cardiovascular-agents and gamma-butyrobetaine

In this study, we aimed to investigate the effects of long-term administration of the cardioprotective drug mildronate on the concentrations of l-carnitine and γ-butyrobetaine in healthy volunteers.. Mildronate was administered perorally, at a dosage of 500mg, twice daily. Plasma and urine samples were collected weekly. Daily meat consumption within an average, non-vegetarian diet was monitored. l-Carnitine, γ-butyrobetaine and mildronate concentrations were measured using the UPLC/MS/MS method.. After 4 weeks, the average concentrations of l-carnitine in plasma significantly decreased by 18%. The plasma concentrations of γ-butyrobetaine increased about two-fold, and this effect was statistically significant in both the male and female groups. In urine samples, a significant increase in l-carnitine and γ-butyrobetaine levels was observed, which provides evidence for increased excretion of both substances during the mildronate treatment. At the end of the treatment period, the plasma concentration of mildronate was 20µm on average. There were no significant differences between the effects observed in female and male volunteers. Meat consumption partially reduced the l-carnitine-lowering effects induced by mildronate.. Long-term administration of mildronate significantly lowers l-carnitine plasma concentrations in non-vegetarian, healthy volunteers.

Topics: Adult; Betaine; Cardiovascular Agents; Carnitine; Diet; Female; Humans; Male; Meat; Methylhydrazines; Middle Aged; Young Adult

The aim of the present study was to investigate the effects of vascular tissue levels of l-carnitine and its precursor, γ-butyrobetaine (GBB), on the development of endothelial dysfunction induced by 5 μmol/L lysophosphatidylcholine (LPC), 10 mmol/L triglycerides (TG) or a high glucose concentration (44 mmol/L). Changes in vascular tissue levels of l-carnitine and GBB were induced by administration of l-carnitine (100 mg/kg), mildronate (100 mg/kg; an inhibitor of l-carnitine synthesis) or their combination to male Wistar rats for 2 weeks. Treatment with l-carnitine elevated vascular tissue levels of l-carnitine, whereas administration of mildronate reduced l-carnitine levels and increased GBB levels. Experimental animals that received the combination of both drugs showed elevated tissue levels of GBB. The results from organ bath experiments demonstrated that increased GBB levels with preserved l-carnitine content in vascular tissues attenuated the development of endothelial dysfunction induced by high glucose. However, changes in vascular tissue l-carnitine and GBB levels had no impact on endothelial dysfunction induced by TG or LPC. The results demonstrate that increased levels of GBB with preserved l-carnitine content in vascular tissue attenuate the development of endothelial dysfunction induced by high glucose concentrations.

Topics: Animals; Aorta; Betaine; Cardiovascular Agents; Carnitine; Drug Therapy, Combination; Endothelium, Vascular; Glucose; Male; Methylhydrazines; Rats; Rats, Wistar

Mildronate, an inhibitor of L-carnitine biosynthesis and uptake, is a cardioprotective drug whose mechanism of action is thought to rely on the changes in concentration of L-carnitine in heart tissue. In the present study, we compared the cardioprotective effect of mildronate (100 mg/kg) and a combination of mildronate and L-carnitine (100 + 100 mg/kg) administered for 14 days with respect to the observed changes in l-carnitine level and carnitine palmitoyltransferase I (CPT-I)-dependent fatty acid metabolism in the heart tissues. Concentrations of L-carnitine and its precursor γ-butyrobetaine (GBB) were measured by ultraperformance liquid chromatography with tandem mass spectrometry. In addition, mitochondrial respiration, activity of CPT-I, and expression of CPT-IA/B messenger RNA (mRNA) were measured. Isolated rat hearts were subjected to ischemia-reperfusion injury. Administration of mildronate induced a 69% decrease in L-carnitine concentration and a 6-fold increase in GBB concentration in the heart tissue as well as a 27% decrease in CPT-I-dependent mitochondrial respiration on palmitoyl-coenzyme A. In addition, mildronate treatment induced a significant reduction in infarct size and also diminished the ischemia-induced respiration stimulation by exogenous cytochrome c. Treatment with a combination had no significant impact on L-carnitine concentration, CPT-I-dependent mitochondrial respiration, and infarct size. Our results demonstrated that the mildronate-induced decrease in L-carnitine concentration, concomitant decrease in fatty acid transport, and maintenance of the intactness of outer mitochondrial membrane in heart mitochondria are the key mechanisms of action for the anti-infarction activity of mildronate.

Topics: Animals; Betaine; Cardiovascular Agents; Carnitine; Carnitine O-Palmitoyltransferase; Chromatography, Liquid; Drug Interactions; Fatty Acids; Male; Methylhydrazines; Mitochondria, Heart; Mitochondrial Membranes; Myocardial Infarction; Myocardial Reperfusion Injury; Rats; Rats, Wistar; Tandem Mass Spectrometry; Vitamin B Complex

Mildronate, an inhibitor of L-carnitine biosynthesis and transport, is used in clinics as a modulator of cellular energy metabolism and is a cardioprotective drug. L-Carnitine is a pivotal molecule in fatty acid oxidation pathways and its regulation in vasculature might be a promising approach for antiatherosclerotic treatment. This study was performed to evaluate the effects of mildronate treatment on the progression of atherosclerosis and the content of L-carnitine in the vascular wall.. ApoE/LDLR(-/-) mice received mildronate at doses of 30 and 100 mg/kg for 4 months. Lipid profile was measured in plasma and atherosclerotic lesions were analyzed in whole aorta and aortic sinus. L-Carnitine concentration was assessed in rat aortic tissues after 2 weeks of treatment with mildronate at a dose of 100 mg/kg.. The chronic treatment with mildronate at a dose of 100 mg/kg significantly reduced the size of atherosclerotic plaques in the aortic roots and in the whole aorta, and slightly decreased the free cholesterol level. In addition, mildronate treatment decreased L-carnitine concentration in rat aortic tissues.. Long-term mildronate treatment decreases L-carnitine content in aortic tissues and attenuates the development of atherosclerosis in apoE/LDLR(-/-) mice.

Topics: Animals; Aorta; Atherosclerosis; Betaine; Cardiovascular Agents; Carnitine; Energy Metabolism; Female; Lipids; Male; Methylhydrazines; Mice; Mice, Knockout; Rats; Rats, Wistar

Mildronate is a cardioprotective drug that improves cardiac function during ischaemia and functions by lowering l-carnitine concentration in body tissues and modulating myocardial energy metabolism. The aim of the present study was to characterise cardiovascular function and liver condition after long-term mildronate treatment in rats. In addition, changes in the plasma lipid profile, along with changes in the concentration of mildronate, l-carnitine and gamma-butyrobetaine were monitored in the rat tissues. Wistar rats were perorally treated daily with a mildronate dose of either 100, 200 or 400 mg/kg for 4, 8 or 12 weeks. The l-carnitine-lowering effect of mildronate was dose-dependent. However, the carnitine levels reached a plateau after about four weeks of treatment. During the additional weeks of treatment, the carnitine levels were not considerably changed. The obtained results provide evidence that even a high dose of mildronate does not alter cardiovascular parameters and the function of isolated rat hearts. Furthermore, the histological evaluation of liver tissue cryosections and measurement of biochemical markers of hepatic toxicity showed that all the measured values were within the normal reference range. Our results provide evidence that long-term mildronate administration induces significant changes in carnitine homeostasis, but it is not associated with cardiac impairment or disturbances in liver function.

Topics: Animals; Betaine; Biomarkers; Blood Glucose; Body Weight; Cardiovascular Agents; Carnitine; Carnitine O-Palmitoyltransferase; Dose-Response Relationship, Drug; Glucose; Heart; Hemodynamics; Lipids; Liver; Liver Glycogen; Male; Methylhydrazines; Myocardium; Rats; Rats, Wistar; Time Factors; Toxicity Tests, Chronic

The inhibition of gamma-butyrobetaine (GBB) hydroxylase, a key enzyme in the biosynthesis of carnitine, contributes to lay ground for the cardioprotective mechanism of action of mildronate. By inhibiting the biosynthesis of carnitine, mildronate is supposed to induce the accumulation of GBB, a substrate of GBB hydroxylase. This study describes the changes in content of carnitine and GBB in rat plasma and heart tissues during long-term (28 days) treatment of mildronate [i.p. (intraperitoneal) 100 mg/kg/daily]. Obtained data show that in concert with a decrease in carnitine concentration, the administration of mildronate caused a significant increase in GBB concentration. We detected about a 5-fold increase in GBB contents in the plasma and brain and a 7-fold increase in the heart. In addition, we tested the cardioprotective effect of mildronate in isolated rat heart infarction model after 3, 7, and 14 days of administration. We found a statistically significant decrease in necrotic area of infarcted rat hearts after 14 days of treatment with mildronate. The cardioprotective effect of mildronate correlated with an increase in GBB contents. In conclusion, our study, for the first time, provides experimental evidence that the long-term administration of mildronate not only decreases free carnitine concentration, but also causes a significant increase in GBB concentration, which correlates with the cardioprotection of mildronate.

Topics: Animals; Betaine; Cardiovascular Agents; Carnitine; Chromatography, High Pressure Liquid; Coronary Circulation; gamma-Butyrobetaine Dioxygenase; In Vitro Techniques; Injections, Intraperitoneal; Male; Methylhydrazines; Myocardial Infarction; Myocardium; Rats; Rats, Wistar