Role of the peripheral catecholaminergic systems in the antistress action of neuropeptides

The mediator activity of the peripheral catecholaminergic systems (the adrenergic nerves of dura mater and the concentrations of noradrenaline and adrenaline in the adrenals of rats) during dynamic and immobilization stress was investigated with the help of fluorescent microscopy and spectrofluorometry. Neuropeptides--dalargin and another enkephalin analog--were injected intraperitoneally, 150 mg/kg. A visible antistress action of these neuropeptides has been demonstrated, it was more marked after treatment with dalargin. The role of peripheral catecholaminergic system in the mechanism of stress-protective effects of neuropeptides is discussed.     

Metabolic level and the function of the peripheral catecholaminergic systems in immobilization hypothermia in rats

Metabolic peculiarities were studied on the model of prolonged immobilization hypothermia in rats (body temperature +20 degrees C for 24 h). Stress reactions and the state of peripheral catecholaminergic systems were compared in hypo- and normothermia. A direct correlation was established between the intensity of metabolism and the mediator activity in adrenergic nerve structures.     

Antagonistic effect of sodium hydroxybutyrate on several effects of aminoxyacetic acid]

A well-known protective effect of aminooxyacetic acid against thiosemicarbazide convulsions was confirmed; it was shown that a similar, although somewhat weaker activity, was exerted by sodium hydroxybutyrate. Surprisingly, the effect of aminooxyacetic acid was diminished by sodium hydroxybutyrate. Sodium hydroxybutyrate in combination with aminooxyacetic acid decreased the protective activity of the latter against thiosemicarbazide convulsions and diminished the extent of GABA accumulation characteristic of aminooxyacetic acid action. This effect is attributed to the competition between the aminooxyacetic acid, sodium hydroxybutyrate and GABA for alpha-ketoglutarate-GABA-transaminase and possible for the GABA-ergic receptor.     

Prophylactic effects of sodium oxybutyrate and lithium oxybutyrate on stress-induced depression of the activity of normal killers in mice

The possible use of sodium hydroxybutyrate and lithium hydroxybutyrate for the prevention of the decrease in splenic natural killer activity has been studied in CBA mice upon 6-hour immobilization stress. Both agents proved to be effective in preventing stress-induced depression of NK activity. However, a protective effect of lithium hydroxybutyrate was observed at a dose 4 times lower than that of sodium hydroxybutyrate.     

Comparative single and double immunolabelling with antisera against catecholamine biosynthetic enzymes: criteria for the identification of dopaminergic,noradrenergic and adrenergic structures in selected rat brain areas

Immunodetection of catecholamine biosynthetic enzymes is frequently used for the visualization of central nervous catecholaminergic systems. Because of the method's limited specificity for the different catecholamines, interpretation of the results often presents difficulties. To determine criteria for the identification of dopaminergic, noradrenergic, and adrenergic afferents to the rat amygdaloid complex, comparative immunolabelling for tyrosine hydroxylase (TH), dopamine--hydroxylase (DBH), and phenylethanolamine-n-methyltransferase (PNMT) was carried out using single- and double-labelling for fluorescence, light- and electron microscopy. The observations were complemented by findings in brainstem and hypothalamic areas. The results indicated that. TH-labelling detected preferentially dopaminergic afferents in the lateral central and intercalated amygdaloid nuclei. DBH-labelling detected noradrenergic axons in nuclei lacking PNMT-immunoreactive fibres, and PNMT was a marker for adrenergic axons in the entire complex. For nuclei with combined dense dopaminergic, noradrenergic and/or adrenergic innervation, morphological and immunolabelling characteristics were described which, to a certain extent, enabled identification of the different afferents in anti-TH or anti-DBH-preparations. Using a monoclonal TH-antiserum, noradrenergic and adrenergic axons displayed weaker immunoreactivity than dopaminergic ones, and possessed characteristic morphological features. TH-immunoreactivity in noradrenergic axons differed depending on their origin, and showed intra-axonal compartmentalization. The present study provides a basis for the use of the detection of biosynthetic enzymes in future investigations into the ultrastructure and connectivity of the catecholaminergic amygdala innervation.     

Study of the mechanism of the anti-hypoxic action of lithium oxybutyrate using cerebral ischemia as a model

A study was made of energy metabolism and concentration of malonic dialdehyde (MDA) in cerebral tissue of mice given sodium hydroxybutyrate and lithium hydroxybutyrate 30 and 60 s after decapitation. Administration of lithium hydroxybutyrate brought about a more economic consumption of the glycogen pool as compared with "hypoxic" control. The differences were revealed in the action of both salts on ATP. The concentration of MDA declined after their administration, lithium hydroxybutyrate being more efficacious. The possible mechanisms of the action of lithium hydroxybutyrate are discussed.     

Neonatal lesions of catecholaminergic system prevents maturation of cholinergic innervation of the rat neocortex

The influence ofcatecholaminergic system on functioning of the somatosensory and cholinergic systems in early ontogenesis in rats was studied. The neonatal systemic administration of the neurotoxin 6-hydroxydopamine modifies sensitivity of neurons in the somatosensory cortex to peripheral stimulation (stimulation of the sciatic nerve). It is shown that in animals with lesions, catecholaminergic system reduces the number of the cortical neurons responsive to stimulation of ascending cholinergic pathways. The sensitivity of these neurons to acetylcholine does not change. The damage in the early ontogeny catecholaminergic mechanisms seems to prevent maturation of cholinergic afferents in the neocortex.     

Psychotropic effect of sodium hydroxybutyrate

A conclusion was drawn on the qualitative features of the spectrum of sodium hydroxybutyrate psychotropic activity from its effect on the conditioned motor-defensive reflex, behaviour in the conflict situation, active avoidance without discriminative control in rats as well as from the lateral position test The results obtained allow the effect of sodium hydroxybutyrate in non-narcotic doses to be characterized as a hypnotic one showing elements inherent in neuroleptics and tranquilizers.     

Effect of sodium oxybutyrate on regional blood circulation and on neural regulation of vascular tonus]

The effect of sodium hydroxybutyrate on the blood flow in the aorta, carotid, mesenteric and femoral arteries were studied on cats and dogs. The circulation was assessed by the electromagnetic and resistographic methods, in the anesthetized and nonanesthetized animals. The tonic activity was recorded in the sympathetic nerves and the EEG. Sodium hydroxybutrate was shown to decrease the sympathetic activity, resulting in the increase of the regional circulation and induced the EEG synchronization. The latter effect was more pronounced in the arotid arteries. It can be assumed that sodium hydroxybutyrate affects the nervous control of the blood vessels.     

Effect of sodium hydroxybutyrate on the ultrastructure of cross-striated muscle tissue myocytes during physical exercise

The ultrastructure of myocytes of the rat myocardium and skeletal muscles was studied in the control during physical exercise and under conditions of two-week sodium hydroxybutyrate pretreatment. It was shown that single maximum physical exercise caused significant changes in the fine structure of cardiomyocytes and somewhat less changes in a pronounced intermyofibrillar edema, the swelling of mitochondria and an acute fall of the glycogen level. A two-week sodium hydroxybutyrate pretreatment prevented the changes in the myocytes. The observed structure normalization induced by the drug is likely to be due to the specific nature of its metabolic transformation and to the effect on the energy exchange.     

A comparative analysis of the change in the EEG spectral characteristics of rats during the activation and suppression of the catecholaminergic systems]

To find EEG-markers of catecholaminergic activation shifts EEG power spectra of white rats were computed before and after intraperitoneal injections of propranolol, metaproterenol, haloperidol, amantadine, or isotonic sodium chloride solution. Differential spectral characteristics were undergone to factor analysis and discriminant analysis. Factors with similar structure for both catecholaminergic systems were revealed in EEG-reactions to mutually antagonistic injections and relatively specific factors as well. The leading factor of adrenotropic injections described the augmentation of the spectral power in the range of 9-16 Hz induced by propranolol and its reduction by metaproternol. Similar factor was also revealed in reactions to dopaminotropic injections with the smaller value of discriminant function coefficient. One more common feature of EEG-reactions to catecholaminergic disturbances was found to consist of the reciprocal narrow-band shifts in the theta- and delta-diapasons. The leading factor for the recognition of dopaminotropic disturbances described the increase of EEG power in the band of 19-30 Hz at activation and its reduction at suppression of the transmitter system.     

The role of peripheral cholinergic and adrenergic receptor systems in the action of histamine on the isolated coronary arteries

The action of peripheral cholinergic and adrenergic receptor systems on the histamine coronary vasospastic effects are investigated in the experiments on the isolated ring-shaped strips of coronary arteries of pigs with the aid of specific agonists and antagonists. It has been demonstrated that neuromediator systems play a significant role in the regulation of contractile activity of the coronary spasm pathogenesis. When medicines are prescribed to patients with ischemic heart disease it is necessary to take into account the character of the preparations interaction which affect the peripheral neuromediator processes such as histaminergic, cholinergic, adrenergic and others.     

Neuromediator shifts in the peripheral blood of dogs resulting from negative emotiogenic exposure

The analysis of negative emotiogenic influence in dogs carried out according to dynamics of levels of acetylcholine and catecholamine content in peripheral blood and concomitant changes of the higher nervous activity, allows to conclude about the participation of both cholinergic and catecholaminergic neurotransmitter systems in reactions to this influence with a relative predominance of the first one. In animals with decreased reactivity and with compensatory abilities of the cholinergic system, the same influence leads to enhancement of the specific significance of the reaction of the catecholaminergic system, and especially of its transmitter, noradrenergic component.     

Ultrastructural Correlates of Enhanced Norepinephrine and Neuropeptide Y Cotransmission in the Spontaneously Hypertensive Rat Brain

The spontaneously hypertensive rat (SHR) replicates many clinically relevant features of human essential hypertension and also exhibits behavioral symptoms of attention-deficit/hyperactivity disorder and dementia. The SHR phenotype is highly complex and cannot be explained by a single genetic or physiological mechanism. Nevertheless, numerous studies including our own work have revealed striking differences in central catecholaminergic transmission in SHR such as increased vesicular catecholamine content in the ventral brainstem. Here, we used immunolabeling followed by confocal microscopy and electron microscopy to quantify vesicle sizes and populations across three catecholaminergic brain areas—nucleus tractus solitarius and rostral ventrolateral medulla, both key regions for cardiovascular control, and the locus coeruleus. We also studied colocalization of neuropeptide Y (NPY) in norepinephrine and epinephrine-containing neurons as NPY is a common cotransmitter with central and peripheral catecholamines. We found significantly increased expression and coexpression of NPY in norepinephrine and epinephrine-positive neurons of locus coeruleus in SHR compared with Wistar rats. Ultrastructural analysis revealed immunolabeled vesicles of 150 to 650 nm in diameter (means ranging from 250 to 300 nm), which is much larger than previously reported. In locus coeruleus and rostral ventrolateral medulla, but not in nucleus tractus solitarius, of SHR, noradrenergic and adrenergic vesicles were significantly larger and showed increased NPY colocalization when compared with Wistar rats. Our morphological evidence underpins the hypothesis of hyperactivity of the noradrenergic and adrenergic system and increased norepinephrine and epinephrine and NPY cotransmission in specific brain areas in SHR. It further strengthens the argument for a prohypertensive role of C1 neurons in the rostral ventrolateral medulla as a potential causative factor for essential hypertension.     

Naloxone inhibits the centrally-mediated hypotensive actions of BHT-933 (azepexole)

Central administration of BHT 933, a highly selective alpha 2 agonist, to pentobarbital-anesthetized, normotensive dogs resulted in a rapid, significant decrease in blood pressure. The maximal response occurred at 30 min and remained significantly decreased for 60 min. Concomitant with the hypotensive response was a decrease in heart rate. Pretreatment with naloxone 15 min prior to the administration of BHT 933 completely abolished the hypotensive response and significantly inhibited the bradycardia. These results suggest a role for central opioidergic systems in the control of blood pressure which may serve as important sites of antihypertensive drug action. The central regulation of sympathetic tone by catecholaminergic systems plays an important role in the control of cardiovascular function in both normal and pathological states. A high density of catecholaminergic nerve terminals is found in regions of the brainstem involved in cardiovascular control. Stimulation of the alpha receptors in these areas decreases peripheral sympathetic tone and subsequently lowers blood pressure. Recent histochemical evidence has demonstrated the presence of opioid peptides in the nucleus tractus solitarii, nucleus ambiguous and hypothalamus as well as other discrete brain areas associated with cardiovascular control. Activation of the opiate receptors in these brain areas decreases sympathetic tone and blood pressure. Additionally, both catecholaminergic and opioidergic systems have been implicated in the reaction to certain stimuli (i.e., pain, stress) which entail important hemodynamic adaptations. The similarity between the central opiate and catecholaminergic systems suggests a relationship between the two systems in blood pressure control and a potential site of antihypertensive drug action. The purpose of the present study was to determine if an opioidergic component is involved in the hypotensive action of BHT 933 (azepexole). BHT 933 is a relatively new hypotensive agent which is a much more specific alpha 2 agonist than clonidine.     

Effect of lithium salts on neuropathological syndromes of spinal origin

Experiments on noninbred rats were made to study the influence of lithium hydroxybutyrate on two patterns of spinal cord pathology: the generalized myoclonus and painful syndrome of spinal origin. The syndromes were induced by generators of pathologically enhanced excitation in the ventral and dorsal horns of the spinal cord. The effects of lithium chloride and sodium hydroxybutyrate were examined to compare the influence of lithium (cation) and hydroxybutyrate (anion) components to elucidate the role of each of the components. Lithium hydroxybutyrate appeared more effective, since it inhibited the generator of pathologically enhanced excitation in the appropriate structures, provoking the anticonvulsant effect in myoclonus and suppressing the painful syndrome.     

Differential Expression of Syntaxin 1A and 1B by Noradrenergic and Adrenergic Chromaffin Cells

The expression and localization of syntaxin isoforms 1A and 1B in adrenergic and noradrenergic chromaffin cells were examined by both immunoblot analysis and confocal immunofluorescence microscopy. Syntaxin 1A was found in higher levels in noradrenergic cells, whereas syntaxin 1B was similarly expressed in most noradrenergic and adrenergic cells. However, some heterogeneity was observed within each catecholaminergic phenotype. Although the majority of adrenergic cells appeared to express low levels of syntaxin 1A, about 7% was strongly stained for syntaxin 1A. A subpopulation of noradrenergic cells, about 17%, expressed greater levels of syntaxin 1B. Syntaxin 1B labeling showed a punctate appearance in the cytoplasm, whereas syntaxin 1A appeared predominantly localized to the plasma membrane. These data show differences in the exocytotic machinery of the two subtypes of chromaffin cells that may underlie some of the distinct characteristics of adrenaline and noradrenaline secretion.     

Redistribution of myocardial blood flow in chronic ischemia under the effects of pharmacological agents

In the experiments with anesthetized dogs under chronic myocardial ischemia the effect of propranolol, diltiazem, lithium and sodium hydroxybutyrate on the myocardial blood flow redistribution was studied with the help of ultrasonic method. The redistribution was estimated by the ratio change of blood flows in veins which drain blood directly from the focus of myocardial ischemia and total myocardial of left ventricular (v cardiac magna). It was established that propranolol increases the ratio and diltiazem decreases it. Some differences in the effect of antihypoxic drugs were revealed. Sodium hydroxybutyrate redistributed the blood flow in favour of the focus of myocardial ischemia and lithium hydroxybutyrate increased the blood flow both in the focus of myocardial ischemia and in the conditionally-intact region of myocardium of left ventricular.     

Antioxidant effects of antihypoxic drugs in cerebral ischemia]

Cerebral ischemia in rats (both carotid arteries occlusion) during 30 min, 3 hours and recirculation (1 hour) after ischemia (30 min) stimulated diene conjugates and fluorescent products accumulation in brain tissue. Intraperitoneal injection of sodium hydroxybutyrate (100 mg/kg), bemitil (50 mg/kg), ethomersol (50 mg/kg) reduced brain lipid peroxidation and did not yield in this respect to emoxypin (5 mg/kg). In contrast to emoxypin, sodium hydroxybutyrate, bemitil and ethomersol had no antiradical activity.     

Sodium oxybutyrate and piracetam acceleration of the compensatory-reparative processes after damage to the cerebral cortex in rats

The effects of sodium hydroxybutyrate and piracetam on compensatory-reparative processes in the central nervous system have been investigated in rats after extirpation of the frontal cortex. The animals were pretrained to conditioned reflex of active avoidance. Extirpation of the frontal cortex has been shown to disturb the conditioned reflex. Sodium hydroxybutyrate (50 mg/kg) and piracetam (200 mg/kg) were found to precipitate the recovery of the damaged reflexes.