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Biomedical subjects

N Siliprandi

Publications and source records attributed to N Siliprandi.

At least 37 records · Page 2Linked to original sources

Influence of L-carnitine administration on maximal physical exercise.

The effects of L-carnitine administration on maximal exercise capacity were studied in a double-blind, cross-over trial on ten moderately trained young men. A quantity of 2 g of L-carnitine or a placebo were administered orally in random order to these subjects 1 h before they began exercise on a cycle ergometer. Exercise intensity was increased by 50-W increments every 3 min until they became exhausted. After 72-h recovery, the same exercise regime was repeated but this time the subjects, who had previously received L-carnitine, were now given the placebo and vice versa. The results showed that at the maximal exercise intensity, treatment with L-carnitine significantly increased both maximal oxygen uptake, and power output. Moreover, at similar exercise intensities in the L-carnitine trial oxygen uptake, carbon dioxide production, pulmonary ventilation and plasma lactate were reduced. It is concluded that under these experimental conditions pretreatment with L-carnitine favoured aerobic processes resulting in a more efficient performance. Possible mechanisms producing this effect are discussed.

Administration, Oral↗

Transport and action of spermine in rat heart mitochondria.

At concentrations of 0.5-1.0 mM, spermine fully prevents the fall of membrane potential induced in rat heart mitochondria either by aging at room temperature or by the addition of palmitoyl CoA. Spermine also prevents the inhibitory action of palmitoyl CoA on adenylate translocase activity. When added to heart mitochondria de-energized by the same damaging conditions (aging or addition of palmitoyl CoA) spermine restores both membrane potential (provided that ATP is also added) and the activity of adenylate translocase. A part of added spermine is immediately bound to anionic sites on mitochondrial membranes, another part is slowly transported into heart mitochondria. Whereas binding is an energy independent process, transport is driven by the transmembrane potential. Spermine penetrates the mitochondrial matrix at significant rates only at high membrane potential, such as that produced either by phosphate transport or addition of nigericin.

Adenosine Triphosphate↗

Transport and functions of carnitine in muscles.

The transport, function and metabolism of carnitine are discussed with regard to their importance in clinical chemistry. In humans carnitine is synthesized from protein-derived trimethyllysine in liver, brain and kidney. Muscles take up carnitine from the blood in an exchange-diffusion process with endogenous deoxycarnitine, the immediate precursor of carnitine. Besides catalysing the transport of long-chain acyl groups in mitochondria, carnitine is necessary for the export of intramitochondrially produced short-chain acyl residues and for the trapping and the elimination of unphysiological compounds (benzoic, pivalic, valproic acids etc.). The detection and quantitation in urine of these physiological and unphysiological carnitine esters is necessary for the diagnosis of carnitine deficiencies. The carnitine esters may be eliminated in the urine and/or distributed in tissues, where some of them (acetyl-, propionyl- and isovaleryl-carnitine) may be utilized for specific purposes. The most important carnitine-dependent metabolic disorders are listed according to their causes.

Animals↗

Carnitine: metabolism and clinical chemistry.

In man carnitine is synthesized from proteic trimethyllysine in liver, brain and kidney. Muscles which contain approximately 98% of carnitine must take it up from the blood in an exchange process with endogenous deoxycarnitine, the immediate precursor of carnitine. Uneven organ distribution of the enzymes catalyzing carnitine synthesis further implies an inter-organ transport of the intermediates. Assay of these intermediates in blood may assist causal definition of carnitine deficiency syndromes. Besides catalyzing the transport of long-chain acyls in mitochondria, carnitine is necessary for the export of intra-mitochondrially produced short-chain acyls and for trapping and elimination of unphysiological acyls (benzoic, pivalic, valproic acids etc.). Unlike the corresponding acyl-CoA, carnitine esters are capable of diffusing across cellular membranes, and may be eliminated in urine, distributed in tissues or both. Assay of physiological and unphysiological carnitine esters in urine is necessary for the diagnosis of carnitine insufficiencies.

Biological Transport↗

Ca2+-mediated action of long-chain acyl-CoA on liver mitochondria energy-linked processes.

The decrease of steady-state transmembrane potential (delta psi) and loss of accumulated Ca2+ are magnified if palmitoyl-CoA is added to rat liver mitochondria exposed to Ca2+ and phosphate. The extent of this damage increases with increasing concentration of long-chain acyl-CoA. Addition of L-carnitine with or without the addition of palmitoyl-CoA considerably delays the deenergization. In the latter case, there is a substantial decrease in the assayed endogenous long-chain acyl-CoA content. This protective action of L-carnitine is abolished by L-aminocarnitine, a powerful inhibitor of carnitine palmitoyl transferase (palmitoyl-CoA: L-carnitine O-palmitoyltransferase, EC 2.3.1.21.). The removal of Ca2+ by EGTA, or the inhibition of its uptake by Ruthenium red or Mg2+ further enhances the degree of protection.

Acyl Coenzyme A↗

Inhibitory action of isovaleryl-L-carnitine on proteolysis in perfused rat liver.

Isovaleryl-l-carnitine inhibits the proteolysis induced by amino acid deprivation in the perfused rat liver to an extent equivalent, or, below 0.4 mM, even greater than that previously found for 1-leucine (Ref. 1). Also the typical concentration-response curve previously found for leucine (Ref. 1) is mimicked by isovaleryl-l-carnitine. The maximum inhibition (approximately 50% of the control) occurred for both l-leucine and isovaleryl-l-carnitine above 0.8 mM. Only at these high concentrations also 1-carnitine and isobutyryl-l-carnitine exhibit a significant, albeit lower, degree of inhibition. The possible mechanism of this proteolysis inhibition is discussed.

Animals↗

Changes in mitochondrial activity caused by ammonium salts and the protective effect of carnitine.

Ammonium salts added to isolated rat liver mitochondria deviate alpha-ketoglutarate to glutamate synthesis, thus decreasing its availability as respiratory substrate. As a consequence a decrease of respiratory rate is observed which is paralleled by progressive mitochondrial swelling. It was demonstrated that L-carnitine may abolish this swelling thus improving structural and metabolic state of mitochondria.

Acetates↗

High doses of L-carnitine in acute myocardial infarction: metabolic and antiarrhythmic effects.

Fatty acids accumulate in the muscle cells in some carnitine deficiency syndromes due to a variety of genetic defects in intermediary metabolism. L-Carnitine administration may relieve this excess by transporting acyl compounds out of the cell as acylcarnitine. Similar fatty acid accumulation occurs during myocardial ischaemia because of the decreased rate of beta-oxidation, and this has been put forward as a cause of ventricular arrhythmias. This study was carried out to investigate whether administration of high doses of i.v. L-carnitine in patients with acute myocardial infarction could increase urinary excretion of acylcarnitine and reduce early ventricular arrhythmias. Fifty-six patients suffering from acute myocardial infarction, admitted to the Coronary Unit between 3 and 12 h after the onset of symptoms, were included in the study. The design of the study was double blind, parallel and placebo controlled. Allocation of treatment to patients was done randomly after stratification (time from onset of pain and site of infarction). The first group (28 patients) received intravenous L-carnitine at a dose of 100 mg kg-1 b.w. every 12 h for 36 h while the second group (28 patients) received placebo intravenously. Immediately before starting treatment two blood samples were taken (at 5-min intervals) and a further 16 samples were taken at regular intervals over the following 48 h. Patients' urine was collected over the same period of time. Concentrations of free carnitine, short chain acylcarnitine esters and long chain acylcarnitine esters in serum and urine were measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

Effect of L-carnitine and L-aminocarnitine on calcium transport, motility, and enzyme release from ejaculated bovine spermatozoa.

Experiments were performed to further elucidate the role of gamma-amino-beta-hydroxybutyric acid trimethylbetaine (carnitine) on the metabolism and functions of spermatozoa. Addition of 20 mM L-carnitine to suspensions of ejaculated bovine spermatozoa resulted in an increase of cellular calcium transport, whereas 20 mM L-aminocarnitine (an inhibitor of carnitine palmitoyltransferase) caused an inhibition of this process. Both L-carnitine and L-aminocarnitine inhibited the progressive motility of spermatozoa, and the oxygen consumption as well as the release of the enzymes hyaluronidase and glutamate-oxaloacetate transaminase from spermatozoa. Labeled carnitine was rapidly taken up by spermatozoa by a process strongly dependent on temperature and extracellular concentration of carnitine. It is concluded that the effects produced by high concentrations of carnitine or aminocarnitine are mainly due to interactions of these compounds with the cellular membranes of spermatozoa.

Acyltransferases↗

On the mechanism of spermine transport in liver mitochondria.

Spermine penetrates the mitochondrial matrix at significant rates which increase sharply and non-ohmically with membrane potential. In this respect, spermine uptake is qualitatively similar to that of other cations whose electrophoretic transport has been studied in mitochondria. At 200 mV and 1 mM spermine, the observed rate of spermine uptake was about 7 nmol x mg-1 x min-1, and the rate constant was about 8 times greater than that of tetraethylammonium cation. These rates are remarkably rapid considering that spermine is largely tetravalent at the pH of the experiment. The fluxes of spermine and tetraethylammonium are log-linear with membrane potential. The slope of the tetraethylammonium plot is consistent with leakage of this ion across a sharp Eyring barrier located in the middle of the membrane. The slope of the spermine plot is half that predicted by such a leak pathway, raising the possibility that spermine may cross the inner membrane by means of a channel. Whatever its mechanism of penetration, if comparable rates of uptake obtain in vivo and if spermine is not metabolized within the mitochondrial matrix, then a separate efflux mechanism would appear to be required to prevent unlimited spermine loading.

Animals↗

Protective action of methylglyoxal bis (guanylhydrazone) on the mitochondrial membrane.

At low concentrations (0.5-1.0 mM) methylglyoxal bis (guanylhydrazone) (MGBG) exhibited a clearcut protection of rat liver mitochondria against the deenergizing action of either Ca2+, or oxidizing agents (butylhydroperoxide and oxaloacetate). Such a protection resulted from the prevention of transmembrane potential decay, discharge of accumulated Ca2+, release of mitochondrial Mg2+, adenine nucleotides and pyridine nucleotides and mitochondrial swelling. At high concentrations (5-10 mM) MGBG induced functional alterations of mitochondria (decrease of transmembrane potential, lower capability to accumulate and to retain Ca2+) which can be reversed by resuspension of mitochondria in a MGBG free medium. These reversible mitochondrial alterations by high MGBG concentrations are interpreted as a consequence of an aggregation and coprecipitation of suspended mitochondria.

Adenosine Triphosphate↗

Effect of L-carnitine on ethanol and acetate plasma levels after oral administration of ethanol in humans.

In a randomized double-blind, cross-over experiment, 0.5 g/kg of ethanol in the form of white wine and 3 g of L-carnitine by intravenous infusion were administered to 15 healthy volunteers. Ethanol and acetate plasma levels and the urine concentrations of acetylcarnitine were determined. Administration of ethanol induced a significant increase of both plasma ethanol and acetate, lasting 6-8 hr. The concomitant administration of carnitine resulted in a significant decrease of plasma acetate, whereas plasma ethanol levels remained unmodified. Urinary acetylcarnitine content significantly increased following administration of ethanol plus carnitine, but not when L-carnitine alone was administered. The resulting conclusion is that administered L-carnitine might trap excess acetyls derived both from free acetate, formed by ethanol oxidation, and from acetyl coenzyme A, accumulated as a result of the ethanol-induced decrease in the Krebs cycle flux.

Acetates↗

Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study.

A double-blind, cross-over study was designed to evaluate the effects of L-carnitine in patients with peripheral vascular disease. After drug washout, 20 patients were randomly assigned to receive placebo or L-carnitine (2 g bid, orally) for a period of 3 weeks and were then crossed over to the other treatment for an additional 3 weeks. The effect on walking distance at the end of each treatment period was measured by treadmill test. Absolute walking distance rose from 174 +/- 63 m with placebo to 306 +/- 122 m (p less than .01) with carnitine. Biopsy of the ischemic muscle, carried out before and after 15 days of L-carnitine administration in four additional patients, showed that treatment significantly increased total carnitine levels. An additional goal of this study was to ascertain the effects of L-carnitine on the metabolic changes induced by exercise in the affected limb. In six patients under control conditions, arterial and popliteal venous lactate and pyruvate concentrations were determined at rest, when the maximal walking distance was reached, and 5 min after the walking test. Twenty-four hours later, L-carnitine was administered intravenously (3 g as a bolus followed by an infusion of 2 mg/kg/min for 30 min) and metabolic assessments were repeated. Five minutes after the walking test, popliteal venous lactate concentration increased by 107 +/- 16% before treatment and by only 54 +/- 32% (p less than .01) after carnitine. Furthermore, carnitine induced a more rapid recovery to the resting value of the lactate/pyruvate ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Carnitine↗

Isovalerylcarnitine is a specific activator of calpain of human neutrophils.

Isovalerylcarnitine (IVC) a product of the catabolism of L-leucine, is a potent activator of the Ca2+-dependent proteinase (calpain) of human neutrophils. At concentrations of Ca2+ in the low micromolar range, activation was 12 to 15-fold, and the activity exceeded that observed with millimolar concentrations of Ca2+ in the absence of the activator. Of the acylcarnitine derivatives tested, IVC was most active; D-isovalerylcarnitine was much less effective and palmitylcarnitine was ineffective. IVC did not increase the activity of calpain that was fully activated by an endogenous cytoskeleton-associated activator protein, but at low concentrations of the latter synergistic effects of the two activators were observed. Activation of neutrophil calpain by IVC is fully reversible. Inhibition by calpastatin was also reversed by IVC.

Calcium↗

Myocardial carnitine transport.

In mammals, carnitine is synthesized from proteic trimethyllysine in the liver, brain and (in human) kidneys. The hydroxylase catalyzing the last step (deoxycarnitine----carnitine) is missing in the remaining tissues, which are thus entirely dependent on carnitine uptake from the blood. On the basis of experimental evidence, or reasonable assumptions, an interorgan transport of carnitine, carnitine precursors and derivatives is described. In particular, evidence demonstrating a bidirectional exchange between carnitine and deoxycarnitine across cardiac sarcolemma have been provided both in vitro and in vivo experiments. It has been demonstrated that in heart slices carnitine-deoxycarnitine exchange, occurring in a close one to one ratio, is (i) insensitive to both glycolysis and oxidative phosphorylation inhibitors and (ii) sensitive to thiol reagents, such as NEM and Mersalyl. It is assumed that deoxycarnitine is released from muscles into the blood, taken up by the liver, or kidneys, to be hydroxylated to carnitine and the latter returned to the muscles. In vivo evidence for carnitine-deoxycarnitine exchange has been obtained by administering carnitine, or deoxycarnitine, to rats and measuring deoxycarnitine and carnitine, respectively, in different tissues and urine. The results clearly indicate that carnitine administration displaces endogenous deoxycarnitine from tissues and vice versa, thus further supporting the existence of a carnitine-deoxycarnitine exchange process.

Animals↗