[Toxicologic characteristics of crown ethers and the semi-products of their synthesis].
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Biomedical subjects
Publications and source records attributed to E I Nazarov.
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The mechanism of tonic component of the frog myocardium potassium contraction was studied. The degree of contraction depended on the potassium, sodium and calcium ions concentrations in extracellular medium. The tonic component of hyperpotassium contraction, as well as the additional contractions due to hyposodium and hypercalcium medium in the tonic component phase seems to stem from activation of sodium--calcium exchange. The latter through the sarcolemma of the heart cells was 3Na: 1Ca. The effect of some mono- and bivalent cations on sodium-calcium exchange in respect ot their inhibiting activity was as follows: Cd+2 greater than Sr+2 greater than Ba+2 greater than Mn+2 much greater than Mg+2 greater than Li+ greater than Cs+.
The effects of the local anesthetic pyromecaine on the action potential parameters of the guinea-pig heart ventricular cardiomyocytes as well as on Na and K ionic currents of the neurons in the rat spinal ganglions have been studied. Pyromecaine was shown to reduce preferentially the first derivative of the ascending phase of cardiomyocyte action potential suggesting the blocking action of the anesthetic on the fast sodium inward current. The experiments on the isolated neurons in the rat spinal ganglions have shown that interaction of pyromecaine with inactivated Na+ channels makes a considerable contribution to the blocking effect of anesthesia.
The macrocyclic polyether 15-crown-5 at a concentration of 5 . 10(-5)-10(-3) M reduced the frequency of the contractions of an isolated rat auricle, increasing the refractory period of the contractions. The polyether lowered the rate of activation of the slow input current of rat spinal ganglionic neurons and blocked the sodium channels of the electroexcitable membrane without disturbing the function of activation and inactivation mechanisms. The compound under study considerably delayed the onset of and decelerated reactivation of the sodium input current. These actions were calcium-dependent, becoming more demonstrable with reduction of Ca2+ concentration outside the cell. 15-Crown-5 interfered with the action of Ca2+ on the lipid bilayer membrane potential. It is assumed that all the effects described are determined by the formation of 15-crown-5-Ca2+ complexes, thereby leading to the impairment of the packing of the membrane lipoprotein matrix.
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The effect of polymethylene- and polyoxyethylene-bis-(2-amino-1, 3-diazepinium) iodides on the membranes of neuromuscular synapsis and mitochondria as on the artificial membranes was studied. The compounds examined were shown to change the amplitude and kinetics of postsynaptic membrane responses to acetylcholine. Inhibition of end plate potentials and oxidative phosphorylation of mitochondria with different derivatives of diazepinium correlated with changes in the surface potential of the artificial phospholipid membrane. It is concluded that the derivatives of diazepinium directly interact with ionic channels of the acetylcholine-activated postsynaptic membrane.
The new psychotropic drug phenazepam inhibits the impulse activity of the neurons which compose visceral ganglia of the garden snail (Helix aspersa) and suppresses stimulating postsynaptic potentials arising in application of acetylcholine to the membrane of isolated neurons. The electrostimulating membrane parameters are not generally changed. Postsynaptic depression of the stimulation of the cholinoreceptive membrane is suggested to be one of the possible mechanisms of the pharmacological action of the drug.
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It is shown that cryptand complexes containing copper inhibit sodium-calcium exchange in sarcolemma of cardiomyocytes. The complexes studied exhibit the superoxide dismutase activity. The binding of copper ions by cryptand prevents the development of cariotoxic effects of the former. Low toxicity, the combined superoxide activity and that inhibiting sodium-calcium exchange of cryptand complexes with copper (II) ions makes the further search for cardioprotective compounds perspective within the series of cryptand copper complexes.
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A study was made of physiological activity of a series of new bisquaternary compounds in which the role of cation heads is played by the residues of 2-amino-1,3-diazepinium. Studies performed on a frog neuromuscular preparation showed that the compounds under test effectively block the responses of the postsynaptic membrane to acetylchinoline. The derivatives of diazepinium have pronounced hypotensive and ganglion-blocking properties. Octamethylene-bis-(2-amino-1,3-diazepinium) iodide that appeared to be the most effective of the compounds under test compares very favourably with benzohexonium. It was found to be 1.5 times more powerful as regards the ganglion-blocking and hypotensive activity.
The authors studied antiarrhythmic properties of macrocyclic polyesters. Some of the esters exhibited antiarrhythmic activity coupled with low toxicity. It was found that antiarrhythmic action of these substances is not mediated via acetylcholine and/or catecholamine system responsible for nervous regulation of the cardiac activity. The compounds under study were found to have marked antifibrillar properties. Experiments on an isolated rat heart demonstrated calcium specificity of the antifibrillar action of cyclolactones. It is assumed that macrocyclic polyesters represent a new class of antiarrhythmic agents having a direct cardiotropic action.
It has been found that some macrocyclic esters have no ionophoric properties, but can block valinomycin-induced potassium transport in mitochondrial membranes and lessen the potassium current induced by valinomycin in phosphatidylcholine bilayers. It has been also discovered that 36-member cyclic esters of succinic acid and propylene glycoles decrease fluorescence of puridine nucleotides in mitochondria and produce a modifying effect on bimolecular phosphatidylcholine membranes in the medium of litium, calcium and magnesium chlorides at unilateral injection. The results obtained suggest that cyclopolyesters under investigation form mixed complexes with the macromolecules in the composition of mitochondrial and phosphatidylcholine membranes with the participation of the integrated ion.
A comparative analysis of new macrocyclic amidoesters effect on the bimolecular lipid membrane as well as on the electroexcitable membrane of snail isolated neurons was carried out. It was shown that the investigated complexes inducing a small change in lipid bilayer conductivity and some changes in Na-Ca neuron current characteristics produce essential changes of rapid potassium as well as late potassium current properties. It was concluded on the basis of these results and potassium compounds specificity that the investigated complexes interact directly with neuron potassium channels.