In vivo studies of intestinal carnitine absorption in rats

We have studied small intestinal absorption of carnitine in vivo using a combination of segmental perfusion techniques and bolus intraluminal injection. We found evidence of a partially saturable absorption process (with Km values of 1035 and 1267 microM for jejunum and ileum calculated for the saturable component) that appeared to be separate from the imino acid transport system. Absorption was characterized by slow mucosal uptake, prolonged mucosal retention, and a very slow mucosal exit process with blood levels of [3H] carnitine still rising 8 h after intraluminal administration. We have also demonstrated the presence of carnitine acetyltransferase in intestinal mucosa and have shown that the intestine forms significant amounts of acetylcarnitine from exogenous carnitine.     

Metabolic and physiological differences between zero-flow and low-flow myocardial ischemia: effects of L-acetylcarnitine

Summary The metabolic and physiologic differences between low-flow and zero-flow ischemia of varying duration were compared in the isolated perfused rat heart. Hearts subjected to 60 and 90 minutes of zero-flow ischemia recovered less cardiac work than hearts subjected to low-flow ischemia. Low-flow ischemia caused a build-up of both myocardial long-chain acyl coenzyme A and acyl carnitine esters, while zero-flow ischemia produced no change in long-chain acyl carnitine and only a transient increase in long-chain acyl coenzyme A. High energy phosphate depletion was greater in zero-flow ischemia. Perfusion with excess free fatty acids decreased the recovery of cardiac work after low-flow ischemia but had no effect after repeated episodes of zero-flow ischemia. L-Acetylcarnitine improved the recovery of cardiac work after low-flow ischemia in hearts perfused with 0.4 and 1.2 mM palmitate. With zero-flow ischemia, L-acetylcarnitine had no effect on the recovery of cardiac work in hearts perfused with 0.4 mM palmitate and a slight but statistically significant effect with 1.2 mM palmitate. Possible protective mechanisms of L-acetylcarnitine against ischemic damage are discussed.     

The effects of caffeine on the ultrastructure and mitochondrial function of the embryonic chick heart

Results from this study indicate that caffeine (at an embryotoxic dose equal to the LD40 administered to 3-day chick embryos produced both ultrastructural and functional abnormalities in embryonic cardiac mitochondria. The principal effects of caffeine on the ultrastructure of embryonic myocardial cells were clearly suggestive of cellular injury and included: (1) a marked disruption of mitochondrial cristae with formation of intramitochondrial myelin-like figures and (2) intracellular edema. A biochemical analysis of mitochondrial function revealed that caffeine inhibited the capacity of mitochondria to oxidize succinate. However, when pyruvate and malate were employed as substrates for isolated mitochondria, caffeine did not significantly alter mitochondrial function. Interference with embryonic cardiac mitochondrial succinate oxidation and/or fragmentation of mitochondrial membranes are suggested as possible events in the pathogenesis of caffeine-induced cardiac cell injury which, in turn, may lead to the embryonic death of the chick.     

Carnitin-Mangel: Eine behandelbare Ursache kindlicher Kardiomyopathien

Zusammenfassung In diesem Bericht werden 2 Familien vorgestellt, in denen kindlicher Carnitin-Mangel zu Kardiomyopathien führte, die in einem Fall erfolgreich behandelt werden konnten. Symptomatik, Diagnose und Therapie des Carnitin-Mangels werden gemeinsam mit seinen biochemischen Grundlagen diskutiert.Carnitin (CAR), eine 4wertige Ammoniumverbindung, die im Körper aus den Aminosäuren Lysin und Methinonin synthetisiert wird, spielt eine wichtige Rolle in der Fettsäureoxidation. CAR dient als Carrier für den Transport langkettiger Fettsäure-CoA-Ester aus dem Cytoplasma in die Mitochondrien. Daher führt Car-Mangel zu Störungen der mitochondrialen Fettsäureoxidation und der Akkumulation von Lipiden im Cytoplasma. Besonders betroffen ist das Herz, das zur Deckung seines Energiebedarfs in großem Umfang von der Fettsäure-Oxidation abhängig ist.CAR-Mangel kann, je nach dem zugrundeliegenden biochemischen Defekt, in verschiedenen Formen auftreten. Systemischer CAR-Mangel wurde in einer Familie entdeckt, in der 4 von 5 Kindern Kardiomyopathien entwickelten und 3 Kinder vor dem Alter von 3 Jahren plötzlich verstarben. Bei der Autopsie wurde die klinische Diagnose einer Kardiomyopathie in allen Fällen bestätigt. Bei der Autopsie des 5, und jüngsten Kindes wurden außerdem Lipidakkumulation und abnorme Mitochondrien im Herz- und Skelettmuskel nachgewiesen, zusammen mit extrem niedrigen CAR-Spiegeln im Plasma (4,5 mM; normal 50±10 mM), im Skelettmuskel (30,9 nmol/g; normal 5000 nmol/g) und Myokard (56,8 nmol/g; normal 2000 nmol/g). Das überlebende 4. Kind hatte ebenfalls eine schwere congestive Kardiomyopathie und Herzinsuffizienz (NYHA III). Plasma (4,8 mM)-, und Muskel (30,9 nmol/g)-CAR-Spiegel waren extrem niedrig. Durch orale Substitutionstherapie mit L-CAR konnte eine dramatische klinische Besserung erreicht werden. Plasma- und Muskel-CAR-Spiegel stiegen, und die Muskelhistologie besserte sich.Wir schließen aus diesem Verlauf, daß es das Krankheitsbild einer kindlichen Kardiomyopathie, die durch Carnitin-Mangel hervorgerufen wird, gibt. Diese Kardiomyopathie ist durch Lipidakkumulation gekennzeichnet und spricht gut auf CAR-Substitution an. Wir glauben, daß bei allen familiär auftretenden Kardiomyopathien unklarer Genese, besonders wenn Lipidakkumulation nachgewiesen ist, der Plasma-Carnitin-Spiegel gemessen und nötigenfalls eine Substitutionstherapie mit L-Carnitin eingeleitet werden sollte.     

Correlation of serum L-carnitine and dehydro-epiandrosterone sulphate levels with age and sex in healthy adults.

OBJECTIVES: L-carnitine and dehydro-epiandrosterone (DHEA) independently promote mitochondrial energy metabolism. We therefore wondered if an age-related deficiency of L-carnitine or DHEA may account for the declining energy metabolism associated with age. METHODS: we evaluated serum levels of L-carnitine and the sulphated derivative of DHEA (DHEAS) in cross-sectional study of 216 healthy adults, aged 20-95. RESULTS: serum DHEAS levels declined, while total carnitine levels increased with age (P < 0.0001). Total and free carnitine and DHEAS levels were lower in women than men (P < 0.0001). Esterified/free (E/F) carnitine (inversely related to carnitine availability) increased with age in both sexes (P=0.012). CONCLUSION: reduced carnitine availability correlates with the age-related decline of DHEAS levels. These results are consistent with the hypothesis that decreased energy metabolism with age relates to DHEAS levels and carnitine availability.     

Carnitine transport in human intestinal biopsy specimens. Demonstration of an active transport system

Although carnitine is present in a variety of foods, the mechanism of its absorption has not been previously studied in humans. We investigated the absorption of carnitine by studying uptake into human intestinal mucosal biopsy specimens. We found evidence of active transport in the duodenum and ileum, but not in the colon. We demonstrated that intracellular concentrations exceeded concentrations in the incubation media at steady states and that uptake against a concentration gradient was abolished by anoxia and by replacement of sodium ion with potassium. Studies of initial rate of uptake over a range of concentrations revealed a curve consistent with a two-component system: a saturable system with a KT of 558 microM and a linear component probably representing passive diffusion. Addition of D-carnitine and L-acetylcarnitine resulted in diminished uptake of L-carnitine, suggesting that these substrates utilize the same transport mechanism. These studies demonstrate the presence of an active intestinal transport system for L-carnitine in human intestinal mucosa.