under the action of 17beta-estradiol (400 mkg/kg of body weight during 3 days) was studied. It was shown that NSE administration per os (50 mg/kg of body weight during 7 days) to intact animals did not change the level of 11-HCS and of testosterone. The administration of NSE to estrogenized male rats decreased the elevated level of 11-HCS and normalized the amount of testosterone in blood. The correction of alterated weight of adenohypophysis and testis of estrogenized male rats compared to control can be a direct evidence of NSE-mediated modelling of the effect on hypothalamic-pituitary hormone system. The effect of NSE in the testis of estrogenized male rats inhibited the process of lipid peroxidation, caused the decrease of the amount of thiobarbituric acid reactive substances and increased the activity of superoxide dismutase and catalase. The NSE showed more expressed antioxidative effect compared to vitamin E. Taking into consideration all above mentioned data we suggested that NSE administration to male rats protected Leydig cells from damage under the increase of estrogen level.
Asunto(s)
Antioxidantes/farmacología , Estradiol/efectos adversos , Etanolaminas/farmacología , Modelos Biológicos , Ácidos Esteáricos/farmacología , Testículo/efectos de los fármacos , 11-Hidroxicorticoesteroides/sangre , Animales , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratas , Testículo/metabolismo , Testosterona/sangreRESUMEN
The biochemical mechanisms of anti-inflammatory effect of endocannabinoid congener N-stearoylethanolamine (NSE) was studied on the model of experimental burn in rats. The animals after the thermal burn of the skin received per os during 7 days the water suspension of NSE in a doze 10 mg/kg of body weight. In the other groups of rats the suspension was applied to the wound (the concentration of NSE was 10 mg/ml). It was shown for the first time that NSE accelerated the process of burn wound healing by the inhibition of proinflammatory cytokines (TNFalpha, IL-6) production. NSE caused the normalization of the iNOS and cNOS activity and of nitrite content in plasma, erythrocytes, liver and spleen of rats. NSE also modified the antioxidant enzymes (catalase, superoxide dismutase and glutathione peroxidase) activity and diminished the level of lipid peroxidation. The discovered anti-inflammatory NSE properties suggest the possibility of its usage for burn treatment.
Asunto(s)
Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Quemaduras/tratamiento farmacológico , Etanolaminas/uso terapéutico , Piel/efectos de los fármacos , Ácidos Esteáricos/uso terapéutico , Administración Cutánea , Administración Oral , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Quemaduras/enzimología , Quemaduras/inmunología , Quemaduras/metabolismo , Catalasa/sangre , Catalasa/metabolismo , Modelos Animales de Enfermedad , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Eritrocitos/metabolismo , Etanolaminas/administración & dosificación , Etanolaminas/farmacología , Glutatión Reductasa/sangre , Glutatión Reductasa/metabolismo , Interleucina-6/sangre , Interleucina-6/inmunología , Hígado/efectos de los fármacos , Hígado/enzimología , Óxido Nítrico Sintasa/metabolismo , Ratas , Piel/enzimología , Piel/lesiones , Piel/metabolismo , Bazo/efectos de los fármacos , Bazo/enzimología , Ácidos Esteáricos/administración & dosificación , Ácidos Esteáricos/farmacología , Superóxido Dismutasa/sangre , Superóxido Dismutasa/metabolismo , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/inmunología , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Results of investigation of biochemical mechanisms of N-stearoylethanolamine (NSE) influence on the processes of allergic responses of immediate and delayed type (anaphylactic shock in guinea pigs and contact hypersensitivity to 2,4-dinitrochlorobenzene in mice) are presented in the paper. NSE was given per os during two weeks. It was found that in anaphylactic animals, NSE prevented the growth of histamine levels in the heart, kidneys and spleen, suppressed NO2(-) level increase in these organs and promoted its normalization. At the same time NSE prevented the decrease of the level of stable metabolite of nitrogen oxide - nitrite-anion (NO2(-)) in the liver and to a lesser degree in the lungs, and also decreased the activity both inducible and constitutive NO-synthases. NSE normalized the content of TBA-reactive products in the lungs and decreased it in the heart, diminished the decline of activity of glutathione peroxidase, catalase and superoxide dismutase. Effects of NSE depended on its daily dose. About 70% of animals which received NSE in a dose 65 mg/kg of body weight had no fatal outcome after the induction of anaphylactic shock. NSE suppressed the delayed type hypersensitivity response and normalized NO2(-) content in the blood plasma of mice but only at the dose of 50 mg/kg of weight. In the thymus of sensitized mice NSE diminished the content of NO2(-). Thus, though NSE has no affinity for specific CB receptors, in other words, it is not a typical endocannabinoid, its ability to influence the immediate and delayed type allergic reactions opens a perspective for creation of new medications which differ principally from existing pharmacological drugs with anti-allergic and immunosuppressive properties.
Asunto(s)
Anafilaxia/tratamiento farmacológico , Dermatitis por Contacto/tratamiento farmacológico , Etanolaminas/uso terapéutico , Inmunosupresores/uso terapéutico , Ácidos Esteáricos/uso terapéutico , Anafilaxia/enzimología , Anafilaxia/inmunología , Anafilaxia/metabolismo , Animales , Moduladores de Receptores de Cannabinoides/metabolismo , Dermatitis por Contacto/enzimología , Dermatitis por Contacto/inmunología , Dermatitis por Contacto/metabolismo , Relación Dosis-Respuesta a Droga , Etanolaminas/farmacología , Cobayas , Liberación de Histamina/efectos de los fármacos , Inmunosupresores/farmacología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Óxido Nítrico/metabolismo , Especificidad de Órganos , Receptores de Cannabinoides/metabolismo , Ácidos Esteáricos/farmacologíaRESUMEN
The aim of the presented experiments was to study the influence of suturated NAE--N-stearoylethanolamine (NSE) on the NO synthesis by NO-synthases in aorta and heart tissues of rats with developmental (12-week) streptozotocin-induced (50 mg/kg of body weight) diabetes. Also we evaluated the state of endothelium-dependent relax reactions of aorta smooth muscles. It was shown that the development of diabetes is accompanied with disbalance of NO-synthesis wich consist in inducible NOS (iNOS) activation and inhibition of constitutive NOS (cNOS) and arginase activities. The aorta smooth muscle endothelium-dependent relax reactions were decreased in diabetic rats. The NSE administration to rats with development streptozotocin-induced diabetes resulted in inhibition of iNOS activity and elevation of cNOS and arginase activities in these tissues. Normalization of NO-synthesis under NSE action was accompanied with restoration of aorta smooth muscle endothelium-dependent relax reactions in diabetic rats.
Asunto(s)
Aorta Torácica/efectos de los fármacos , Diabetes Mellitus Experimental , Etanolaminas/farmacología , Miocardio , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico/biosíntesis , Ácidos Esteáricos/farmacología , Animales , Aorta Torácica/enzimología , Aorta Torácica/metabolismo , Glucemia/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Experimental/metabolismo , Masculino , Relajación Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Miocardio/enzimología , Miocardio/metabolismo , Ratas , Ratas Wistar , EstreptozocinaRESUMEN
The effect of N-stearoylethanolamine (NSE) on the lipid peroxidation process, antioxidant enzymes activity, phospholipid and fatty acid content in the rat liver tissues under acute morphine administration was studied. It was shown that morphine administration (30 mg/kg of body weight) caused an increase of the amount of thiobarbituric acid reactive substances (TBARS), alteration of antioxidant enzymes activity, decrease the protein level, quantity of total lipids and phospholipids, phosphatidylcholine, cholesterol esters; altered the content of some individual fatty acids. NSE administration (50 mg/kg of body weight) promoted normalization of the antioxidant enzymes activity and prevented the TBARS accumulation and decreased the total lipid and phospholipid quantity, increased the content of free and total cholesterol, corrected the level of free and individual fatty acids. It was assumed that NSE possessed antioxidative, membranoprotective and adaptive properties.
Asunto(s)
Antioxidantes/farmacología , Etanolaminas/farmacología , Ácidos Grasos/análisis , Peroxidación de Lípido/efectos de los fármacos , Hígado , Morfina/envenenamiento , Ácidos Esteáricos/farmacología , Enfermedad Aguda , Animales , Antioxidantes/uso terapéutico , Etanolaminas/uso terapéutico , Ácidos Grasos/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Masculino , Intoxicación/tratamiento farmacológico , Intoxicación/metabolismo , Ratas , Ácidos Esteáricos/uso terapéuticoRESUMEN
Effects of an antagonist of AT-1 receptors for angiotensin-II (Ang-II) irbezantane on the NO-synthase and arginase ways of the metabolism of L-arginine were studied in plasma and erythrocytes of the patients with arterial hypertension. The intensity of the non-oxidative arginase way of L-arginine metabolism in plasma and erythrocytes has been shown to be inhanced at hypertension versus the normotensive patients, while the activity of the alternative oxidative NO-synthase way was reduced. Inhibiting AT-1 receptors for Ang-II with high-affinity antagonist irbezantane normalized the ratio between two alternative ways of L-arginine metabolism through inhibiting the arginase way and reciprocal activating the NO-synthase way both in human plasma and erythrocytes.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Antihipertensivos/uso terapéutico , Arginina/sangre , Compuestos de Bifenilo/uso terapéutico , Hipertensión/tratamiento farmacológico , Tetrazoles/uso terapéutico , Angiotensina II/metabolismo , Antihipertensivos/farmacología , Arginasa/sangre , Compuestos de Bifenilo/farmacología , Donantes de Sangre , Presión Sanguínea , Eritrocitos/enzimología , Eritrocitos/metabolismo , Humanos , Hipertensión/metabolismo , Irbesartán , Óxido Nítrico Sintasa/sangre , Receptores de Angiotensina/metabolismo , Tetrazoles/farmacologíaRESUMEN
We have examined in vivo capacities of two C27-steroid hormones-phytoecdysteroid ecdysterone (20-hydroxyecdysone, 10(-8)M) and calcitriol (1 alpha, 25-dihydroxyvitamin D3, 10(-12)M), as a modulators of neutral lipids hydrolysis in the brain and heart cells. Severe lines of evidence indicate that both hormones may acts as positive regulators of cholesterol esters and triacylglycerol hydrolysis in early (0.5-30 min) pregenomic phase of its actions, yielding known (DAG, free polyunsaturated fatty acids) and possible (free cholesterol) lipid second messengers.
Asunto(s)
Calcitriol/fisiología , Ecdisterona/fisiología , Metabolismo de los Lípidos , Animales , Encéfalo/metabolismo , Ésteres del Colesterol/metabolismo , Hidrólisis , Miocardio/metabolismo , Ratas , Ratas Wistar , Triglicéridos/metabolismoRESUMEN
We have examined in vivo the capacities of two C27-steroid hormones--phytoecdysteroid ecdysterone (20-hydroxyecdysone, 10(-8)M) and calcitriol (1 alpha, 25-dihydroxyvitamin D3, 10(-12)M), as a modulators of phosphatidylcholine hydrolysis in the brain and heart cells of rats. Sever lines of evidence indicate that both hormones may acts as positive regulators of membrane phosphatidylcholine hydrolysis by phospholipases A2, C and D in early (0.5-30 min) membrane phase of its actions, yielding known lipid second messengers (diacylglycerol, phosphatidic acid) and soluble products, that may acts as second messengers (choline,choline phosphate, glycerophosphocholine).
Asunto(s)
Encéfalo/metabolismo , Calcitriol/metabolismo , Ecdisterona/metabolismo , Lípidos de la Membrana/metabolismo , Miocardio/metabolismo , Fosfatidilcolinas/metabolismo , Animales , Hidrólisis , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Three metabolic channels producing active forms of oxygen (OH.), carbon (CO) and nitrogen (NO) were studied for their contribution to the mechanism of early activation of guanylate cyclase by hydroxysterols: ecdysterone (20-hydroxyecdysone) and calcitriol (1 alpha, 25-dihydroxyvitamin D3) which are steroid agonists of phospholipid signal system in target tissues. It is established that in the cells of target tissues (brain, heart, liver) affected by the mentioned hydroxysterols only NO- and CO- metabolic lipid channels are activated while the nucleotide metabolic channel of generation of OH--radical is blocked. It is supposed that the nucleotide OH. metabolic channel activation due to oxidation of oxypurines and dihydroorotic acid most probably takes no part in formation of the negative feedback and termination of the signal of phospholipid signalling system by means of activation of soluble guanylate cyclase in contrast to the lipid channel of OH. formation due to oxidation of arachidonic acid.