[Studying intermediatory regulation of heart rhythm using Daphnia magna as the alternative test object].

A functional test using Daphnia magna Straus hydrobionts is proposed for studying the role of intermediatory relationships in the heart rate (HR) regulation. It is established that the M-cholinomimetic carbamylcholine increases for two hours and decreases after 24 hours the HR in D. magna. Caffeine (a nonselective antagonist of adenosine receptors) potentiates the action of carbamylcholine during the first hour and then ceases to influence the drug effect. Caffeine normalizes the HR rate D magna, which was decreased by the cholinolytic atropine and the beta-adrenolytic atenolol. The possibilities of using the proposed test for the investigation of intermediatory relationships in the HR regulation, rapid analysis of the cardiothropic action of xenobiotics, and the primary screening of drugs for the pharmacological correction of HR disturbances are discussed.

[Heart rate in Daphnia magna as a functional test for assessing efficacy of chemical agents].

It is suggested to use Daphnia magna Straus as a biotest object for the evaluation of heart rate (HR) as a functional parameter. The influence of cholinergic ligands (atropine and carbamylcholine) on the Daphnia cardiac rhythm has been studied. It is found that the cholinergic agonist and antagonist produced opposite influence on the HR and are capable of prevent the action of each other. The Daphnia HR variation test can be used in evaluating the effect of xenobiotics and in selecting agents for the pharmacological correction of this functional parameter.

[Daphnia magna (straus): a new test object for modeling of dopaminergic neurotransmission deficiency induced by the selective neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine].

The possibility of using Daphnia magna (Straus) hydrobionts as a test object in modeling the disturbances of dopaminergic neurotransmission was investigated. The toxic action of a selective dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on D. magna was determined in a broad interval of concentrations (from 2 x 10(-5) to 10(-2) M). Plots of the real time of daphnia death versus MPTP concentration are presented and the concentration limits of its specific activity are evaluated. Experiments on daphnia under the conditions of MPTP intoxication were used to study the modulating effects of drugs producing a pharmacological correction of dopamine secretion disturbances in mammals. It is shown that the exogenous dopamine, muscarinic cholinoblocker pentifine, and antioxidant unithiol exhibit a protective action. Reduced glutathione does not possess protective properties. It is suggested to use D. magna as a simple and informative test object for the modeling of dopaminergic transmission deficiency and for the primary screening of various substances intended for the pharmacological correction of dopamine transmission disturbances.

[Daphnia magna Straus: a test object for the pharmacological evaluation of GABA-ergic drugs in the whole organism].

The toxicity of a series of GABAlytics (11 drugs) representing different pharmacological groups was evaluated in comparative experiments on Daphnia magna Straus and white mice. A high degree of correlation was established between the toxicity of GABA antagonists studied in daphnia and mice. The pharmacological analysis of the interaction of agonists and antagonists of GABA/benzodiazepine/ionophore-receptor complex--the competitive ligands for various binding sites--was carried out. It is suggested that the ability of GABA agonists to prevent the action of GABA antagonists in whole organism is mainly determined by their pharmacokinetic and pharmacodynamic features, rather than by direct competition for binding sites within the receptor complex.

[Daphnia magna Straus: a new model for evaluating the antioxidant acton of water-soluble preparations in vivo].

Hydrobionta species of Daphnia magna Straus were used as a test objects for in vivo evaluation of the antioxidant activity of three hydrophilic thiol compounds: reduced gluthatione, unithiol, and cysteine. These compounds exhibited significant differences in activity under oxidative stress conditions, in the dynamics of observed effects, and in the probability of inversion from anti- to pro-oxidant action. The main advantage of the proposed test objects in comparison to the conventional in vitro experiments (where the antioxidant effect is evaluated over a period of time from several minutes to several hours) is that the development of drug activity (pro- and antioxidant effects) can be monitored over a prolonged period of time (up to several days). In comparison to the tests on mammals, the new method is much simpler and allows the entire antioxidant protection (rather than separate systems) to be evaluated. It is recommended to use Daphnia magna Straus species for comparative evaluation of the antioxidant action of water-soluble preparations in vivo.

Effect of M4-cholinoceptor blockade on haloperidol-produced catatonic syndrome in rats.

We studied the relationship between the efficiency of muscarinic receptor antagonists in preventing haloperidol-induced catatonia and their activity in tests for the interaction of ligands with various subtypes of muscarinic receptors (M1-M4) in rats. Mathematical modeling showed that affinity of the ligand for M4 receptors positively affects its ability to correct extrapyramidal disorders (catatonic syndrome) produced by haloperidol, while affinity for M2 receptors had a negative effect on this characteristic.

[Differences in prooxidant effect of neuroleptics haloperidol and aminazine]. / Razlichiia prooksidantnogo deistviia neiroleptikov galoperidola i aminazina.

In the in vitro experiments with hydrobiont Daphnia magna Straus as the test-object the comparative evaluation of the prooxydant activity of two neuroleptics galoperidol and aminazine, was performed. It was shown that galoperidol possesses the pronounced prooxydant activity compared with hydrogen peroxyde. Aminazine didn't display such an action. The exogenios reduced glutathione is capable to protect Daphnia from the prooxydant action of galoperidol may be used for the investigation of anti- and prooxydant effects of toxicants and medicines in vivo.

[Daphnia magna for studies of cholinergic preparations]. / Daphnia magna kak ob''ekt pri issledovanii preparatov kholinergicheskogo tipa deistviia.

Published data and original experimental results are summarized to justify biochemically the use of Daphnia magna Straus as an additional or alternative test object for the study of cholinotropic substances. The data of radioligand analysis provide direct evidence that the organism of Daphnia contains M-cholinoreceptors identical (with respect to pharmacodynamic parameters) to those in the human and animal organism.

[Pharmacological analysis of the pathogenesis of acute poisoning with the synthetic pyrethroid cypermethrin using the hydrobiont Daphnia magna Straus]. / Farmakologicheskii analiz mekhanizmov patogeneza ostrogo otravleniia sinteticheskim piretroidom tsipermetrinom s ispol'zovaniem gidrobiontov Daphnia magna Straus.

The results of pharmacological analysis are presented which provide information on the pathogenesis of acute cypermethrin poisoning that involves disturbances in various systems of the organism. These include changes in the system of excitatory amino acids (EAAs) and violation of the free radical generation processes, Na + channel functioning, cholinergic transmission, etc. The screening of drugs belonging to various pharmacological groups influencing the toxicity of pyrethroids (EAA receptor antagonists, antioxidants, Na + channel blockers, M-cholinoreceptor blockers) revealed promising agents for the treatment of cypermethrin poisoning.

[New approaches to analysis of the interrelationship between cholinergic and dopaminergic mediator systems]. / Novye podkhody k analizu vzaimootnoshenii kholinergicheskoi i dofaminergicheskoi mediatornykh sistem.

Intermediatory relationships between the cholinergic and dopaminergic neurotransmission systems were analyzed using published data and the original experimental results obtained on Daphnia magna Straus, a new test object. Based on these results, the antihaloperidol activity of a series of M- cholinoblocking agents with different receptor selectivities were studied in comparison to the new cholinoblocker pentifin exceeding in the activity the classical antiparkinsonian drugs such as cyclodol, amedin, and norakin.

[Subtypes and neuronal localization of muscarinic receptors in rat cerebral hemispheres]. / Otsenka tipovoi prinadlezhnosti i neironal'noi lokalizatsii muskarinovylh retseptorov bol'shikh polushrii golovnogo mozga krys.

The subtypes of pre- and postsynaptic muscarinic receptors in rat cerebral hemispheres were determined using a new approach based on the radioligand analysis.

[Characteristics of effects of acetylene amino alcohols M-cholinoreceptor blockers on the dopaminergic system in Daphnia magna]. / Osobennosti mekhanizma deistviia m-kholinoblokatorov iz gruppy atsetilenovykh aminospirtov na dofaminergicheskuiu sistemu Daphnia magna.

Haloperidol and dimethpromide exhibit the properties of dopamine antagonists in the experiments on Daphnia magna Straus (Crustaceae family). Haloperidol, in contrast to dimethpromide, does not significantly influence the toxic effect of apomorphine. It is suggested that acetylene aminoalcohol derivatives are selective ligands for one of the subtypes of dopamine receptors.

[The role of the blockade of separate subtypes of muscarinic receptors in realizing the antidotal effect of m-cholinolytics in dimethyl dichlorovinyl phosphate poisoning]. / Rol' blokady otdel'nykh podstipov muskarinovykh retseptorov v osushchestvlenii antidotnogo éffekta m-kholinolitikov pri otravlenii dimetildikhklorvinilfosfatom.

On comparison of the values of receptor selectivity of a series of m-cholinoblockers in vitro with those of the selectivity of their effect in in vivo experiments, pharmacological tests characterizing the interaction of ligands with m1, m2, and m3-subtypes of muscarine receptors were determined. Analysis of the protective effect of m-cholinoblockers in poisoning with organophosphorus compounds (OPC) depending on their activity in the determined tests showed that blocking of the m1-cholinoceptors is responsible for the antidotal effect of the antagonists, whereas block ing of m2-cholinoceptors prevents it. It is suggested that the negative effect of m2-cholinoceptor blocking on the protective effect of the drugs in OPC poisoning is mediate d by increased excretion of the mediator into the synaptic cleft as a result of interaction of the ligands with the presynaptic autochol inoceptors.

[The presynaptic mechanism of interaction of cholinesterase reactivator and muscarinic antagonists in the animal's defence in organophosphate intoxication]. / Presinapticheskil mekhanizm vzaimodelstviia reaktivatorov kholinésterazy muskarinovykh antagonistov pri zashchite zhivotnykh ot toksicheskogo delstviia fosfororganicheskikh soedinenil.

The presynaptic and antidote activity of various combinations of cholinesterase reactivators and that of muscarinic antagonist were compare it was show that the mechanism of the antidote effect of some cholinesterase reactivators in poisoning with organophosphorous compounds, in addition to restoring the activity of the enzyme, includes the effect of counteraction to the effect of muscarinic antagonists in increased acetylcholine secretion into the synaptic cleft. The expression of this effect depends on the presynaptic activity of the reactivator and on the selectivity of muscarinic antagonist. It is suggested that the type relation of the presynaptic muscarin receptors in the cerebral hemispheres and the brain stem is different and that the probability of the functional value of the ligand presynaptic interaction for the protection from organophosphorous compounds is higher in the brain higher in the brain stem than in the cerebral hemispheres of rats.

[The role of adenylate cyclase and phosphoinositide second messenger systems in regulation of acetylcholine secretion in synapses of the cerebral hemispheres and brain stem in rats]. / Rol' adenilattsiklaznoi i fosfoinozitidnoi sistem vtorichnykh messendzherov v reguliatsii sekretsii atsetilkholina v sinapsakh bol'shikh polusharii i stvolovogo otdela mozga krys.

Changes in acetylcholine secretion in the cholinergic synapses of the rat cerebral hemispheres and brain stem were studied in in vivo experiments against the background of modulation of the activity of the adenylate cyclase and phosphoinositide secondary messenger systems by injection of caffeine and lithium chloride. The level of mediator secretion was determined according to the content of bound acetylcholine fractions in the homogenate of the indicated parts of the animal's brain. It was established that secretion of the mediator in the rat hemispheres is regulated by postsynaptic N-cholinoceptors located on the body of cholinergic neurons which have a phosphoinositide system actiung as secondary mediators and, possibly are related to subtype M1. It is also possible that the secretion is also regulated by presynaptic autoreceptors connected with the adenylate cyclase system, which function according to the mechanism of negative feedback and is related to subtype M2. Acetylcholine secretion in the brain stem synapses is regulated according to the negative feedback mechanism by muscarine receptors linked with the adenylate cyclase system and probably related to subtype M4.

[New approaches to determining the type classification of presynaptic acetylcholine receptors]. / Novye podkhody k opredeleniiu tipovoi prinadlezhnosti presinapticheskikh retseptorov atsetilkholina.

A complex of special tests which took into account the coupling of the specific physiological responses with individual subtypes of muscarinic cholinoceptors, and radioligand analysis showed the predominance of M3- and M2-subtype presynaptic receptors in the rat brain hemispheres. The autoreceptors regulating the presynaptic release of acetylcholine are related mainly to the M2-subtype and account for the smaller part of the mixed population of presynaptic receptors.

[The mechanisms of the antidotal action of bispyridinium oximes when used in combination with M-cholinolytics in dimethyl dichlorovinyl phosphate poisoning]. / Mekhanizmy antidotnogo deistviia bispiridinievykh oksimov v usloviiakh ikh kombinirivannogo primeneniia s M-kholinolitikami pri otravlenii dimetildikhlorvinilfosfatom.

The results of in vitro and in vivo experiments were used to compare the capacity of bispiridinium oximes to modulate the presynaptic secretion of acetylcholine and to demonstrate the protective activity against organophosphate intoxication during combined application with various M-cholinolytics. It is suggested that bispiridinium oximes combined with M-cholinolytics can play a corrective role in eliminating the adverse presynaptic effect of a cholinolytic, thus lowering the severity of intoxication.

[The polymorphism of the pharmacological effects of calcium channel blockers]. / Polimorfizm farmakologicheskikh éffektov blokatorov kal'tsievykh kanalov.

In experiments on mice and rats it was shown that the studied calcium channel blockers--verapamil (finoptin, isoptin), nifedipine (corinfar), sensit (phendilin), cinnarizine (stugeron), diltiazem--are heterogeneous by their pharmacological properties. No relationships between the antiarrhythmic, anticonvulsant and cholinolytic effects of the compounds were revealed. It was supposed that the cholinolytic activity of nifedipine and diltiazem in arecoline salivation test reflects not their competitive relations with acetylcholine on the active surface of the receptor, but rather is realized at the level of the signal transmembrane transmission systems.

[Possible approaches to an analysis of the heterogeneous response of the transcription complex to cholinergic actions]. / O vozmozhnykh podkhodakh k analizu geterogennoi otveta transkriptsionnogo kompleksa na kholinergicheskie vozdeistviia.

The accumulation of tyrosine-aminotransferase (TAT) as a marker of the individual gene activation was studied in the rat tissue after the administration of cholinomimetics and cholinolytics in order to elucidate the relations between cholinoreceptor functional state and the genetic apparatus. The regulation of TAT synthesis was found to be controlled by both cholinomimetic concentration and the density of cholinoreceptors in hepatocytes. Transsynaptic regulation of TAT activity was shown to be different in the brain and liver. It is suggested that the approaches discussed might be useful for the analysis of the relationship between cholinoreceptor state and the regulation of biochemical functions of target cells.