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PubMed1987

Carnitine metabolism in valproate-treated rats: the effect of L-carnitine supplementation.

The effect of the administration for 7 days of valproate (500 mg/kg/day) or valproate (500 mg/kg/day) plus L-carnitine (200 mg/kg/day) on carnitine concentrations in serum, red blood cells, muscle, liver, and urine was evaluated. In the serum and muscle of the valproic acid (VPA) group, free carnitine levels decreased, while acyl-carnitine levels and acyl/free ratio increased, when compared to those of the control. When L-carnitine was given to the VPA group, the free carnitine levels increased in the serum, muscle, and liver, and the acyl/free ratio decreased in all tissues when compared to those of the VPA group. The mean of free carnitine level in urine of the VPA group was not different but acylcarnitine increased when compared to values of controls, and after the supplementation with L-carnitine the acylcarnitine (from day 4 to 7) levels were decreased compared to the VPA group. The serum beta-OH-butyrate level in the VPA group was decreased when compared to those of controls and VPA plus L-carnitine groups. These results indicate that L-carnitine supplementation protects against the alteration in carnitine metabolism induced by the administration of VPA.

Animals↗
PubMed1982

Effects of L-carnitine on action potential or canine papillary muscle impaired by long chain acyl carnitine.

It has been reported that long chain acyl carnitine accumulates in ischemic myocardium, and L-carnitine prevents ventricular arrhythmias as well as the accumulation of long chain acyl carnitine in ischemic and free fatty acid supplemented hearts. The purpose of this study was to observe the electrophysiological effects of long chain acyl carnitine, and to evaluate the protective effect of L-carnitine on the transmembrane action potential impaired by long chain acyl carnitine. Using standard microelectrode techniques, transmembrane action potentials were recorded from isolated canine papillary muscle. Palmitoyl carnitine (0.3 mM and 0.6 mM) decreased the resting membrane potential, action potential amplitude and maximum upstroke velocity of phase 0, and shortened action potential duration and effective refractory period in a concentration-dependent manner. Application of L-carnitine (25 mM) prevented the effect of palmitoyl carnitine (0.3 mM) on the transmembrane action potential. These results suggest that long chain acyl carnitine plays an important role in arrhythmogenesis, and that the effect is prevented by L-carnitine.

Action Potentials↗
PubMed1993

Changes in the subcellular distribution of free carnitine and its acyl derivatives in diabetic rat hearts following treatment with L-carnitine.

Carnitine deficiency has been demonstrated in diabetic hearts, and it is also well known that L-carnitine administration has a beneficial effect on cardiac function. Carnitine treatment would be expected to reduce the accumulation of long-chain acylcarnitine. However, many reports have shown that myocardial long-chain acylcarnitine levels were increased following treatment with L-carnitine in whole-heart studies. Since acylcarnitine exists in both the mitochondrial and cytosolic compartments, it is difficult to investigate changes in subcellular distribution by studying whole-heart preparations. The present study investigated the myocardial subcellular distribution of carnitine and its acyl derivatives in diabetic rats with or without L-carnitine treatment. Approximately 90% of total cellular carnitine was located in the cytosol in the diabetic hearts. Both mitochondrial and cytosolic levels of free carnitine and short-chain acylcarnitine were significantly decreased in the diabetic heart. However, the mitochondrial level of long-chain acylcarnitine was significantly increased. L-carnitine treatment reduced the mitochondrial level of long-chain acylcarnitine, but the cytosolic level of long-chain acylcarnitine was significantly increased. These results show that L-carnitine treatment prevents the accumulation of long-chain acylcarnitine in the mitochondrial space and then reduces the detergent effect of long-chain acylcarnitine on the mitochondrial membrane. We suggest that it is a possible mechanism of the beneficial effect of L-carnitine treatment on the diabetic heart.

Animals↗
PubMed1990

Fluorometric determination of carnitine in serum with immobilized carnitine dehydrogenase and diaphorase.

A fluorometric flow-injection method for determining carnitine with use of immobilized enzymes carnitine dehydrogenase (EC 1.1.1.108) and diaphorase (EC 1.8.1.4) was developed and applied to the assay of carnitine in serum of patients treated with valproic acid. After fractionation and hydrolysis of carnitines in serum samples by perchloric acid and potassium hydroxide, liberated carnitine was converted to resorufin by immobilized carnitine dehydrogenase and diaphorase in the presence of beta-NAD+ (1.0 mmol/L), resazurin (12.5 mumol/L), and Tris acetate (0.6 mol/L, pH 9.0) at 37 degrees C. The fluorescence intensity of resorufin was monitored at lambda Ex 560 nm and lambda Em 580 nm. The calibration curve was linear for carnitine amounts from 0.1 to 1.0 nmol. Quantitative analytical recovery and satisfactory within- and between-run imprecision of carnitine in each carnitine fraction were obtained. Interference by bilirubin, serum albumin, and hemoglobin was negligible. Carnitine deficiencies were detected in about 20% of the valproic acid-treated patients (n = 198). The present method should be useful for monitoring carnitine deficiencies in clinical laboratories.

Alcohol Oxidoreductases↗
PubMed1987

Plasma carnitine and acetyl-carnitine levels at different times of the day.

An interest in both biochemical and clinical carnitine investigation has recently developed. A more complete and extensive study is obtained if acetyl-carnitine as well as carnitine are investigated. This research, using an improved and simplified method for carnitine and acetyl-carnitine determination in the same sample (1 ml) without radioisotopic tracer use, investigates if there are the same differences in their plasma levels at different times of the day. The sample was eluted in a chromatographic column (55 X 15 mm) containing Sephadex G-25M with phosphate buffer (25 mmol/l, pH 7.4). The fraction containing acetyl and free carnitine was divided and employed separately for two assays. The carnitine assay uses an enzymatic reaction catalyzed by carnitine acetyl-transferase (CAT) and measurements are carried out spectrophotometrically. The calibration curve shows r = 0.987 and sensitivity at 5 mumol/l (reference plasma values: 38 +/- 3 mumol/l in 9 subjects). The acetyl-carnitine assay is carried out concentrating the sample by lyophilization and then measuring the enzymatic coupled reactions catalyzed by CAT, malate dehydrogenase and citrate synthase fluorimetrically. The calibration curve gives r = 0.991 and sensitivity at 1.4 mumol/l (reference plasma values: 2.8 +/- 0.3 mumol/l in 9 subjects). Both assay methods are measured at the end point. The carnitine and acetyl-carnitine measured in the plasma of 6 normal subjects at different times of the day vary respectively from 28 to 37 mumol/l and from 1.1 to 5.2 mumol/l in agreement with plasma free fatty acid (FFA) variation from 230 to 779 microEq/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcarnitine↗
PubMed1996

The effects of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition on tissue levels of carnitine and carnitine acyltransferase activity in the rabbit.

Recently, a new class of lipid lowering agents [3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors] was introduced into clinical practice. The use of these agents could lead to a secondary deficiency in carnitine, which may manifest clinically as a myalgia/myositis-a side effect that is occasionally seen with this class of drugs. In the present study, we examined the effect of an HMG-CoA reductase inhibitor (lovastatin) on serum and tissue levels of carnitine and carnitine acyltransferase activities in the rabbit. Rabbits (n = 6) were fed chow containing lovastatin (30 mg/d) for 16 wk. Blood was collected and tissues (liver, heart, and skeletal muscle) harvested at sacrifice. Free and total carnitine were measured in serum and tissues by a radioenzymatic method. Carnitine acetyltransferase and carnitine palmitoyltransferase (CPT) activities were determined and expressed relative to DNA. Serum free (24.0 +/- 2.6 vs. 29.4 +/- 3.1 microM) and total (35.1 +/- 4.7 vs. 52.8 +/- 8.8 microM) carnitine levels increased significantly with 16 wk of treatment. This increase in total carnitine was mainly due to an increase in the levels of serum acylcarnitine (12.7 +/- 3.1 vs 26.5 +/- 5.7 microM). Tissue levels of total carnitine were significantly decreased by the treatment. Carnitine acetyltransferase was unaffected by the treatment, whereas there was a significant increase in the activity of CPT in the liver and heart.

Animals↗
PubMed1997

Effect of dehydroepiandrosterone sulfate on carnitine acetyl transferase activity and L-carnitine levels in oophorectomized rats.

Alteration in energy metabolism of postmenopausal women might be related to the reduction of dehydroepiandrosterone sulfate (DHEAS). DHEA and DHEAS decline with age, leveling at their nadir near menopause. DHEA and DHEAS modulate fatty acid metabolism by regulating carnitine acyltransferases and CoA. The purpose of this study was to determine whether dietary supplementation with DHEAS would also increase tissue L-carnitine levels, carnitine acetyltransferase (CAT) activity and mitochondrial respiration in oophorectomized rats. Plasma L-carnitine levels rose following oophorectomy in all groups (P < 0.0001). Supplementation with DHEAS was not associated with further elevation of plasma L-carnitine levels, but with increased hepatic total and free L-carnitine (P = 0.021 and P < 0.0001, respectively) and cardiac total L-carnitine concentrations (P = 0.045). In addition, DHEAS supplementation increased both hepatic and cardiac CAT activities (P < 0.0001 and P = 0.05 respectively). CAT activity positively correlated with the total and free carnitine levels in both liver and heart (r = 0.764, r = 0.785 and r = 0.700, r = 0.519, respectively). Liver mitochondrial respiratory control ratio, ADP:O ratio and oxygen uptake were similar in both control and supplemented groups. These results demonstrate that in oophorectomized rats, dietary DHEAS supplementation increases the liver and heart L-carnitine levels and CAT activities. In conclusion, DHEAS may modulate L-carnitine level and CAT activity in estrogen deficient rats. The potential role of DHEAS in the regulation of fatty acid oxidation in postmenopausal women is worthy of investigation.

Animals↗
PubMed2000

Kinetics of carnitine palmitoyltransferase-I are altered by dietary variables and suggest a metabolic need for supplemental carnitine in young pigs.

To examine the kinetics of carnitine palmitoyltransferase-I (CPT-I) and the influence of dietary variables, young pigs (18 kg, n = 20) were fed corn-soybean meal diets supplemented with 40 g soy oil/kg and containing either 136 or 180 g crude protein/kg and either 0 or 500 mg/kg L-carnitine (2 x 2 factorial design). Diets were offered for 10 d (85% of ad libitum); CPT-I activities in liver and skeletal muscle mitochondria were determined, and enzyme kinetic constants (V:(max) and K:(m) for carnitine) were estimated. Kinetics of CPT-I in muscle were not affected by diet (P: > 0.1; carnitine K:(m) = 480 +/- 44 micromol/L). In contrast, the K:(m) for carnitine in liver was increased from 164 to 216 +/- 20 micromol/L by dietary L-carnitine supplementation (P: < 0.01) and from 169 to 211 +/- 20 micromol/L by high protein feeding (P: < 0.05). Dietary L-carnitine increased muscle and liver free carnitine concentrations by 72 and 158% over control concentrations (770 and 80 micro;mol/kg wet muscle and liver, respectively). Because tissue carnitine concentrations were within the range of the respective K:(m) for both liver and muscle tissue, it is inferred that alteration of tissue carnitine concentrations via dietary supplementation could modulate CPT-I activity in young pigs.

Animals↗
PubMed1982

Stimulation of the anaerobic growth of Salmonella typhimurium by reduction of L-carnitine, carnitine derivatives and structure-related trimethylammonium compounds.

In view of the development of a L-carnitine deficiency, the metabolism of L-carnitine and structure-related trimethylammonium compounds was studied in Salmonella typhimurium LT2 by means of thin-layer chromatography (TLC). L-Carnitine, crotonobetaine and acetyl-L-carnitine stimulated the anaerobic growth in a complex medium significantly. The stimulation depended on the formation of gamma-butyrobetaine. The reduction of L-carnitine proceeded in two steps: (1) Dehydration of the L-carnitine to crotonobetaine, (2) hydrogenation of crotonobetaine to gamma-butyrobetaine. The reduction of crotonobetaine was responsible for the growth stimulation. Terminal electron acceptors of the anaerobic respiration such as nitrate and trimethylamine N-oxide, but not fumarate, suppressed the catabolism of L-carnitine completely. Glucose fermentation, too, inhibited the reduction of L-carnitine but optimal growth with a high carnitine catabolism was achieved by D-ribose. The esters of carnitine with medium- and long-chain fatty acids inhibited the growth considerably because of their detergent properties.

Anaerobiosis↗
PubMed1980

Clofibrate enhancement of mitochondrial carnitine transport system of rat liver and augmentation of liver carnitine and gamma-butyrobetaine hydroxylase activity by thyroxine.

The possibilities that the hypotriglyceridemic effect of clofibrate involves activation of carnitine-dependent oxidation of fatty acids in liver and that this may be partially mediated through thyroxine have been examined. 0.25% clofibrate in diet for 10-15 days, was found to increase carnitine 3-fold in livers of male as well as female rats. Liver carnitine was nearly doubled by L-thyroxine, 6 mg/kg of diet fed for 10 days, and so was the activity of gamma-butyrobetaine hydroxylase. Clofibrate decreased carnitine in heart and urine; thyroxine did not affect these parameters but increased serum carnitine by 26%. Clofibrate feeding doubled the concentration of hepatic long-chain acyl(-)carnitine, mitochondrial carnitine, and the rate of mitochondrial carnitine-acylcarnitine translocase reaction, and enhanced acetoacetate production in liver homogenates as well as mitochondrial oxidation of palmitoylcarnitine in the presence of malonate. The ratio of esterified to free carnitine in urine and serum was also increased by clofibrate. These results suggest that clofibrate and thyroxine may exert their hypotriglyceridemic effect, in part, through the activation of carnitine-mediated transport of fatty acids in liver mitochondria.

Acetoacetates↗
PubMed2005

L-carnitine and propionyl-L-carnitine improve endothelial dysfunction in spontaneously hypertensive rats: different participation of NO and COX-products.

L-carnitine and propionyl-L-carnitine are supplements to therapy in cardiovascular pathologies. Their effect on endothelial dysfunction in hypertension was studied after treatment with either 200 mg/kg of L-carnitine or propionyl-L-carnitine during 8 weeks of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Endothelial function was assessed in aortic rings by carbachol-induced relaxation (CCh 10(-8) to 10(-4) M) and factors involved were characterized in the presence of the inhibitors: L-NAME, indomethacin, the TXA2/PGH2 Tp receptor antagonist ICI-192,605 and the thromboxane synthetase inhibitor-Tp receptor antagonist, Ro-68,070. The effect on phenylephrine-induced contractions was also observed. To identify the nature of vasoactive COX-derived products, enzyme-immunoassay of incubation media was assessed. Involvement of reactive oxygen species was evaluated by incubating with superoxide dismutase and catalase. Nitric oxide production was evaluated by serum concentration of NO2+NO3.Treatment with both compounds improved endothelial function of rings from SHR without blood pressure change. Propionyl-L-carnitine increased NO participation in WKY and SHR. L-carnitine reduced endothelium-dependent responses to CCh in WKY due to an increase of TXA2 production. In both SHR and WKY, L-carnitine enhanced concentration of PGI2 and increased participation of NO. Results in the presence of SOD plus catalase show that it might be related to antioxidant properties of L-carnitine and propionyl-L-carnitine. Comparison between the effect of both compounds shows that both may reduce reactive oxygen species and increase NO participation in endothelium-dependent relaxations in SHR. However, only L-carnitine was able to increase the release of the vasodilator PGI2 and even enhanced TXA2 production in normotensive rats.

Administration, Oral↗
PubMed1982

Carnitine deficiency presenting as familial cardiomyopathy: a treatable defect in carnitine transport.

We studied a boy who presented at age 3 1/2 years with cardiomegaly, a distinctive electrocardiogram, and a history of a brother dying with cardiomyopathy. From age 3 1/2 to 5 years, cardiac disease progressed, resulting in intractable congestive heart failure. Skeletal muscle weakness developed and a muscle biopsy showed lipid myopathy. Muscle and plasma carnitine were reduced to 2 and 10% of the normal mean values, respectively. Therapy with L-carnitine (174 mg/kg/da) was begun at age 5 1/2 years and continued to the present (age 6 1/2 years). The cardiac disease has resolved and the muscle strength has returned to normal. Plasma carnitine concentrations have risen to the low-normal range, while urinary carnitine excretion has increased to values which are 30 times normal. The renal clearance of carnitine exceeds normal at all plasma concentrations and plasma carnitine values do not change acutely after an oral carnitine load. These results suggest that there is a distinct form of carnitine deficiency which presents as cardiomyopathy and may be successfully treated with L-carnitine. A defect in renal and possibly gastrointestinal transport of carnitine is a likely cause of this patient's disorder.

Cardiomyopathies↗
PubMed1984

Effect of carnitine on lipid metabolism in the neonate. II. Carnitine addition to lipid infusion during prolonged total parenteral nutrition.

The effect of carnitine administration on lipid metabolism and carnitine and acylcarnitine plasma values of newborn infants, given total parenteral nutrition for the first 7 days of life, was studied during a 4-hour infusion of Intralipid. An increase in plasma concentrations of total carnitine, free carnitine, and short-chain and long-chain acylcarnitine was found, but no significant change in triglycerides, free fatty acids, glycerol, or beta-hydroxybutyrate plasma values was noted, as compared with values obtained without carnitine administration. Moreover, the low free carnitine and short-chain and long-chain acylcarnitine plasma levels found in newborn infants after 7 days of total parenteral nutrition did not seem to impair the utilization of infused lipids. The results support the concept that the relation between the carnitine pool and lipid metabolism can be influenced by intravenous glucose infusion. Low carnitine plasma concentrations do not necessarily signify a depletion of body carnitine, and sufficient tissue carnitine concentrations can probably maintain good lipid utilization for an extended period.

3-Hydroxybutyric Acid↗
PubMed1997

Synthesis of O-[11C]Acetyl CoA, O-[11C]Acetyl-L-carnitine, and L-[11C]carnitine labelled in specific positions, applied in PET studies on rhesus monkey.

The syntheses of L-carnitine, O-acetyl CoA, and O-acetyl-L-carnitine labelled with 11C at the 1- or 2-position of the acetyl group or the N-methyl position of carnitine, using the enzymes acetyl CoA synthetase and carnitine acetyltransferase, are described. With a total synthesis time of 45 min, O-[1-11C]acetyl CoA and O-[2[11C]acetyl CoA was obtained in 60-70% decay-corrected radiochemical yield, and O-[1-11C]acetyl-L-carnitine and O-[2-11C] acetyl-L-carnitine in 70-80% yield, based on [1-11C]acetate or [2-11C]acetate, respectively. By an N-methylation reaction with [11C]methyl iodide, L-[methyl-11C]carnitine was obtained within 30 min, and O-acetyl-L-[methyl-11C]carnitine within 40 min, giving a decay-corrected radiochemical yield of 60% and 40-50%, respectively, based on [11C]methyl iodide. Initial data of the kinetics of the different 11C-labelled L-carnitine and acetyl-L-carnitines in renal cortex of anaesthetized monkey (Macaca mulatta) are presented.

Acetyl Coenzyme A↗
PubMed1991

Carnitine status and lipid utilization in neonatal piglets fed diets low in carnitine.

Forty-eight newborn piglets were assigned to dietary regimens to examine carnitine status and lipid utilization by piglets nursing sows (Diet 1), fed a high-carnitine (1507 mumol carnitine/kg dry matter) casein-whey formula (Diet 2) or fed a low-carnitine (35 mumol carnitine/kg dry matter) egg white protein formula (Diet 3). Four piglets were killed at birth, and four per dietary group were killed at 3, 7, 14 and 21 d of age. Piglets fed Diet 3 had lower (P less than 0.01) carnitine in plasma and liver by d 7 and carnitine remained lower to d 21. Heart carnitine tended to be lower in piglets fed Diet 3, but the differences were not significant. Longissimus muscle carnitine was not affected. In vitro palmitate oxidation was lower (P less than 0.05) on d 7 in the liver from piglets fed Diet 3 but not on d 3, 14 and 21. Low dietary carnitine did not affect in vitro liver beta-hydroxybutyrate production or oxidation of palmitate by longissimus muscle. Plasma glucose and nonesterified fatty acids were higher (P less than 0.05) in piglets nursing sows than those fed Diets 2 or 3. Piglets receiving Diet 3 had reduced carnitine in plasma and certain tissues, and liver lipid oxidation was depressed on d 7 of age, compared with those receiving the other two diets. Feeding the low carnitine diet did not alter glucose status or plasma lipids and ketones.

Animal Nutritional Physiological Phenomena↗
PubMed1996

Milk carnitine affects organ carnitine concentration in newborn rats.

Previous studies suggest that exogenous milk carnitine may be necessary during the suckling period to maintain normal fat metabolism. To characterize the relationship between milk carnitine and carnitine in body organs, newborn rats were fed from birth a rat milk substitute with or without 300 micromol/L L-carnitine, corresponding to the concentration present in rat milk, for either 2 or 4 d. Carnitine concentrations in heart, skeletal muscle, liver and small intestine were compared with levels in rat pups that were never fed (d 0) and those that were nursed by their mothers for 4 d. Carnitine supplementation resulted in significantly higher concentrations of carnitine in all organs studied after 4 d compared with nursed controls. Relative intestinal carnitine pool size was 38.1 +/- 3.0, 22.6 +/- 1.0, 7.9 +/- 0.5 and 2.3 +/- 0.7 micromol/g body wt in supplemented, nursed, unsupplemented and never fed pups, respectively (P < 0.05, compared with one another). These results indicate that carnitine organ concentrations are related to dietary intake during the early suckling period and that the small intestine is a considerable and previously unrecognized proportion of the carnitine pool of suckling animals.

Animals↗
PubMedDate not supplied

Changes of plasma free amino acids and renal clearances of carnitines in premature infants during L-carnitine-supplemented human milk feeding.

Eighteen breast-fed infants with a mean post-natal age of 26 days (range 16-41 days) were studied. Following 1 control day, the infants were fed for 7 consecutive days with pooled human milk supplemented with 300 nmol L-carnitine/ml milk. Both plasma fractions of acid-soluble carnitines increased as a consequence of carnitine application. The level of beta-hydroxybutyrate also increased significantly. Of the circulating free amino acids, the levels of alanine (p less than 0.025) and glutamine (p less than 0.01) were found to be lower, with a decreased urea level (p less than 0.005) by the last day of carnitine administration, compared with the control day. The urinary output of total nitrogen also decreased. There were no statistically significant changes in the level of free fatty acids and glucose. On the control day, the renal clearance rate of esterified carnitines significantly exceeded that of free fraction, thus the relative renal reabsorption calculated on the base of creatinine excretion rates was higher for free (mean 98.1%) than for acylated (mean 90.6%) carnitine. In response to enhanced carnitine intake, the clearance rates for each fractions of carnitines significantly exceeded the presupplementary values. The increased clearance rates was more pronounced for free (mean 13.2-fold) than for esterified (mean 8.08-fold) carnitines. Despite the increased clearance rates, considerable relative reabsorption was seen for free carnitines (mean 70.0%) as well as for acylcarnitines (mean 65.3%).

Absorption↗
PubMed1981

Primary systemic carnitine deficiency. II. Renal handling of carnitine.

Renal tubular reabsorption rates, reabsorptive maxima, and apparent renal plasma excretory thresholds for carnitine were determined in four children with primary systemic carnitine deficiency (SCD), in two of the mothers of these children, in one patient with muscle carnitine deficiency (MCD), and in seven controls. In SCD the observed values were well below those found in six of seven controls, but one control, a healthy 20-year-old woman with normal muscle carnitine level, also exhibited a renal carnitine leak. In the two mothers of patients with SCD and in the case of MCD some of the parameters of the renal handling of carnitine were slightly altered. Tubular secretion of short-chain acylcarnitines was noted in patients and controls at high plasma free carnitine levels. Augmented excretion of short-chain acylcarnitines occurred at lower plasma free carnitine levels in the patients with SCD than in the other subjects. Free and short-chain acyl-carnitines may compete for the same renal reabsorptive site. A renal defect cannot fully account for primary SCD but may contribute to the carnitine depletion in this disorder.

Carnitine↗