Plasma Carnitine Concentrations Research Articles

Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. Evidence for alterations in tissue carnitine transport.

The human primary carnitine deficiency syndromes are potentially fatal disorders affecting children and adults. The molecular etiologies of these syndromes have not been determined. In this investigation, we considered the hypothesis that these syndromes result from defective transport of carnitine into tissues, particularly skeletal muscle. The problem was approached by mathematical modeling, by using the technique of kinetic compartmental analysis. A tracer dose of L-[methyl-3H]carnitine was administered intravenously to six normal subjects, one patient with primary muscle carnitine deficiency (MCD), and four patients with primary systemic carnitine deficiency (SCD). Specific radioactivity was followed in plasma for 28 d. A three-compartment model (extracellular fluid, muscle, and "other tissues") was adopted. Rate constants, fluxes, pool sizes, and turnover times were calculated. Results of these calculations indicated reduced transport of carnitine into muscle in both forms of primary carnitine deficiency. However, in SCD, the reduced rate of carnitine transport was attributed to reduced plasma carnitine concentration. In MCD, the results are consistent with an intrinsic defect in the transport process. Abnormal fluctuations of the plasma carnitine, but of a different form, occurred in MCD and SCD. The significance of these are unclear, but in SCD they suggest abnormal regulation of the muscle/plasma carnitine concentration gradient. In 8 of 11 subjects, carnitine excretion was less than dietary carnitine intake. Carnitine excretion rates calculated by kinetic compartmental analysis were higher than corresponding rates measured directly, indicating degradation of carnitine. However, we found no radioactive metabolites of L-[methyl-3H]carnitine in urine. These observations suggest that dietary carnitine was metabolized in the gastrointestinal tract.

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.

Carnitine Status at Birth of Newborn Infants of Varying Gestation

This study assessed and compared the plasma and red blood cell concentrations of carnitine in cord blood samples from preterm (less than or equal to 36 wk, n = 53) and term (greater than or equal to 37 wk, n = 72) neonates. The mean (+/- S.E.) plasma carnitine concentration (PL[C]) was significantly higher in preterm than in term neonates (29.0 +/- 1.8 versus 22.4 +/- 0.8 nmole/ml; P less than 0.001). Likewise, the mean (+/- S.E.) red blood cell carnitine concentration (RBC[C]) was significantly higher in preterm than in term neonates (0.24 +/- 0.02 versus 0.14 +/- 0.01 nmole/mg Hgb; P less than 0.001). Both PL[C] and RBC[C] were particularly elevated in extremely immature neonates (less than or equal to 33 wk gestation). Linear regression analysis showed a significantly negative correlation between PL[C] and gestational age (r = -0.332; P less than 0.001), and between RBC[C] and gestational age (r = -0.531; P less than 0.001). Approximately 72.2 +/- 1.1% (mean +/- S.E.) of carnitine in blood was estimated to be contained in the RBC, and 27.8 +/- 1.1% (mean +/- S.E.) of carnitine was estimated to be in the plasma.

Sodium dependence of carnitine transport in isolated perfused adult rat hearts.

In heart muscle, the intracellular carnitine concentration is approximately 40 times higher than the plasma carnitine concentration, suggesting the existence of an active transport process. At physiological serum carnitine concentrations (44 microM), 80% of total myocardial carnitine uptake occurs via a carrier-mediated transport system. The mechanism of this carrier-mediated transport was studied in isolated perfused rat hearts. Carnitine transport showed an absolute dependence on the extracellular sodium concentration. The rate of carnitine transport was linearly related to the perfusate sodium concentration at every perfusate carnitine concentration examined (15-100 microM). Total removal of extracellular sodium completely abolished the carrier-mediated transport. Decreasing the perfusate potassium concentration from a control of 5.9 to 0.6 mM stimulated transport by 35%, whereas increasing the extracellular potassium concentration from 5.9 to 25 mM reduced transport by 60%. The carrier-mediated transport was inversely proportional to the extracellular potassium concentration. Acetylcholine (10(-3) M), isoproterenol (10(-7) M), or ouabain (10(-3) did not alter the rate of carnitine transport. Addition of tetrodotoxin (10(-5) stimulated carnitine transport by about 40%, while gramicidin S (5 X 10(-6) M) decreased uptake by about 18% relative to control. The data provide evidence that carnitine transport by cardiac cells occurs by a Na+-dependent cotransport mechanism that is dependent on the Na+ electrochemical gradient.

Plasma carnitine in women. Effects of the menstrual cycle and of oral contraceptives.

The plasma concentrations of carnitine were determined in a group of 35 women and 35 men admitted to a clinic, and in another group of 18 women during their menstrual cycle. The values found for the women (45.1 +/- 2.6 nmol/ml of free carnitine and 59.1 +/- 2.8 nmol/ml of total carnitine) were not significantly different from the values obtained in men (respectively 42.4 +/- 1.7 and 55.5 +/- 1.9 nmol/ml). No direct relationship between the free or total carnitine concentrations and the concentrations of circulating lipids could be demonstrated. During the menstrual cycle the plasma concentrations of free and total carnitine remained unchanged. Intake of oral contraceptives caused an elevation in blood triacylglycerols and decreases in the levels of luteinizing hormone, follicle-stimulating hormone, and free and total carnitine.

Carnitine deficiency and hyperammonemia associated with valproic acid therapy

Plasma carnitine and blood ammonia concentrations were measured in 25 severely handicapped patients, ages 3 to 21 years, and 27 age-matched control subjects. Fourteen of the handicapped patients were treated with anticonvulsant drugs including valproic acid; the remaining 11 patients were treated with drugs excluding valproic acid. Plasma carnitine concentrations were lower and blood ammonia values were higher in patients treated with valproic acid than in the untreated patients and control subjects. A significant inverse relationship was found between plasma carnitine concentrations and the dosage of valproic acid, and between plasma carnitine and blood ammonia values. After oral administration of D,L-carnitine (50 mg/kg/day) for four weeks, both carnitine deficiency and hyperammonemia were corrected.

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.

Sex steroid regulation of urinary excretion of carnitine in rats

The concentration of acid soluble carnitine was determined in several body tissues and fluids in rats under various conditions of sex steroid regulation. Intact female rats had significantly greater liver carnitine concentrations and urinary excretion rates, and lower blood plasma and heart carnitine concentrations than intact male rats. Ovariectomy increased blood plasma carnitine concentrations ( P < 0.01) and the excretion of carnitine in the urine ( P < 0.05). The administration of either estradiol or testosterone to ovariectomized rats did not alter blood plasma concentrations or urinary excretion of carnitine. Orchidectomized rats had similar blood plasma carnitine concentrations when compared to intact males but excreted significantly ( P < 0.01) greater quantities of carnitine in their urine. Administration of testosterone to orchidectomized rats reduced ( P < 0.01), whereas estradiol stimulated ( P < 0.05) the excretion rate of carnitine in the urine; however, blood plasma carnitine concentrations were not affected by these hormones. These data suggest that a major site for modulation of body carnitine concentration in the male resides in the control of kidney excretion by androgens. Liver, heart and skeletal muscle carnitine concentrations were not altered by the administration of either estradiol or testosterone to orchidectomized or ovariectomized rats.

Dietary-dependent carnitine deficiency as a causeof nonketotic hypoglycemia in an infant

Recurrent episodes of hypoglycemia, prostration, vomiting, and hepatomegaly were observed in an infant fed a carnitine-free soy formula. The extremely low plasma and urinary carnitine concentrations, elevated plasma free fatty acids, disproportionately low plasma beta hydroxybutyrate, and elevated urinary dicarboxylic acids, in the presence of a fatty liver, suggested that carnitine deficiency was the basis for this child's metabolic disturbance. When the infant was fed an enriched carnitine diet, remarkable clinical, biochemical, and histologic improvement was observed. The possibility that carnitine may be an essential nutrient for some infants is raised by the findings in this patient.

Plasma carnitine concentrations and dyslipidemia in children on maintenance hemodialysis

Plasma carnitine concentrations and dyslipidemia in children on maintenance hemodialysis

Carnitine in the Perinatal Metabolism of Lipids I. Relationship Between Maternal and Fetal Plasma Levels of Carnitine and Acylcarnitines

Since premature infants have a limited capacity for fatty acid oxidation, supplementation with carnitine may improve their utilization of fat. Documentation of the source and extent of fetal carnitine reserves should explain the possible need for exogenous carnitine in the neonate. Correlation between free carnitine concentration in maternal and umbilical arterial plasma at birth (r = .45, P less than .01) indicates that the initial concentration of free carnitine in the newborn depends on the maternal level. Thin-layer chromatography shows more gamma-butyrobetaine in maternal than umbilical arterial plasma indicating higher availability of the precursor of carnitine biosynthesis. Elevated fatty acid oxidation in maternal tissues seems to be reflected by larger amounts of long-chain acylcarnitines in maternal plasma. Short-chain acylcarnitines, mainly acetylcarnitine, are higher in the umbilical vein than in maternal plasma (P less than .01) indicating that the conceptus (the placenta or fetus) is either producing more or utilizing less acetylcarnitine. Plasma levels of carnitine rapidly decrease in premature newborns during the first three days after birth if no exogenous carnitine is given (P less than .001), while no significant changes of total carnitine were detected in adult patients on total parenteral alimentation for one week. This difference indicates lower carnitine depots or limited capacity for carnitine biosynthesis in neonates. The possibility still requires further investigation that the development of the optimal rate of fatty acid oxidation in human newborns, as well as in other newborn mammals, may depend on the supply of exogenous carnitine.

Relationship of carnitine and acylcarnitines in ejaculated sperm to blood plasma testosterone of dairy bulls.

Blood plasma testosterone concentrations were significantly negatively correlated (r = -0.91, P<0.05) with blood plasma carnitine concentrations among dairy bulls of varying fertility levels. Blood plasma testosterone was positively correlated with spermatozoa total carnitine (r = 0.32), spermatozoa acylcarnitines (r = 0.35), and sperm motility (r = 0.49), whereas blood plasma carnitine concentration was negatively correlated with spermatozoa acylcarnitines (r = -0.48), spermatozOa total carnitine (r = -0.36), and sperm motility (r = -0.39). Furthermore, the concentrations of total carnitine (r = 0.67), free carnitine (r = 0.75), and acylcarnitines (r = 0.60) of spermatozoa were positively correlated with sperm motility ratings. Bulls exhibiting the highest fertility levels also had the higher concentration of blood plasma testosterone and lower concentration of blood plasma carnitine. Although several correlation coefficients are not statistically significant, they compare favorably with published values and support the biological importance of these blood plasma constituents as they are related to spermatozoa carnitines and their function in maintaining sperm motility and thus fertility.

Plasma carnitine levels in adult males in India: effects of high cereal, low fat diet, fat supplementation, and nutrition status

Effects of diet and nutrition status on plasma carnitine levels was examined in adult Indian men. Apparently healthy subjects from middle and low income groups, consuming predominantly cereal-based diets had normal levels of plasma carnitine and albumin. Subjects with clear-cut evidence of malnutrition as judged by anthropometry, who, however, had normal plasma albumin, tended to have higher concentrations of plasma carnitine. Conversely, subjects with nutritional edema had markedly reduced plasma carnitine which improved with treatment. Among subjects with plasma albumin above 3.0 g/dl, plasma carnitine showed a weak but significant inverse correlation with anthropometric index (weight/height2 X 100). Increased intake of dietary fat reduced plasma free carnitine markedly and total carnitine marginally, but raised acyl carnitine. The results suggest that plasma carnitine levels in adults may be regulated by a balance between factors influencing its availability through the diet or its synthesis (availability of precursor amino acids, activity of synthetic enzymes), and utilization (body weight, quality and quantity of fat).

Carnitine, acetylcarnitine and the activity of carnitine acyltransferases in seminal plasma and spermatozoa of men, rams and rats.

The concentration of total carnitine (i.e. carnitine plus acetylcarnitine) was measured in seminal plasma and spermatozoa of men and rams. In ram semen, there was a close correlation between the concentration of spermatozoa and that of total carnitine in the seminal plasma, indicating that the epididymal secretion was the sole source of seminal carnitine. The percentage of total carnitine present as acetylcarnitine was 40% in seminal plasma and 70-80% in spermatozoa. The acetylation state of carnitine in seminal plasma was apparently not influenced by the metabolic activity of spermatozoa in ejaculated ram semen as no change was found in the plasma concentration of carnitine or acetylcarnitine up to 45 min after ejaculation. In spermatozoa, the activity of carnitine acetyltransferase (EC 2.3.1.7) was approximately equivalent to that of carnitine palmitoyltransferase (EC 2.3.1.21); and the activity of these enzymes was similar in ram and human spermatozoa but greater in rat spermatozoa. It is concluded that there is no correlation between the content of either total carnitine or the carnitine acyltransferases and the respiratory capacity of spermatozoa.

Active transport of carnitine into skeletal muscle.

Skeletal muscle carnitine concentration exceeds plasma carnitine concentration. To determine whether this concentration gradient is maintained by active transport we studied rat soleus and extensor digitorum longus muscles. Observations consistent with the existence of an active transport mechanism were that the soleus accumulated carnitine linearly for 3 hours of incubation to exceed a distribution ratio of 1; the temperature coefficient for carnitine accumulation between 33 degrees C and 43 degrees C was 2.0; anaerobic incubation reduced carnitine accumulation by 30 percent; and the rate of carnitine accumulation was saturated at high substrate concentrations and competitively inhibited by gamma-butyrobetaine. The Km for carnitine of the carnitine transport mechanism of the soleus muscle was 0.259 mM and of the extensor digitorum longus muscle, 0.585 mM. The greater affinity of the soleus transport mechanism may explain the difference in carnitine transport by red and white muscle in intact animals. A defect in active transport of carnitine may be involved in the pathogenesis of some human myopathies characterized by excessive lipid storage and in diphtheritic cardiomyopathy.

Animal toxicology

Animal toxicology

224 EFFECT OF CARNITINE ON KETONE BODY PRODUCTION IN HUMAN NEWBORNS

The importance of carnitine as an intermediary in fatty acid oxidation in newborn mammals is well recognized. In newborn infants who are maintained on diets which contain no carnitine (i.e. soy protein based formulas) there is a significant decrease in the plasma levels of carnitine and acetylcarnitine compared to plasma levels in infants who are receiving diets which contain carnitine(human breast milk and cow's milk based formulas). The plasma concentration of Δ -hydroxybutyrate is significantly lower in the group of infants maintained on a carnitine free diet;moreover plasma Δ -hydroxybutyrate increases logarithmically with increasing plasma carnitine. There is also a direct correlation between the plasma concentration of acetylcarnitine and Δ -hydroxybutyrate.These results suggest that the absence of dietary carnitine during the newborn period results in a less than optimal concentration of carnitine in liver, indicated by decreased ketone body production, in infants whose plasma concentration of carnitine and acetylcarnitine is low. It is not clear at present whether carnitine is increasing ketone body production by stimulating fatty acid oxidation and producing excess acetyl Co A or if carnitine, after conversion to acetylcarnitine, can participate directly in ketone body production.Supported by NIH grant No. HDO4946.

Metabolism of labeled carnitine in the rat

In two series of rats, the concentration of carnitine in plasma was 39.9 and 37.8 μmol/ liter, in skeletal muscle tissue 2.97 and 3.26 μmol/g dry wt and the urinary excretion 3.2 and 2.4 μmol/24 h. The renal clearance of carnitine was calculated to 88 and 76 ml/24 h. L-[ Me- 14C]Carnitine and DL-[ Me- 14C]carnitine have been administered to rats. Only labeled l-carnitine has been found on chromatographic analysis of plasma, urine, and muscle tissue. The specific radioactivity of carnitine in plasma, urine, and muscle tissue has been followed for up to 16 days. A two-compartment metabolic model has been used to interpret the result of the experiment with labeled l-carnitine and the rate constants and compartment sizes have been calculated. The total body content of carnitine was 57 μmol (about 35 μmol/100 g body wt) and the daily turnover was about 7% of the body pool. The daily synthesis of carnitine in the rat is estimated to about 2 μmol/100 g body wt.

Concentration of carnitine in human muscle tissue

The concentration of acid-soluble carnitine has been determined in human muscle tissue and in plasma. One group of subjects consisted of patients mainly suffering from cholecystolithiasis or varicose veins. Biopsies were surgically obtained under general anesthesia. The other group consisted of normal subjects in which the biopsies were obtained by a percutaneous technique. We could not demonstrate a significant change in concentration of carnitine along a muscle fiber bundle or a difference in the concentration between specimens from superficial and deep levels. The rectus abdominis muscle had a lower carnitine concentration than the muscles of the leg. The median values were 13.7 μmoles/g dry weight (range 7.7–32.5) and 17.9 μmoles/g dry weight (range 6.5–24.1), respectively. Men had slightly higher concentrations in the rectus adbominis muscle than women. Median values were 15.4 μmoles/g dry weight (range 7.7–32.5) and 12.9 μmoles/g dry weight (range 9.8–17.7), respectively. Two subjects from whom biopsies were obtained with an interval of 91 and 42 days showed nearly the same values on both occasions. No correlation was found between age and carnitine concentration in muscle tissue. The carnitine concentration in two biopsies of human heart muscle was 4.2 μmoles/g dry weight and 4.8 μmoles/g dry weight, respectively. The median value of plasma carnitine concentration was 46.2 μmoles/1 (range 17.9–74.7). The concentration of carnitine in plasma was not correlated with the concentration of carnitine in muscle tissue.