[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.

[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.

[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.

[Effect of the calcium antagonists ryodipine and verapamil on the carnitine-dependent metabolism of fatty acids in the rat heart]. / Vliianie antagonistov kal'tsiia riodipina i verapamila na karnitinzavisimyi metabolizm zhirnykh kislot v serdtse krys.

Riodipine (10 days, 10 mg/kg) was shown to prevent in rats an isoproterenol-induced increase of free fatty acid concentration in the blood serum and heart and to promote normalization of long-chain acylcarnitine content in the heart. Under the same conditions verapamil caused an increase in free acid concentration in the blood serum and prevented their accumulation in the heart. Its ability to limit accumulation of long-chain acylcarnitine manifested itself in a lesser degree as compared to riodipine. Riodipine exerted no effect on oxidation of 1-14-C-palmitic acid by the rat heart homogenate, verapamil suppressed oxidation of this fatty acid.

[Effect of DL-carnitine and gamma-butyrobetaine hydroxylase inhibitor 3-(2,2,2-trimethylhydrazinium) propionate on isoproterenol-induced changes in the metabolism of the rat myocardium]. / Vliianie DL-karnitina i ingibitora gamma-butirobetaingidroksilazy 3-(2,2,2-trimetilgidrazinii) propionata (TGP) na vyzyvaemye isoproterenolom izmeneniia v metabolizme miokarda krys.

3-(2,2,2-trimethyl hydrazinium) propionate (THP) is known as an inhibitor of gamma-butyrobetaine hydroxylase in rat liver tissue. At the same time, THP, administered per os at a dose of 100 mg/kg within 10 days, prevented the isoproterenol-induced (subcutaneously, 50 mg/kg) acylcarnitine accumulation. This effect of THP, accompanied by a distinct decrease of free carnitine in rat myocardium, occurred due to inhibition of carnitine biosynthesis from gamma-butyrobetaine. THP protected the myocardium energetics against isoproterenol action as the drug prevented the acylcarnitine accumulation. Although D,L-carnitine (200 mg/kg, per os, 10 days) inhibited also the isoproterenol-stimulated acylcarnitine accumulation in rat myocardium and fatty acids of blood serum, in did not exhibit any favourable effect on myocardium bioenergetics. Inefficiency of D,L-carnitine as cardioprotective drug may be a result of intensification of fatty acids metabolism occurring simultaneously with isoproterenol-mediated myocardium ischemia. Use of inhibitors of carnitine-dependent oxidation of fatty acids oxidation (as exemplified by THP) in order to correct myocardium metabolism is of importance especially in relation to impairing effects caused by catecholamines.

[Prevention of ischemic myocardial damage by reducing the intracellular free carnitine level]. / Predotvrashchenie ishemicheskikn povrezhdenii miokarda putem znizheniia vnutrikletochnoi kontsentratsii svobodnogo karnitina.

3-(2, 2, 2-trimethylhydrazinium) propionate (THP) inhibits gamma-butyrobetaine hydroxylase, which is accompanied by a drop in myocardial free carnitin content. In rabbits, 200 mg/kg THP, administered intraperitoneally for 10 days, decreases free carnitin and long-chain acylcarnitin by 59.8 and 59.2%, respectively. In a carnitin-depressing dose, THP helps to recover contractility of isolated atria after hypoxic exposure. THP prevents isoproterenol-induced accumulation of long-chain acylcarnitin and ATR fall in the rat myocardium. The protective effect of THP is realized in the presence of considerably reduced (by an average of 77.8%) myocardial free carnitin levels. Inhibition of carnitin-dependent fatty acids metabolism by reducing intracellular carnitin concentration is a pathogenetically justified method of myocardial protection against ischemic damage.