Effect of Sodium Nitrite and L-NNA on the Outcome of Experimental Ischemic Stroke.

We studied the effect of sodium nitrite in doses of 5 and 50 mg/kg and NO synthase inhibitor L-NNA in a dose of 20 mg/kg on the course of experimental ischemic stroke caused by occlusion of both carotid arteries. Sodium nitrite and NO synthase inhibitor were administered 1 h prior to occlusion of еру carotid arteries and 5 sec after brain ischemia. Sodium nitrite in a dose of 5 mg/kg had a protective effect on the time course of neurological disorders and reduced animal mortality. NO synthase inhibitor L-NNA aggravated the neurological symptoms.

[Inhibitors of neuronal and inducible NO-syntases enhance the effect of short-term adaptation to hypoxia in rats of Krushinsky-Molodkina strain].

We found that selective inhibitors of neuronal and inducible NOS (7-nitroindazole and aminoguanidine) significantly enhance the protective effect of short-term adaptation to hypoxia on the development of stress lesions in rats Krushinsky-Molodkina.

Protective effect of magnesium nitrate against neurological disorders provoked by cerebral ischemia in rats.

The study examined effects of inorganic magnesium agents: magnesium nitrate Mg(NO3)2, magnesium sulfate MgSO4, and magnesium chloride MgCl2 on the development of neurological disorders and mortality in rats resulting from cerebral ischemia provoked by a single-stage bilateral occlusion of the common carotid arteries. The rats were injected with one of examined magnesium preparations (5 mg/1 kg body weight) 1 h prior to or 1-2 sec after occlusion. The control group rats were treated with physiological saline at the same terms. Irrespective of the moment of injection, magnesium nitrate demonstrated significant protective effect on dynamics of neurological disorders and mortality, while similar effects of magnesium sulfate and magnesium chloride were insignificant.

[The influence of inhibitors of neuronal and inducible NO-synthases on experimental hemorrhagic stroke]. / Vliianie ingibitorov neironal'noi i indutsibel'noi NO-sintaz na razvitie gemorragicheskogo insul'ta v éksperimente.

Objectives. To study the effect of inhibitors of neuronal and inducible NO-synthase on the development of hemorrhagic stroke in rats Krushinsky-Molodkina (KM) without adaptation to hypoxia and with short-term adaptation to hypobaric hypoxia. Material and methods. Ninety rats were included in the study. Experiments with short-term adaptation to hypobaric hypoxia were performed on 48 rats. The inhibitor of inducible NO-synthase (aminoguanidine, "Sigma") or the inhibitor of neuronal NO-synthase (7-nitroindasol, "Sigma") were injected in dosage 2.5 mg/100g intraperitoneally. Results. Selective inhibitors of neuronal and inducible NO-synthase had a protective effect on stress injuries in KM rats. The inhibitor of neuronal NO-synthase was more effective than the inhibitor of inducible NO-synthase in the experiments without adaptation to hypoxia. Markedly greater protective effect was achieved by the simultaneous introduction of inhibitors of neuronal and inducible NO-synthase. The greatest protective effect in the development of stress damage in rats of KM was observed in short-term adaptation to hypobaric hypoxia with simultaneous introduction of both inhibitors. Conclusions. It can be assumed that an excessive amount of NO produced by neuronal and inducible NO-synthases during the acoustic exposure in KM rats leads to stress damage. Use of selective inhibitors reduce the excess NO synthesis and the development of audiogenic stress damage caused by hemorrhagic stroke.

[The effect of magnesium nitrate on the outcome of experimental acute ischemic stroke]. / Vliianie nitrata magniia na iskhod ostrogo éksperimental'nogo ishemicheskogo insul'ta.

Objectives. To explore the effect of inorganic forms of magnesium (magnesium nitrate, magnesium sulfate, magnesium chloride) on the course of experimental ischemic stroke (II). Material and methods. The experimental ischemic stroke caused by the occlusion of two carotid arteries in Wistar rats was studied. Animals were divided into 6 case (n=168) and 2 control groups (n=56). In case groups, magnesium was injected 1h before the occlusion of both carotid arteries and 1-2h after the brain ischemia. Control groups received physiological solution in the same periods. Results. Magnesium nitrate, regardless of the period of injection, had the significant positive effect on the dynamics of neurological lesions and mortality of animals. Conclusions. Magnesium nitrate meets the majority of criteria required for ideal pharmacological drugs: it is inexpensive, easy available, easy injectable and does not cause any serious adverse effects.

Effect of cation type and concentration of nitrates on neurological disorders during experimental cerebral ischemia.

Experiments were performed on the model of ischemic stroke due to bilateral occlusion of the carotid arteries. Nitrates had various effects on the dynamics of neurological disorders and mortality rate of Wistar rats, which depended on the cation type and concentration.

[The possible role of nitrogen dioxide produced in the field of bifurcation of vessels, in the processes of their damage in hemorrhagic strokes, and the formation of atherosclerotic plaques].

According to modern views the formation of atherosclerotic plaques is associated with accumulation of cholesterol in the vascular wall. This is due to an imbalance between the intake of cholesterol in the intima of vessels, together with the low-density lipoproteins (LDL) and its output with high-density lipoprotein (HDL). Change of LDL (glycosylation, lipid peroxidation, hydrolysis of phospholipids) and the effective release of cholesterol from the endothelium of the vascular wall are the factors that cause an imbalance in cholesterol metabolism. In this paper we propose a new concept of the mechanism of initial formation of atherosclerotic plaques, which can complement the existing concepts. According to this concept an important role in the early stages of atherosclerosis are highly reactive molecules of nitrogen dioxide (NO2), resulting from the violation of the cycles of nitric oxide and superoxide anion radical. Hypothesized that the mechanism of antiradical protection of cells and the organism as a whole, above all, laid out in most of the cyclic organization of metabolic processes that involve the formation of free radicals. Violation of this cyclic mechanism may be one of the causes of many diseases associated with hypoxia/ischemia and inflammation. The review considers the hypothesis of the possibility of participation of NO2 and OH-radicals formed in violation of the cycles of NO and superoxide, in the mechanisms of vascular damage with hemorrhagic stroke and in the formation of atherosclerotic plaques.

[The effect of nitrates on the outcome of acute experimental ischemic stroke].

Effects of nitrates NaNO(3), KNO(3), Mg(NO(3)) 2 on animals (Wistar rats) were studied on the basis of the experimental model of ischemic stroke induced by the occlusion of two carotid arteries. The animals were divided into two groups: the main group (n=60) and the control group (n=30). Three series of experiments were conducted. In each experiment, the rats of the main group were treated with one of nitrates and the control group was treated with physiological solution. It has been shown that nitrates exert either positive or negative effect depending on the cation type, nitrate concentration and the duration of their action on the dynamics of neurologic disturbances. Conditions of the development of neuroprotective effect of nitrates are discussed.

[Experimental hemorrhagic stroke: the effect of the peptide preparation cortexin in the formation of Hb-NO-complexes and other blood paramagnetic centers].

Using electronic paramagnetic resonance (EPR), we studied the effect of the peptide cortexin on the content of hemoglobin nitrozyl complexes (Hb-NO-complexes) and other paramagnetic centers (transferrin, methemoglobin) in the blood of rats of Krushynsky-Molodkina line in the experimental hemorrhagic stroke induced by acoustic stress. After the acoustic exposure, the level of Hb-NO-complexes have increased by more than 6 times. The intensity of the EPR signal of the plasma peptide transferrin increased by 1,5 times. The level of blood methemoglobin was also elevated, though not significantly, after the acoustic stress. Cortexin substantially reduces the formation of Hb-NO-complexes and, therefore, the level of nitride oxide while the contents of transferrin and methemoglobin remain intact.

Effect of inhibitors of inducible and neuronal NO synthases on the development of audiogenic stress-induced damage in Krushinskii-Molodkina rats.

Experiments on the models of epileptiform seizure and hemorrhagic stroke (Krushinskii-Molodkina rats) showed that selective inhibitors of inducible and neuronal NO synthases (aminoguanidine and 7-nitroindazole) significantly decrease the mortality rate, reduce the severity of motor disorders, and prevent the development of intracranial hemorrhages under conditions of audiogenic stress.

[EPR study of the influence of hypoxia on nitric oxide formation in the blood of Krushinskii-Molodkina rats].

The influence of hypoxia on nitric oxide formation in the blood of Krushinskii-Molodkina rats has been studied by electron paramagnetic resonance. It was found that nitric oxide synthesis in Krushinskii-Molodkina rats is increased compared with that in Wistar rats. A significant enhancement of the EPR signal of Hb-NO complexes in the animal blood was observed after hypoxia simulating the altitude of 5000 m above the sea level, in particular in the presence of sodium nitrite and the NO-synthase inhibitor L-nitroarginine. It was assumed that NO synthesis and nitro-/nitrite- reductase systems are activated under hypoxic conditions.

[Nitric oxide is involved in the protective effects of short-term adaptaion to hypoxia in the course of stress-induced disorders in Krushinsky-Molodkina rats].

A possible involvement of nitric oxide in the protective effect of short-term adaptation of Krushinsky-Molodkina rats to mild hypoxia simulating 5000 m above sea level was studied. Nitric oxide proved to have a considerable protective effect on stress-induced disorders in Krushinsky-Molodkina rats as demonstrated using NO-synthase inhibitors and NO monitoring by electron spin resonance under different experimental conditions.

Effects of an NO synthase inhibitor on aggressive and sexual behavior in male crickets.

The mechanisms of the effects of some types of behavior on others have received little study. The present investigation addresses the phenomenon present in male crickets of the species Gryllus bimaculatus, consisting of the powerful activation by transient flight (3 min) of aggression to another male and of the female courtship program. We found that flight did not evoke these behavioral changes in males injected with the NO synthase inhibitor LNNA. The intensity and duration of fights with another male, the frequency of ritual singing by the victor, and the intensity with which the victor pursued the vanquished only increased significantly after flight in control male crickets injected with Ringer's solution, but not in experimental crickets. Similarly, flown males injected with LNNA were no different from unflown males in terms of the intensity of female courtship (the latent period and relative duration of courtship singing); in controls, the latent period was significantly shorter and the duration of singing was significantly greater in flown crickets. LNNA had no effect on aggressive or sexual behavior in unflown males. These results demonstrate that flight may increase NO synthesis, making a significant contribution to the formation of the flight-evoked behavioral state.

[NO-synthase inhibitor prevents flight-induced activation of agressiveness and courtship in male].

Previous experience of flying enhances the aggressiveness (Hofmann and Stevenson, 2000, Nature, 403: 613) and accelerates the courtship behaviour (Dyakonova and Krushinski, 2003, DAN, 390: 709-712) of crickets Gryllus bimacultus. We present evidence that these effects may be mediated by activation of nitric oxide synthesis. The effects of flying on fighting and courtship were largely abolished in crickets who received haemocoel injections of a nonspecific NO-synthase inhibitor LNNA. Unlike this, LNNA exerted no significant effects on aggressive and courtship behaviour of nonflown males.

[Antistress and angioprotective influence of nitric oxide in epilepsy-prone rats of Krushinskii-Molodkina strain].

In rats of Krushinsky-Molodkina strain (KMR), the audiogenic stress induced epileptiform seizure and development of acute disturbances of cerebral circulation of hemorrhagic nature. The inhibitor of NO-synthase (L-NNA) increased the severity of clinical symptoms, mortality, and the intensity of intracranial hemorrhages. In contrast, L-arginine elevated the resistance of KMRs to acoustic stress. The intensity of nitrergic innervation was analyzed in preparations of the middle cerebral artery with the use of histochemical NADPH-diaphorase staining. In preparations of control KMRs, a net of NADPH-positive perivascular nerve fibers was found, while in experimental KMRs, in an hour after sound stimulation, such fibers practically were not revealed. Preliminary exposure of KMRs in hypoxic conditions (1 hour in hypobaric chamber at simulated altitude of 5000 m above the sea level) decreased the development of stress lesions. The protective effect of hypoxic training disappeared after the administration of NO-synthase inhibitor (L-NNA). The study demonstrated participation of nitric oxide (NO) in adaptive reactions of cerebral hemodynamics linked with the significant increase of cerebral blood flow.

[Adaptation to periodic hypoxia restricts subdural hemorrhages in audiogenic epileptiform convulsions in rats]. / Adaptatsiia k periodicheskoi gipoksii ogranichivaet subdural'nye krovoizliianiia pri audiogennykh épileptiformnykh sudorogakh u krys.

A potent sound stimulation induces in Krushinskii-Molodkina rats epileptiform seizures associated with increased blood levels of stressor hormones and subdural hemorrhages in the brain. Adaptation to periodic hypoxia carried out in a pressure chamber prolonged twofold the latent period of seizure development and blood hydrocortisone content after seizures. Such adaptation reduced the incidence of subdural hemorrhages and the mean size of these hemorrhages. Adaptation scheme used in our experiments is virtually the same as that clinically used at present in the management of patients with allergic diseases and neuroses.

[The protective action of different types and regimens of adaptation to hypoxia on the development of stress-induced lesions in KM strain (Krushinskii-Molodkina) rats]. / Protektornoe deistvie raznykh vidov i rezhimov adaptasii k gipoksii na razvitie stressovykh povrezhdenii u krys linii KM.

The effect of preliminary adaptation to hypoxia on the development of stress-induced lesions was studied on the model of acoustic stress in the Krushinskii-Molodkina line rats genetically predisposed to audiogenic seizures. At different regimens of adaptation to hypoxia (long- and short-term, continuous, intermittent), a decrease of the death rate, severity of motor disorders, incidence and degree of intracranial hemorrhages occurred. Only when using a hypoxic gas mixture, a reduction of excitability of the c.n.s. was revealed: the latency increased whereas the intensity of the seizure decreased. Two-hour normobaric hypoxic stimulation prevented an increase in the lipid peroxidation products and contributed to a rise of cyclic nucleotides concentration in the brain hemispheres of the KM line rats exposed to acoustic stress.