[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 M2 muscarinic receptor blockade in rats with haloperidol-produced catatonic syndrome.

We studied the functional role of individual subtypes of muscarinic cholinoceptors in the pathogenesis of neuroleptic parkinsonism in rats. Blockade of M4 receptors prevented the development of extrapyramidal disorders, which was abolished by simultaneous blockade of M2 receptors. The data suggest that various subtypes of muscarinic receptors are involved in the regulation of dopamine concentration.

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.

Effects of cholinoblockers on acetylcholine content in rat striatum in neuroleptic-induced parkinsonism.

Correction of neuroleptic-induced parkinsonism in rats with two central cholinoblockers atropine and pentifine (acetylene aminoalcohol synthesized at Institute of Toxicology) were studied by measuring the content of acetylcholine in the striatum. The content of the transmitter secretion was estimated from the content of bound acetylcholine fraction in homogenates of the above-mentioned compartment of the brain. The results indicate that atropine and pentifine in doses equally effectively preventing catalepsy in rats had different effects on acetylcholine secretion in the striatum. Hence, cholinolytics with different pharmacological selective effects differently interact with central muscarine receptor subtypes.

[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.

In vitro effects of pentifin on some neurotransmitter systems in the brain.

Pentifin and dopamine D1 receptor antagonist SCH-23390 possess similar pharmacological properties. In the present work we studied in vitro effects of Pentifin on dopamine receptors. Experiments on rat ductus deferents showed that Pentifin acts as a weak ligand of dopamine receptors. Our results indicate that the antihaloperidol effect of Pentifin is not related to the blockade of dopamine receptors.

Qualitative assessment of selective blockade of M(4)-cholinoreceptors in the whole organism.

Quantitative assessment of selective blockade of M4-subtype muscarinic receptors was performed by the number of pilocarpine-induced movements of lower jaw in rats. Three antagonists (atropine, cyclodol, and glipin) were used in the experiments. Glipin produced the most potent blockade of M4 receptors in the whole organism compared to other test antagonist.

Mathematical analysis of subtypes of muscarinic receptors modulating heart and respiratory rhythms in rats.

Mathematical analysis of the data obtained in experiments on the whole organism revealed that blockade of M(2)-cholinergic receptors increased both heart and respiratory rates. Blockade of M(1)-cholinergic receptors alleviated tachycardia induced by M(2)-receptor blockade.

[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.

[Effect of M3-choline receptor blockade on the ability of muscarinic antagonists to prevent catalepsy induced by haloperidol in rats]. / Vliianie blokady M3-kholinoretseptorov na sposobnost' muskarinovykh antagonistov preduprezhdat' katalepsiiu, vyzvannuiu galoperidolom u krys.

A relationship between the indices of efficacy of the muscarinic antagonists in preventing the haloperidol catalepsy and their activity in the tests characterizing the interaction of these ligands with various subtypes of m-cholinoreceptors was studied in rats. A mathematical model was formulated that confirmed the previous conclusion concerning the role of of the m1- and m2-cholinoreceptor blockade in the antiparkinsonian activity of muscarinic antagonists. It was established that blocking of the m3-cholinoreceptors decreases the anticataleptic activity of m-cholinoblockers with respect to haloperidol. It is suggested that the high antihaloperidol activity of pentiphine (an acetyleneamine alcohol) is explained by its dopaminomimetic properties rather than by the anticholinergic activity.

[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.

[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 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.