[Features of autonomic regulation of the cardiovascular system in human late ontogenesis.]

Using the method of arterial piezopulsometry, statistical and spectral analyzes of variable parameters (VmaxPP and TNN) of pulse waves of blood pressure in patients aged 18 to 85 years were performed. The individual characteristics of the autonomous (vegetative and neuroendocrine) regulation of the muscular effectors (ME) of the cardiovascular system (CVS) in an elderly man (75 years old) and a young woman (20 years old) were estimated with high accuracy. These data, as well as the results of a comparative study of patients of different ages, made it possible to identify a certain pattern of directed change in the sympathoadrenal regulation of ME CVS in human ontogenesis. It is concluded that in the course of their lives, people undergo a restructuring of the physiological mechanism of the autonomous regulation of their ME CVS, aimed at replacing short-term sympathetic regulation in young people with more effective and more stable regulation by humoral catecholamines in elderly.

[AGED CARDIOHEMODYNAMICS COMPLICATED BY STROKE].

A new method of arterial piezopulsometry allowed a 12-year study of the peculiarities of age-related changes in cardiac hemodynamic indices in an aged man after ischemic stroke. The ob-tained results enable use of these indicators as prognostic criteria of an individual organism's re-sistance to acceleration factors of aging, as well as its resistance to the development of the cardi-ovascular pathology caused by the stroke. Simultaneous dual registration of piezopulsograms al-lowed establishing a significant increase of the augmentation index of pulse pressure (AIxPP) and the velocity of the pulse wave of blood pressure propagation through the radial artery (Var) in a paralyzed right arm, compared to the left hand control (p < 0,05). Range fluctuations in the relative values of this difference can serve as an objective indicator of the functional state of a paralyzed arm of a patient during rehabilitation treatment, and a sharp decrease of this difference and its subsequent stabilization can serve as an indicator of the beginning of recovery.

[MECHANISMS OF THE EFFECT OF Li+ ON MYOCARDIUM OF VERTEBRATES].

The effect of Li+ on the frog Rana temporaria myocardium and its influence on the ion transport in the rat heart mitochondria (RHM) were studied. Li+ added to the normal Ringer solution (Li(+)-R) was found to attenuate myocardial tension, decrease the maximal rate of tension development and its half-relaxation time. Comparison of the cardiac muscle contraction parameters in the Li(+)-R with the effect of the voltage-gated Ca(2+)-channels (Cav1.2), verapamil and CdCl2, showed that the negative inotropic effect of the Na+ replacement by Li+ in the limited intermembrane ("fuzzy") space is underlain by the blocking of Ca2+ influx into the myoplasm via the reverse Ca2+/Na(+)-exchanger in the plasma membrane (PM). This, in turn, prevents Ca(2+)-induced massive Ca2+ release into the myoplasm via the RYR2-channels in the sarcoplasmic reticulum (SR) leading in aggregate to suppression of Ca(2+)-dependent myocardial contractions. In the experimental studies of the Li+ effect on the RHM it was established that Li+ just slightly increases the passive permeability of the inner mitochondrial membrane (IMM) for K+ and H+ and decreases the intensity of ion pumping out of the energized mitochondrial matrix to the external medium. This may also indicate the lack of relationship between the mitochondrial oxidative processes and the reduction in the myocardial contractile activity under the Na+ replacement by Li+.

[Ca2+ signaling in prokaryotes].

The role of Ca2+ ions in the regulation of motility, cell cycle, and division of prokaryotes is dis- cussed, as well as their involvement in pathogenesis of come infectious diseases. The structural and functional organization of the prokaryotic Ca2+ signal system and the mechanisms of Ca2+ membrane transport and homeostasis are described. Special attention is paid to the role of Ca2+ cation channels, Ca2+ transporters, and Ca2+ -binding proteins in the regulation of the intercellular Ca2+ concentration.

[Action of yttrium on calcium-dependent processes in myocardium of vertebrates].

This work deals with study, of effect of yttrium acetate (Y3+) on myocardium of the frog Rana redibunda and of its action on the ion transport across the inner membrane of the rat heart mitochondria. It was found that Y3+ decreased strength of heart contractions and facilitated transport of ions in rat heart mitochondria stimulated by 10 mM glutamate and 2 mM malate. In the presence of Y3+, the energy-dependent transport of Ca2+ in mitochondria was inhibited; this was manifested as a decrease of their swelling in the medium containing 125 mM NH4NO3 and Ca2+ or 25 mM potassium acetate, 100 mM sucrose and Ca2+. It is assumed that the Y(3+)-caused decrease of the heart muscle contractility is not only due to its direct blocking effect on the potential-operated Ca2+ channels of the pacemaker and contractile cardiomyocytes, but also due to its mediated action on active transport of Ca2+ in mitochondria. The data that Y3+ activates transport of K+ via the mitochondrial potassium uniporter and blocks Ca(2+)-channels of the inner mitochondrial membrane are important for better understanding of mechanisms of action Y3+ on cardiomyocytes of vertebrate animals and humans and the possible use of Y3+ in medicine.

[Evolution of mechanisms of Ca(2+)-signaling. Role of Ca2+ in regulation of specialized functions of cardiomyocytes in chronic heart diseases].

The review considers role of Ca2+ ions in regulation of specialized functions of cardiomyocytes (CM) in disturbances of heart activity. Problems of Ca(2+)-dependent signaling mechanisms leading to pathological hypertrophy, arrythmogenesis, and heart failure are elucidated. A particular attention is paid to analysis of Ca(2+)-dependent molecular mechanisms leading to remodeling of contractile proteins, apoptosis, or pathological growth of CM.

[Evolution of mechanisms of Ca(2+)-signalization. Role of Ca2+ in regulation of specialized cell functions].

The review considers peculiarities of Ca(2+)-signalization in electroexcitable cells of the higher eukaryotes. The light has been thrown upon the problems of Ca(2+)-dependent mechanisms of regulation of muscle contractility and of neuronal synaptic plasticity in the higher vertebrate animals. A particular attention has been paid to analysis of contribution of such poorly studied components of Ca(2+)-signalization as non-selective TRPC-channels, Orai channels, sensory STIMI proteins, Ca(2+)-controlled K(+)-channels of high and low conductivity, and neuronal Ca(2+)-sensors (NCS).

[Action of La3+ on the systems providing contractility of vertebrate myocardium].

The inotropic action of La3+ on frog myocardium was studied with taking into account of its effect on mitochondria of cardiomyocytes (CM). It has been established that in the range of studied concentrations (0.2-6 mM), La3+ decreases dose-dependently the strength of cardiac contractions (by 3.3-92.2 %). In parallel experiments on isolated rat heart mitochondria (RHM), La3+ at a concentration of 25 microM has been shown to cause swelling of non-energized and energized mitochondria in isotonic medium with 125 mM NH4NO3 and in hypotonic medium with 25 mM CH3COOK. The study of oxidative processes in mitochondria with aid of polarographic method of measurement of oxygen concentration has shown that La3+ at concentrations of 50 and 100 microM increases the oxygen consumption rate by mitochondria in the state 2. However, La3+ does not decrease the respiration rate of isolated mitochondria in the state 3, as this takes place in the case of use of Cd2+ or at the Ca(2+)-overloading of mitochondria. The rate of endogenous respiration of isolated mitochondria in the medium with La3+ was higher than in control, which implies its effect on ion permeability of the inner membrane. The data obtained in this work indicate that the La(3+)-produced decrease of the contractility of cardiac muscle is not only due to the direct blocking effect on the potential-controlled Ca2+ channels, but is also mediated by its unspecific action on the CM mitochondria. This action is manifested in acceleration of the energy-dependent K+ transport in matrix and in an increase of ion permeability of the inner mitochondrial membrane (IMM).

[Influence of activator and inhibitors of Ca2+ channels on proliferative activity in Tetrahymena pyriformis infusoria].

It was determined that change in DNA content in macronuclei occurs in the T. pyriformis infusoria under the influence of an activator (caffeine) and inhibitors of Ca2+ channels (verapamil), NiCl2, and CdCl2. Caffeine (10 mM) stimulates DNA synthesis. Verapamil (5 microM), CdCl2 (125 microM), and NiCl2 (100 microM) decrease DNA content in macronuclei by 30 min after proliferative stimulation. By 4 h of incubation, there is, on average, 10% less DNA in macronuclei of Tetrahymena preprocessed with verapamil than in the control cells. The cells preprocessed with CdCl2 and NiCl2 differ from the control cells by lower DNA content almost at all studied periods, but they restore the level of nuclear DNA by 4 h. It is assumed that transmission of proliferative signals in the T. pyriformis has a Ca2+ -dependent character.

[Influence of oxidative processes in mitochondria on contractility of the frog Rana temporaria heart muscle. Effects of cadmium].

The inotropic Cd2+ action on frog heart is studied with taking into account its toxic effects upon mitochondria. Cd2+ at concentrations of 1, 10, and 20 microM is established to decrease dosedependently (21.3, 50.3, and 72.0%, respectively) the muscle contraction amplitude; this is explained by its competitive action on the potential-controlled Ca2(+)-channels of the L-type (Ca 1.2). In parallel experiments on isolated rat heart mitochondria (RHM) it was shown that Cd2+ at concentrations of 15 and 25 microM produces swelling of non-energized and energized mitochondria in isotonic (with KNO2 and NH4NO3) and hypoosmotic (with 25 mM CH3COOK) media. Study of oxidative processes in RHM by polarographic method has shown 20 microM Cd2+ to disturb activity of respiratory mitochondrial chain. The rate of endogenous respiration of isolated mitochondria in the medium with Cd2+ in the presence of malate and succinate was approximately 5 times lower than in control. In experimental preparations, addition into the medium of DNP-uncoupler of oxidation and phosphorylation did not cause an increase of the oxygen consumption rate. Thus, the obtained data indicate that a decrease in the cardiac muscle contractility caused by Cd2+ is due not only to its direct blocking action on Ca2(+)-channels, but also is mediated by toxic effect on rat heart mitochondria, which was manifested as an increase in ion permeability of the inner mitochondrial membrane (IMM), acceleration of the energy-dependent K+ transport into the matrix of mitochondria, and inhibition of their respiratory chain.

[Signal function of calcium-binding proteins in lower eukaryotes].

This review summarizes data on the signaling role of calcium-binding proteins (CaBP) in lower eukaryotes cells. The contributions of calmodulin (CaM)-like proteins, calcium-dependent protein kinases (CDPK), as well as calcineurin B-like phosphatase (CaNB) and some other proteins to Ca(2+)-dependent regulation of cellular functions is considered.

[Influence of mitochondrial oxidative reactions on myocardial contractility. Effects of Ni2+].

Inotropic effects of Ni2+ and mitochondrial oxidative readions were accordingly tested by the use of frog myocardial preparations, excised from left frog ventricle, and rat heart mitochondria (RHM). Amplitude of the cardiac contraction was increased in the presence of 10-200 microM Ni2+ in dose-dependent manner. It was found that Ni2+ is not toxic for RHM. State 4 in a KCI medium was stimulated by 100 microM Ni2+. At the same time, Ni2+ did not affected state 3 and 2,4-dinitrophenol-stimulated respiration of RHM. Our findings allow to be supposed that Ni2+-induced increase in the amplitude of the cardiac contraction can be affected by energetic state of RHM.

[T-channels and Na+,Ca2+-exchangers as components of the Ca2+-system of the myocardial activity regulation of the frog Rana temporaria].

Earlier we have shown that regulation of rhythm and strength of the frog heart contractions, mediated by transmitters of the autonomic nervous system, is of the Ca2+-character. In the present work, we studied chrono- and inotropic effect of verapamil--an inhibitor of Ca2+-channels of the L-type, of nickel chloride--an inhibitor of Ca2+-channels of the T-type, and of Na+,Ca2+-exchangers as well as of adrenaline and acetylcholine (ACh) after nickel chloride. It has been found that the intracardially administered NiCl2 at a dose of 0.01 microg/kg produced a sharp fall of amplitude of action potential (AP) and an almost twofold deceleration of heart rate (HR). The intracardiac administration of NiCl2 (0.01 microg/kg) on the background of action of verapamil (6 mg/kg, i/m) led as soon as after 3 min to even more prominent HR deceleration and to further fall of the AP amplitude by more than 50% as compared with norm. The intracardiac administration of adrenaline (0.5 mg/kg) partly restored the cardiac activity. However, preservation of the myocardium electrical activity in such animals was brief and its duration did not exceed several minutes. Administration of Ni2+ on the background of acetylcholine (3.6 mg/kg) led to almost complete cessation of cardiac activity. As soon as after 3 min after injection of this agent the HR decreased to 2 contractions/min. On EG, the 10-fold fall of the AP amplitude was recorded. The elucidate role of extra- and intracellular Ca2+ in regulation of heart contractions, isometric contraction of myocardium preparations was studied in response to action of NiCl2 (10-200 microM), verapamil (70 microM), adrenaline (5 microM), and acetylcholine (0.2 microM) after NiCl2. It is found that Ni2+ caused a dose-dependent increase of the muscle contraction amplitude. Minimal change of the contraction amplitude (on average, by 14.9% as compared with control) was recorded at a Ni2+ concentration of 100 microM. An increase of Ni2+ in the sample to 200 microM increased the cardiac contraction strength, on average, by 41%. The negative inotropic action of verapamil was essentially reduced by 100 microM Ni2+. Adrenaline added to the sample after Ni2+ produced stimulating effect on the cardiac muscle, with and almost twofold rise of the contraction amplitude. ACh (0.2 microM) decreased the cardiac contraction amplitude, on average, by 56.3%, whereas Ni2+ (200 microM) administered after ACh not only restored, but also stimulated partly the myocardial work. Within several parts of percent there was an increase of such isometric contraction parameters as amplitude of the muscle-developed effort, maximal rate, maximal acceleration, time of semirise and semifall. The obtained experimental results indicate that the functional activity of the frog pacemaker and contractile cardiomyocytes is regulated by the Ca2+-dependent mechanisms. Structure of these mechanisms includes the potential-controlled L- and T-channels of the plasma membrane as well as Na+,Ca2+-exchangers characteristic exclusively of contractile cardiomyocytes. The existence of these differences seems to be due to the cardiomyocyte morphological peculiarities that appeared in evolution at the stage of the functional cell specialization.

[Characteristics of the signal transduction in parasitic lower eukaryotes].

The review summarizes current data about pathways of the signal transduction in parasitic unicellular eukaryotes at the initial stage of the invasion and during their intracellular adaptation, growth and replication. The role of the factors that influence virulence of the unicellular parasites is reviewed. A special attention is paid to aspects of intracellular communications of the parasites and host cells.

[Regulation of the life span in unicellular eukaryotes].

The review considers the mechanisms of nucleic and mitochondrial control of the life span of unicellular eukaryotes. Special attention is given to analysis of the mechanisms of functioning of telomerase complex, the mechanisms of varied expression of the genes regulating the cell cycle, and the mitochondrial retrograde pathway.

[Posttranslation regulation of programmable cell events in unicellular eukaryotes].

The review considers the up to date achievements about posttranslational regulation of programmable cell events: growth, development, and apoptosis in unicellular eukaryotes mediated by histone modifications and DNA metylation. Special attention is given to the evolution aspects of the problem.

[Evolution of mechanisms of Ca2+-signaling. Role of Ca2+ in regulation of fundamental cell functions].

The review considers mechanisms of Ca2+-dependent regulation of cell growth, differentiation, and apoptosis in cells of the higher eukaryotes by modulation of the signal Ras-MAPK pathway.

[Peculiarities of Ca2+ regulation of functional activity of myocardium of frog Rana temporaria].

To elucidate role of intra- and extracellular Ca2+ in regulation of rhythm and strength of frog heart contractions, there were studied ECC and isometric contraction of myocardium preparations in response to verapamil, adrenaline, and blockers of alpha- and beta-adrenoreceptors. It has been shown that after an intramuscular injection of verapamil (6 mg/kg), bradycardia develops, the heart rate (HR) decreasing by 50-70 %. Further, the cardiac arrest occurred; however, administration to the animals of adrenaline (100 mg/kg) restored the cardiac rhythm for a short while. After an intramuscular injection of adrenaline at doses of 0.1-10 mg/kg, no essential changes were observed in the potential action amplitude and HR; an increase of the administered adrenalin concentration to 100 mg/kg was not accompanied by the cardiac rhythm stimulation, as this takes place in homoiothermal animals and human; on the contrary, an essential HR deceleration was revealed. Phentolamine (5 mg/kg) gradually decelerated HR rhythm by 32-45 %. The potential amplitude changed insignificantly. A subsequent intracardiac injection of adrenaline (100 mg/kg) on the background of block of alpha-adrenoreceptors produced acceleration of the rhythm (by 13-21%) and fall of the electrogram amplitude. These results can indicate that in the frog heart, phentolamine interacts predominanty with alpha-adrenoreceptors. An intracardiac administration of propranolol (1 mg/kg) to frogs promoted inhibition of beta-adrenergic receptors and produced a gradual cardiac rhythm deceleration. In experiments on assessment of verapamil effect on the character of contractions this preparation at a concentration of 150 microM was established to produce a significant dosedependent decrease of the contraction strength. A rise of verapamil concentration in the sample to 200 microM led to a decrease of the amplitude, on average, by 68-70 % and in individual preparations -- by 80-85 %; however, administration into the sample of adrenaline (10 microM) restored the cardiac contraction strength. Adrenaline (1 nM--100 microM) increased markedly the contraction amplitude. Phentolamine (10 microM) did not inhibit transmission of contractile signal to cardiomyocytes; this was manifested in that the contraction amplitude after addition of adrenaline (10 microM) into the sample was approximately the same as in the sample containing no phentolamine. Propranolol (10 microM) eliminated the stimulatory action of adrenaline (10 microM). The results of these experiments indicate that in the frog ventricular cardiomyocytes the main adrenaline acceptors are beta-adrenoreceptors.

[Changes in the DNA content in EGF-stimulated ciliate Tetrahymena pyriformis under effect of caffeine, KCl, and inhibitors of PLC and PKC].

It has been established that DNA content in ciliata Tetrahymena pyriformis changes under effect of the caffeine, and PLC and PKC inhibitors (U 73122 and chelerythrine accordingly). 10 mM caffeine stimulated DNA synthesis in these cells, 1 microM U 73122 and 25 microM chelerythrine, on the contrary, blockades the synthesis. 50 and 500 mM KCl, the agent which causes depolarization of plasma membrane stimulating Ca2+ entry into the cells, has no effect. The transduction of the proliferative signals in T. pyriformis cells has been proposed to be of Ca(2+)-dependent nature.

[Role of acetylcholine in the Ca2+-dependent regulation of functional activity of myocardium of frog Rana temporaria].

To study role of ACh in the Ca2+-dependent regulation of rhythm and strength of cardiac contractions in frog Rana temporaria, the ACh chrono- and inotropic effects have been studied in parallel experiments on the background of blockers of potential-controlled Ca2+-channels, ryanodine and muscarine receptors. The obtained results indicate participation of acetylcholine in the Ca2+-dependent regulation of rhythm and strength of frog cardiac contractions.