[The antiarrhythmic action of the synthetic acetylcholine analog EDIHYP in calcium chloride- and strophanthin-induced heart rhythm disorders]. / Antiaritmicheskoe deistvie sinteticheskogo analoga atsetilkholina EDIGIP pri khloridkal'tsievykh i strofantinovykh narusheniiakh serdechnogo ritma.

The experiments on Wistar rats and chinchilla rabbits showed that EDIHYP (5 mg/kg intravenously) completely prevented cardiac fibrillation and mortality in rats with calcium-chloride-induced arrhythmias, (CaCl2-200 mg/kg intravenously). Administration of atropine (0.1 mg/kg, if administered subcutaneously, 30 minutes before the acute experiment) exerts no influence on the drug's antiarrhythmic activity but eliminates its cholinergic component--salivation and lacrimation. When administered in the same dose EDIHYP to a great extent prevents oubaine (strophanthin)-induced arrhythmias in rabbits but fails to influence aconitine-induced arrhythmias. This suggests that EDIHYP's ability of direct or indirect blockade of slow Ca-channels underlies the mechanism of its antiarrhythmic action.

[Effect of a carnitine analog on the level of bile lipids of the enterohepatic system in rabbits in cholelithiasis]. / Vliianie analoga karnitina na urovni zhelchnykh lipidov énterogepaticheskoi sistemy u krolikov pri kholelitiaze.

Lipid components were studied in enterohepatic system of rabbits with cholelithiasis after administration of plant components contained in meadow hay as well as of their mixture with a synthetic analogue of carnitine. Hypothetic mechanism of the carnitine derivative effect, contributing to elevation of phosphatidyl choline production in hepatocytes and to accumulation of the phospholipid in bile, is discussed. During the treatment course the calculous form of hepatocholecystitis was not detected in the experimental animals.

[The effect of mildronate on carnitine-dependent and carnitine-independent ketogenesis in rats]. / Vliianie mildronata na karnitinzavisimyi i karnitinnezavisimyi ketogenez u krys.

Mildronate of 3-(2,2,2-trimethylhydrozinium)propionate, a novel anti-ischemic drug, inhibits the biosynthesis of carnitine from Y-butyrobetaine. Continuous administration of mildronate (200, 400 mg/kg for 10 days orally) to rats exerted a marked antiketogenic action on the animals deprived of food for 48 hours. In the fed rats receiving sodium octanoate a course treatment with mildronate elevated to concentration of ketone bodies in blood serum. Selective regulation of carnitine-independent and carnitine-dependent metabolism appears justified for the treatment of such pathological states as ischemic heart disease, diabetes and obesity.

[Bioelectrical mechanism of the anti-arrhythmia effect of a synthetic acetylcholine analog EDIHYP]. / Bioélektricheskii mekhanizm antiaritmicheskogo deistviia sinteticheskogo analoga atsetilkholina EDIGIP.

The synthetic acetylcholine analogue ethyl-3-(2,2-dimethyl-2-ethyl-hydrazinium) propionic iodide (EDIHYP) exerts a powerful antiarrhythmic action in cardiac ischemic, reperfusion, and adrenergic lesions, as well as in infarction and postinfarction cardiosclerosis, as evidenced by animal experiments. The study was undertaken to examine the electrophysiological mechanism of EDIHYP s action on isolated rat heart cardiomyocytes. It was shown that the agent substantially reduced the resting potential, as well as action potential amplitude and duration in total ischemia and resultant reperfusion. The antiarrhythmic changes provided a multiple decrease in the duration of ventricular tachycardia and cardiac fibrillation in reperfusion. Thus, the fact that EDIHYP has a direct action on the bioelectrical activity of cardiomyocytes may play an important role in its antiarrhythmic effect in the whole body.

[The effect of a structural analog of gamma-butyrobetaine, mildronate, [3-2,2,2-trimethylhydrazine)propionate] on dynamic carnitine-dependent metabolism]. / Vozdeistvie strukturnogo analoga gamma-butirobetaina mildronata [3-(2,2,2-trimetilgidrazinii)propionata] na karnitinzavisimyi metabolizm v dinamike.

Inhibitor of carnitine-dependent metabolism mildronate, 3-(2,2,2-trimethylhydrazinium) propionate, administered into rats at a dose of 200 mg/kg, per os, within 10 days, caused a decrease in concentration of free carnitine and of long-chain acylcarnitine in myocardium as well as contributed to accumulation of free fatty acids in blood serum. Besides, the rate of I-14C-palmitic acid turnover to 14CO2 was decreased in myocardium homogenate. The drug inhibitory effect on carnitine biosynthesis from gamma-butyrobetaine was responsible for the phenomenon observed. Content of the metabolites studied was altered gradually both during treatment of rats with mildronate and after the drug abolition, thus demonstrating an opportunity of gentle influence on carnitine-dependent metabolism by means of the drug treatment and its abolition.

[Potentiation of the antiketogenic effect of exogenous glucose with the help of the new beta-oxidation inhibitor mildronate--3-(2,2,2-trimethylhydrazine)propionate]. / Potentsirovanie antiketogennogo deistviia ékzogennoi gliukozy s pomoshch'iu novogo ingibitora beta-okisleniia mildronata--3-(2,2,2-trimetilgidrazinii)propionata.

Antiketogenic effect of exogenous glucose (2 g/kg, per os, 1 hr before death) was potentiated after preadministration of mildronate 3-(2,2,2-trimethylhydrazinium) propionate into rats either kept on usual ration or fasting within 48 hrs at a dose of 200 and 400 mg/kg, per os, during 10 days. Mildronate is inhibitor of carnitine-dependent metabolism of fatty acids affecting at the step of gamma-butyrobetaine turnover into carnitine. The drug inhibitory influence studied appears to be realized via activation of the glycolytic pathway of glucose metabolism specific for inhibitors of beta-oxidation.

[The effect of the carnitine biosynthesis inhibitor mildronate on the lipid metabolic indices of rats]. / Vliianie ingibitora biosinteza karnitina mildronata na nekotorye pokazateli lipidnogo obmena u krys.

The course administration of a carnitine biosynthesis inhibitor mildronate (100 mg/kg, orally, for 10 and 30 days) was shown to increase the rat blood serum concentration of free fatty acids. By the 30th day of the treatment no changes in the rat myocardium contents of free fatty acids, triglycerides and cholesterol were found that along with the prevention of the accumulation of long chain metabolites of fatty acids in the heart under conditions of adrenergic actions indicated the pathogenetically right approach to the treatment of ischemic heart disease with mildronate.

[Correction of disorders of electric stability of the heart and arrhythmia by using a synthetic analog of acetylcholine]. / Ustranenie narushenii élektricheskoi stabil'nosti serdtsa i aritmii s pomoshch'iu sinteticheskogo analoga atsetilkholina.

It was shown in experiments on Wistar male rats that ethyl, 3/2, ethyl, 2/2, dimethylhydrazine propionate iodate (EDIHYP), a synthetic acetylcholine analogue, eliminates in situ the fall of the ventricular fibrillation threshold and the extrasystole observed on the background of vagal bradycardia in experimental myocardial infarction and postinfarction cardiosclerosis. The elimination of disturbed heart electric stability was not accompanied by cholinergic, negative chronotropic effect of the drug. In isolated heart, high concentrations of EDIHYP (10(-4) M) had negative chronotropic effect but lacked antiarrhythmic effect in local ischemia and reperfusion. The bradycardia induced by EDIHYP was absent and the antiarrhythmic effect was strikingly pronounced on the background of muscarinic receptors blockade with atropine. Thus EDIHYP realizes its antiarrhythmic effect not via muscarinic receptors but by some other way which requires studying by methods of molecular pharmacology.

[The effect of mildronate on disorders of the cardiac contractile function in rats caused by an excess of free fatty acids and ischemia]. / Vliianie mildronata na narusheniia sokratitel'noi funktsii serdtsa krys, vyzyvaemye izbytkom svobodnykh zhirnykh kislot i ishemiei.

Oral administration of mildronate, 3-(2,2,2-trimethylhydrazine)propionate, an inhibitor of carnitine-dependent metabolism, in a dose of 50-100 mg/kg for 10 days promoted a rapid restoration of contractility of Langendorf perfused rat heart preparations during postischemic perfusion and protected the rat hearts against inhibition of contractile function resulting from continuous perfusion with palmitic acid. Mildronate inhibits gamma-butyrobetaine hydroxylase, depresses carnitine biosynthesis and reduces carnitine-dependent fatty acid metabolism. The cardioprotective effect of mildronate is particularly manifest upon continuous administration.

[Angeli salt as a producer of nitrogen oxide in animal tissues]. / Sol' Anzheli kak produtsent oksida azota v organizme zhivotnykh.

Sodium trioxodinitrate (NaN2O3, Angeli salt) injected intraperitoneally to mice and intraarterially to rats is decomposed to form nitrogen oxide which is bound in tissues to the Fe2(+)-DETC complex or hemoglobin. The nitrosyl complexes formed thereby were studied by the EPR method. As can be judged from the number of complexes formed, nitrogen oxide produces 3-4% of exogenous NaN2O3 which provides for the hypotensive properties of Angeli salt as well as for its ability to cause the relaxation of isolated segments of rabbit femoral artery. In this respect NaN2O3 is by one order of magnitude less effective compared to sodium nitroprusside.

[Anti-arrhythmic effect of adaptative activation of the vagus nerve system and a new synthetic acetylcholine analog]. / Antiaritmicheskii éffekt adaptatsionnoi aktivatsii sistemy bluzhdaiushchego nerva i novogo sinteticheskogo analoga atsetilkholina.

A higher vagal tone or its stimulation under certain conditions is known to increase the threshold of cardiac fibrillation and even to arrest developing arrhythmias. This effect is usually evaluated as a result of limiting the excessive adrenergic effect on the heart, which is observed in stress and ischemia. The following two facts have been first identified: 1) adaptation to moderate continuous stress may induce tonic excitation of parasympathetic regulation of the heart and enhance its resistance to ischemic and reperfusion arrhythmias; 2) this antiarrhythmic effect is completely reproducible by the recently synthesized acetylcholine analogue EDIHYP, ethyl-3/2-ethyl-2,2-dimethylhydrazinium/propionate iodate.

[The cardioprotective action of carnitine and its structural analog 3-(2,2,2-trimethylhydrazine)propionate on cardiac energy metabolism in experimental occlusion of the coronary artery in rats]. / Kardioprotektornoe deistvie karnitina i ego strukturnogo analoga 3-(2,2,2-trimetilgidrazinii)propionata na énergeticheskii obmen serdtsa pri éksperimental'noi okkliuzii koronarnoi arterii u krys.

The effects of carnitine and its structural analogue 3-(2,2,2-trimethylhydrazine) propionate (THP) were studied in rats with experimental myocardial infarction caused by occlusion of the left descending branch of the coronary artery. After one day in the group of untreated animals the relative lethality was 40.3 +/- 10.5%, the size of the infarction zone was 29.8 +/- 2.0%. Carnitine and THP decreased on the average twice the parameters as well as lactate level in the myocardium. THP prevented a reduction of ATP and AMP levels by 35 and 37%, respectively, and a decrease of adenine nucleotide pool by 30%. In this case carnitine was ineffective. It is suggested that inhibition of beta-oxidation of fatty acids by THP is energetically more beneficial for the myocardium during regional ischemia than substitution therapy with carnitine.

[Regulation of carnitine-dependent metabolism of fatty acids in the rat myocardium using 3-(2,2,2-trimethylhydrazinium) propionate]. / Reguliatsiia karnitinzavisimogo metabolizma zhirnykh kislot v miokarde krys pri pomoshchi 3-(2,2,2-trimetilgidrazinii) propionata.

3-(2,2,2-Trimethyl hydrazinium) propionate (THP), possessing a cardioprotective effect, is a noncompetitive inhibitor of butyrobetaine hydroxylase and inhibits fatty acid oxidation. The effect of THP, detected during the drug medicinal application, was related to inhibition of carnitine biosynthesis. THP exhibited the inhibitory action on carnitine acetyl transferase contributing to an increase in acetyl-CoA availability for intramitochondrial metabolic pathways. The drug prevented L-carnitine induced stimulation of U-14C-palmitic acid oxidation in vitro. During administration as well as after addition into incubation medium THP did not show any significant effects on 1-14C-palmitoyl-L-carnitine oxidation but decreased the exogenous L-carnitine induced oxidation of the substrate in vitro. The drug did not affect the activity of carnitine palmitoyl transferase I. Action of THP on the carnitine-dependent oxidation of fatty acids might be related to the drug inhibitory effect on activities either of carnitine acyl transferase II or carnitine acylcarnitine translocase. The data obtained suggest that THP carried out the following functions: 1) inhibition of carnitine biosynthesis, 2) direct inhibition of carnitine dependent transport of fatty acids in mitochondria, 3) inhibition of carnitine acetyl transferase. Inhibition of carnitine dependent oxidation of fatty acids at the step of their activation was the drug integral effect.

[The use of lysosomotropic preparations in treating severe experimental chemical eye burns]. / Primenenie lizosomotropnykh preparatov v lechenii tiazhelykh khimicheskikh ozhogov v éksperimente.

The action of membranotropic preparations--mildronat and phosphaden on the course of a severe burn process of the cornea with changes in lysosomal membranes revealed in pathogenesis has been studied in 80 rabbits. As a marking lysosomal enzyme, acid phosphatase was used. Besides this, peculiarities of the clinical course of the burn process have been studied, when treated by common methods and in a complex with the mentioned preparations. The results of the study have shown expressed stabilizing action of the preparations on lysosomal membranes of the cornea in early terms of the treatment, correlative relationship between results of biochemical investigations and clinical manifestations of the action of membranotropic preparations, high effectiveness of therapeutic action of mildronat as compared with phosphaden. The results obtained can serve as a foundation for the usage of the preparations in complex treatment of patients with severe chemical burns of the eye.

[Stimulation with quaterin of DNA replication and repair]. / Stimuliatsiia kvaterinom intensivnosti replikativnogo i reparativnogo sinteza DNK.

Quaterine [3-(2,2,3-trimethylhydrasinium)propionate] possessing a wide spectrum of physiological activity has been studied for its effect on the intensity of replicative and reparative DNA synthesis in different rat tissues (liver, thymus, heart, intestine mucosa and spleen) in order to investigate molecular mechanisms of its action. It is shown that the pronounced stimulation of DNA synthesis in all tissues, as a rule, takes place 1-6h after quaterine administration in doses of 25 and 100 mg/kg. The estimation of the given compound effect on DNA synthesis after its multiple administration to animals (for 5, 10, 15 days in a dose of 100 mg/kg) permits supposing that 3-(2,2,2-trimethylhydrasinium)propionate is able of providing either stable proliferation of cells (thymus, spleen) or their hyperplasia and polyploidization (heart, liver). The data obtained make it possible to explain (to some extent) quaterine ability to activate immune responses, to stimulate healing of wounds and burns.

[Cardioprotective effect of carnitine and its synthetic analog 3-(2,2,2-trimethylhydrazinium) propionate in rats with experimental myocardial infarction]. / Izuchenie kardioprotektornogo deistviia karnitina i ego sinteticheskogo analoga 3-(2,2,2-trimetilgidrazinii) propionata pri éksperimental'nom infarkte miokarda u krys.

Effect of carnitine and its synthetic analogue 3-(2,2,2-trimethylhydrazinium) propionate (THP) has been studied in rats with experimental infarction of myocardium following occlusion of the left anterior descending coronary artery. Morphological and biochemical changes were determined within 24 hrs after occlusion. The infarcted area was diminished from 29.8% down to 18.7% and 10.9%, in rats treated with THP and carnitine, respectively. The both drugs studied affected favourably the activities of malate dehydrogenase, lactate dehydrogenase and of their isoenzymes as well as the aminotransferase activities in blood plasma. Administration of carnitine caused an increase in the content of lactate and pyruvate in blood plasma, while their ratio was decreased. Thus, the modulation of fatty acids metabolism using betaine derivatives caused a cardioprotective effect.

[Effect of quaterin and S-methylmethionine on the intensity of chromatin protein methylation]. / Vliianie kvaterina i S-metilmetionina na intensivnost' metilirovaniia belkov khromatina.

It is known that 3-(2,2,2-trimethylhydrazinium) propionate (quaterin) synthetized at the Institute of Organic Synthesis of the Latvian SSR Academy of Sciences has a stimulating effect on cell proliferation in the process of healing wounds and burns. In this connection the above preparation is studied for its effect on the methylation intensity of histones and nonhistone proteins of rat tissues possessing different proliferative activity. For comparison S-methylmethionine (vitamin U), a known stimulator of the methylation reactions, was studied. The experiments conducted have shown that the methylation processes in all the studied tissues (heart, liver, small intestine mucosa, thymus and spleen) depend on the quaterin and the S-methylmethionine effect. On the whole, quaterin 1-6 h after its administration increases, as a rule, the methylation levels of histones and nonhistone proteins. This effect is the least in the thymus and the highest in the liver and spleen. When quaterin is applied daily for 5-15 days considerable changes occur in the levels of chromatin proteins methylation. The data obtained indicate that the processes of chromatin proteins methylation are an important link in the realization of quaterin action on transcription and replication which underlie the proliferative cell response.

[Biochemical characteristics of the anti-ischemic action of the new structural analog of gamma-butyrobetaine 3-(2,2,2,-trimethylhydrazine)propionate]. / Biokhimicheskaia kharakteristika antiishemicheskogo deistviia novogo strukturnogo analoga gamma-butirobetaina 3-(2,2,2-trimetilgidrazinii)propionata.

A structural analogue of gamma-butyrobetaine 3-(2,2,2-trimethylhydrazine)propionate (THP) administered orally in doses of 50 and 150 mg/kg for 10 days prevented isoproterenol-induced increase of the activity of the hepatic isoform of lactate dehydrogenase in the rat blood serum and in a dose of 150 mg/kg prevented an increase of creatine phosphokinase activity. Against a background of the course administration of THP isoproterenol failed to cause the accumulation of acyl-insoluble acylcarnitine in the myocardium. In this case a dose-dependent decrease of free carnitine concentration and accumulation of fatty acids in the myocardium were noted. The cardioprotective effect of THP manifested itself in prevention of a decrease of ATP and ADP concentrations, accumulation of AMP and a reduction of energy charge under the influence of isoproterenol. The ability of THP to decrease the intracellular concentration of free carnitine and to depress as a result carnitine-dependent oxidation of free fatty acids may underlie the anti-ischemic effect of THP.

[Effect of a new structural analog of gamma-butyrobetaine-- 3-(2,2,2-trimethylhydrazine)propionate (THP) on carnitine level, carnitine-dependent fatty acid oxidation and various indices of energy metabolism in the myocardium]. / Vliianie novogo strukturnogo analoga gamma-butirobetaina-- 3-(2,2,2-trimethylgidrazinii)propionat (TGP) na soderzhanie karnitina, karnitinzavisimoe okislenie zhirnykh kislot i nekotorye pokazateli énergeticheskogo obmena v miokarde.

Contents of carnitine and long chain acylcarnitine were decreased as well as oxidation of I-14C-palmitate was inhibited in rat myocardium after intraperitoneal administration of 3-(2,2,2-trimethylhydrazine) propionate (THP) at doses of 50 and 150 mg/kg within 10 days into animals maintained at a diet enriched with fat. THP did not affect the ATP content, elevated during the fat-enriched diet, but decreased the lactate concentration in myocardium. After administration of D,L-carnitine oxidation of I-14C-palmitate and content of lactate were increased with simultaneous decrease in ATP level. Combined administration of D,L-carnitine and THP did not affect the content of ATP and lactate as well as oxidation of fatty acids. The decrease in carnitine content caused by THP may be responsible for the alterations of energy metabolism in myocardium.