[Destabilization of the cytosolic calcium level and cardiomyocyte death in the presence of long-chain fatty acid derivatives].

It has been shown using the fluorescent microscopy technique that long-chain fatty acid derivatives, myristoylcarnitine and palmitoylcarnitine, exert the most toxic effect on rat ventricular cardiomyoctes. The addition of 20-50 microM acylcarnitines increases calcium concentration in cytoplasm ([Ca2+]i) and causes cell death after the 4-8 min lag-period. This effect is independent on extracellular calcium and L-type calcium channel inhibitors. Free acids (myristic and palmitic acids) at a concentration of 300-500 microM have a little effect on [Ca2+]i within 30 min. We suggest that the toxic effect is due to the activation of sarcoplasmic reticulum calcium channels by acylcarnitines and resulting acyl-CoA. Mitochondria play a role of calcium-buffer system in these conditions. The calcium capacity of this buffer determines the lag-period. Phosphate increases the calcium capacity of mitochondrial and the lag-period. In the presence of rotenone and oligomycin the elevation of [Ca2+]i after the addition of acylcarnitines occurs without the lag-period. The exhaustion of the mitochondrial calcium-buffer capacity or significant depolarization of mitochondrial leads to a rapid release of calcium from mitochondria and cell death. Thus, the activation of reticular calcium channels is the main reason of the toxicity of myristoylcarnitine and palmitoylcarnitine.

[Ionic mechanisms of cardiotropic action of a new class III antiarrhythmic drug RG-2]. / Ionnye mekhanizmy kardiotropnogo deistviia preparata III klassa RG-2.

A perforated patch-clamp analysis of the effect of a novel class III antiarrhythmic agent RG-2, on voltage-dependent currents was made in rat ventricular myocytes. In these cells, RG-2 decreased delayed rectifier outward K(+) current, I(k), in concentration dependent manner with threshold concentration 0.1 microM/l. In contrast, the drug did not have significant effects on the transient outward and inward rectifier K(+) current. RG-2 in concentration dependent manner decreased Ca(2+) current (I(Ca,L)) with threshold concentration 1 microM/l, tenfold higher than threshold concentration for I(k). We can conclude that decreasing of I(k) may explain prolongation of cardiac repolarization induced by RG-2, and contribute to its antiarrhythmic action.

[Modulation of neuronal evoked responses to the medial septal area of hibernating ground squirrels by some neuropeptides after chronic disconnection between septum and preoptico-hypothalamic structures]. / Moduliatsiia neiropeptidami vyzvannykh otvetov neironov medial'noi septal'noi oblasti giberniruiushchikh suslikov v usloviiakh ee khronicheskoi izoliatsii ot preoptiko-gipotalamicheskikh struktur.

Effects of some neuropeptides identified in the brain of hibernators (TSKYR, TSKY, DY) and of monoaminergic neurotransmitters (noradrenaline and serotonin) on responses of the medial septal neurons evoked by intraseptal electrical stimulation were analyzed in slices taken from the ground squirrels with chronic basal undercutting of the septum. Despite the elimination of direct contacts with the preoptic area and afferents ascending in the medial forebrain bundle, the neurons retained almost normal level of reactivity and distribution of the reaction types. The neuropeptides effectively modulated neuronal responses of various types, including oligosynaptic short-latency single-spike responses. The latter were strongly facilitated by the neuropeptides. As a rule, changes in the responses to electrical stimulation were independent of the spontaneous activity shifts (in 78% of the tests). It was suggested that the neuropeptides exert a double influence on the septal neurons: direct nonsynaptic effects on the pacemaker potential responsible for the background activity and modulation of synaptic processes. Our experiments showed that descending influences of the septo-hippocampal system are not crucial for the entrance into the hibernation state and its tonic maintenance. The influences of the thermoregulatory--circadian structures of the preoptico-hypothalamic area determine the paradoxically increased latent excitability of septal neurons that allows the septo-hippocampal system to gate external stimuli and organize arousal of the forebrain during hibernation in case of emergency.

[Effect of chronic disconnection between septal area and hypothalamus on modulation of background activity of septal neurons by biologically-active substances in hibernators]. / Vliianie khronicheskogo raz''edineniia septal'noi oblasti i gipotalamusa na moduliatsiiu fonovoi aktivnosti septal'nykh neironov biologicheski aktivnymi veshchestvami u gibernantov.

Our previous work demonstrated paradoxically increased excitability of the medial septal (MS) neurons during hibernation of ground squirrels in comparison to waking animals. Recently this was supported by demonstration of higher efficacy of the neuropeptides identified in the brain of hibernators in septal slices of hibernating animals. To decide whether this increased excitability is determined by endogenous properties of the pacemaker septal neurons, or it depends on the influences of thermoregulatory-circadian mechanisms of preoptico-hypothalamic area, testing of the neuropeptides (TSKYR, TSKY, DY) and neurotransmitters participating in control of hibernation (serotonin and noradrenaline) was repeated on septal slices taken from the brain of hibernating animals two weeks after operation disconnecting it from the hypothalamus. Effects of neuropeptides in the deafferented hibernating animals neither quantitatively (low reactivity level), nor qualitatively (distribution of inhibitory and excitatory responses) differed from the data obtained in waking animals. Decrease of reactivity occurred at the expense of the neurons with regular pacemaker-like spontaneous activity. Thus, increased reactivity of the MS neurons to neuropeptides in hibernating animals depends mainly on influence of the hypothalamic centres controlling hibernation behavior upon pacemaker neurons of the MS. Contrary to the neuropeptides, serotonin and noradrenaline were highly effective in deafferented septum. They evoked stronger changes of background activity (shorter latencies and more rapid development of maximal shifts), presumably as a result of development of denervation hypersensitivity after deafferentation.

[Selective cytostatic and cytotoxic effects of avermectins]. / Izbiratel'noe tsitostaticheskoe i tsitotoksicheskoe deistvie avermektinov.

A natural avermectin complex, aversectin C, was shown to be capable of exerting selective cytostatic effect. It killed proliferating neuroblastoma B 103 cells but was non-toxic for differentiated cells of this culture. The activity of aversectin C was related neither to activation of the GABA alpha-receptors nor to their blocking and was at a large extent due to the action of avermectin A1, a component of aversectin C.

[Effect of avermectns on Ca(2+)-dependent chloride currents in plasmalemma of Chara corallina cells]. / Deistvie avermektinov na Ca(2+)-zavisimyi khlornyi tok plazmalemmy kletok Chara corallina.

A natural complex of avermectins, aversectin C, and a component of this complex, avermectin A1, were shown to change the conductivity of Ca(2+)-dependent chloride channels of plasmalemma of Chara corallina cells by acting only from the outer side of the cellular membrane. Low concentrations of aversectin C and avermectin A1 increased the chloride current: K1/2 = 3.5 x 10(-5) mg/ml for the whole complex and K1/2 = 2.1 x 10(-3) mg/ml for A1. Relatively high concentrations of the compounds suppressed the chloride current: K1/2 = 2.2 x 10(-3) mg/ml for aversectin C and K1/2 = 4.2 x 10(-6) mg/ml for A1. The Hill coefficients for the interaction of avermectin A1 with the corresponding targets for stimulation and suppression of the chloride current were 2.8 and 2.5 respectively. Bicuculine, a non-specific inhibitor of the GABA alpha-receptors, did not influence stimulation of chloride currents caused by action of low concentrations of avermectins, but at the same time blocked suppression of the chloride currents associated with the action of high doses of avermectins. Avermectins A2, B1 (abamectin), B2 and 22,23-dihydroavermectin B1 (vermectin) in the concentration range studied, did not affect the chloride currents of Chara corallina cells.

[Effects of the afferent stimulation on neurons in the medial septal region slices and their modulation by biologically active compounds in hibernating and waking ground squirrels]. / Vliianiia afferentnoi stimuliatsii na neirony v srezakh medial'noi septal'noi oblasti i ikh moduliatsiia biologicheski aktivnymi veshchestvami u giberniruiushchikh i bodrstvuiushchikh suslikov.

Responses of the medial septal (MS-DB) neurons to electrical stimulation of the medial forebrain bundle (MFB) and their modulation by some neuropeptides and monoamines were investigated in brain slices taken from two groups of ground squirrels-hibernating (HGS) and waking (WGS). Electrical stimulation evoked mostly inhibitory effects of various duration. Besides, responses by phase reset of the background rhythmic bursts and short-latency single spike responses were observed. The neuropeptides identified in the brain of hibernators differentially and reversibly modulated responses even in those neurons where they did not influence the level and pattern of the background activity. Effects of the peptides were state-dependent. E.g., the peptide TSKYR increased the duration of inhibitory effects in the HGS but shortened them in the WGS, while TSKY which had low efficacy in the HGS, increased the duration of inhibition in the WGS. Dipeptide DY depressed inhibitory components and augmented excitatory components of responses in the HGS but was much less effective in the WGS. Effects of noradrenaline and serotonin had stronger correlation with their influence on spontaneous activity. It is suggested that endogenous substances provide for the increased latent excitability and reactivity of the MS-DB neurons during seasonal hibernation. Thus, the MS-DB may function as a "sentry post" participating in signal detection and urgent arousal during hibernation.

[The state-dependent action of neuropeptides and monoamines on the background neuronal activity of the medial septal area in hibernating animals]. / Zavisiashchee ot sostoianiia deistvie neiropeptidov i monoaminov na fonovuiu aktivnost' neironov medial'noi septal'noi oblasti u gibernantov.

Neuronal activity of the medial septal area (MS-DB) was recorded extracellularly in brain slices from two groups of Yakutian ground squirrels Citellus undulatus--hibernating (winter period) and actively waking (summer period). Effects of three neuropeptides identified in the brain of hibernators (TSKYR, TSKY, and DY) and of two monoamines (serotonin and noradrenaline) on spontaneous activity were analyzed. All neuropeptides reversibly changed the levels of the background activity, but in the hibernating ground squirrels (HGS) the level of reactivity (47-56%) was significantly higher than in the waking ground squirrels (WGS, 25-30%). Serotonin also showed some tendency to higher efficacy in the HGS. Only noradrenaline was equally effective and had absolutely dominating excitatory effect in both states, although the level of excitation in the HGS was higher. All other substances evoked excitatory and inhibitory effects in various proportions. Their distribution was state-dependent, the rate of development, intensity and duration of the effects were greater in the HGS. The experiments confirmed the data on higher excitability and reactivity of the septal neurons in the state of hibernation. It is suggested that the tested neuropeptides may participate in the control of hibernation.

[A comparative analysis of the intracellular potassium content for the cardiomyocyte in papillary muscle tissue and in a primary heart culture]. / Sravnitel'nyi analiz vnutrikletochnogo soderzhaniia kaliia dlia kardiomiotsita v tkani papilliarnoi myshtsy i v pervichnoi kul'ture serdtsa.

This work was aimed to examine potassium contents in heart myocytes. The intracellular concentration of this element was measured with electron probe microanalysis (EPMA). The cardiomyocyte was studied in samples of the papillary muscle tissue and in heart primary culture. The low temperature fixation was applied to the sample preparation. As a result, cells of the primary heart culture were shown to be separated into three kinds of myocytes, defined by their different shape, size and cellular potassium content. The rod cardial cell, to be used for electrophysiological assays, has potassium and sodium concentrations close to those of the papillary muscle. The difference in potassium concentrations is to be explained presumably by the injury of cell membrane during the primary culture preparation. Healing over the membrane is likely to parallel with the membrane damage resulting from a continuous destruction of the cellular assembly in primary culture.

[Biologically active peptides isolated from the brain of hibernating ground squirrels]. / Biologicheski aktivnye peptidy, bydelennye iz mozga zimospiashchikh suslikov.

More than 20 peptides have been isolated and sequenced from the brain of hibernating ground squirrel Citellus undulatus. Some of the isolated peptides were chemically synthesized and investigated for the spectrum of biological activity. One of the isolated peptides, neokyotorphin (Thr-Ser-Lys-Tyr-Arg), earlier known as a weak analgetic, is found to have a cardiotropic and thermoregulatory activity. Neokyotorphin activates in vitro voltage-dependent calcium and blocks ATP-dependent potassium currents in the frog atrial fibres. Intraperitoneal injection of this peptide in hibernating ground squirrels speeds up the arousal of animals increasing sharply the heart rate and oxygen consumption. Intraperitoneal and intranasal administrations of neokyotorphin in rats raises body temperature in thermoneutral conditions (26-28 degrees C) exerting no effects at low (4-6 degrees C) and high (31-32 degrees C) environmental temperatures. Another isolated peptide, Asp-Tyr, blocks the inward voltage-dependent calcium current in the frog atrial fibres and slightly increases the outward potassium current. Sulfated analogue of this dipeptide (aspartyl-O-sulfate-tyrosine) more effectively blocks the inward voltage-dependent calcium current in the frog atrial fibres and have no effects on the outward potassium current.

[Modification by cycloheximide of the effects of insulin on the transport of calcium by sarcolemma of the myocardium]. / Modifikatsiia tsiklogeksimidov éffektov insulina na transport kal'tsiia sarkolemmoi miokarda.

The inhibitory effect of insulin on Ca2+-current was supposed to be due to activation of phosphoproteinphosphotases stimulated by a specific intracellular insulin messenger. The results obtained support the above suggestion. Pretreatment of myocardial preparation with cycloheximide in low concentrations completely blocks the inhibitory insulin effect on Ca2+-current due, probably, to a decrease in peptide formation. Moreover, prolonged effect of the hormone involves a considerable increase of the current as compared to its initial value. Possible mechanisms of modifying effect of cycloheximide on the function of insulin-dependent regulatory system in the myocardium, are discussed.

[Effect of insulin on the calcium current of the frog myocardium]. / Vliianie insulina na kal'tsievyi tok miokarda liagushki.

The experiments on frog atra tuberculae revealed that insulin could induce biphasic changes of calcium currents of different directions. The current is inhibited with hormone due to a decrease both in the conductivity of channel system and reversal potential. In some cases prior to inhibition of calcium current, a short rise of this current occurred (3-6 min) induced by increased reversal potential. Possible mechanisms of insulin electrophysiological effects are discussed.

[Instability and propagation of waves of excitation in a model of a catalytic reaction. III. Non-trivial regimes of propagation of excitation]. / Neustoichivost' i rasprostranenie voln vozbuzhdeniia v modeli kataliticheskoi reaktsii. III. Netrivial'nye rezhimy rasprostraneniia vozbuzhdeniia

The regime of excitation propagation in a uniform model of an active medium is studied within the parameters where the initial concentrated system is a trigger one. In a distributed system propagation trigger waves as well as impulses can propagate. A means for initiating such impulses is suggested, an unstationary regime of their imitation is investigated by calculations. Piece-linear solutions obtained analytically are shown to be a good approximation for stationary regimes.

[Analysis of electrophysiologic characteristics of the frog atrial trabecular membrane by ionic currents at a fixed potential]. / Analiz élektrofiziologicheskikh kharakteristik membrany trabekuly predserdiia liagushki po ionnym tokam fiksatsii potentsiala

The membrane of frog auricle trabecula was studied by the method of potential fixation. On the basis of the records of ionic currents zyro-isoclines of approximative differential equations of the 2nd order, describing the membrane studied, were plotted. The mathematical model of this membrane was analysed with the help of qualitative methods of the oscillation theory. The analysis has shown that the following phenomena which have not been observed experimentally should take place in the membrane of frog auricle trabecula: 1. absence of the minimum gradient and accomodation growth of thresholds; 2. absence of anode-disconnecting excitation; 3. coincidence of the current of repeated responses with that of the rheobase; 4. uneven depolarization.