Cardiomegaly in the juvenile visceral steatosis (JVS) mouse is reduced with acute elevation of heart short-chain acyl-carnitine level after L-carnitine injection

The long-term administration of L-carnitine was very effective in preventing cardiomegaly in juvenile visceral steatosis (JVS) mice, which was confirmed by heart weight as well as the lipid contents in heart tissue. After i.p. injection of L-carnitine, the concentration of free carnitine in heart remained constant, although serum free carnitine level increased up to 80-fold. On the other hand, a significant increase in short-chain acyl-carnitine level in heart was observed. These results suggest that increased levels of short-chain acyl-carnitine, not free carnitine, might be a key compound in the protective effect of L-carnitine administration in JVS mice.     

Lack of effect of oral L-carnitine treatment on lipid metabolism and cardiac function in chronically diabetic rats

L-Carnitine is necessary for the transfer of long-chain fatty acids into the mitochondrial matrix where energy production occurs. In the absence of L-carnitine, the accumulation of free fatty acids and related intermediates could produce myocardial subcellular alterations and cardiac dysfunction. Diabetic hearts have a deficiency in the total carnitine pool and develop cardiac dysfunction. This suggested that carnitine therapy may ameliorate alteration in cardiac contractile performance seen during diabetes. In this study, heart function was studied in streptozotocin diabetic rats given L-carnitine orally. Oral L-carnitine treatment (50-250 mg.kg-1.day-1) of 1- and 3-week diabetic rats increased plasma free and total carnitine and decreased plasma acyl carnitine levels. In both groups, myocardial total carnitine levels were increased. However, L-carnitine (200 mg.kg-1.day-1) treatment of diabetic rats for 6 weeks had no effect on plasma carnitine levels. Similarly, plasma lipids remained elevated whereas cardiac function was still depressed. These studies suggest that in the chronically diabetic rat, the route of administration of L-carnitine is an important factor in determining an effect.     

Tissue specific depletion of L-carnitine in rat heart and skeletal muscle by D-carnitine

L-carnitine deficiency in heart and skeletal muscle was induced by intraperitoneal injection of D-carnitine into starved or fed rats. Carnitine levels in kidney were slightly lowered, but liver, brain and plasma were unaffected. L-carnitine deficient hearts were unable to maintain normal cardiac function when perfused in an isolated working heart apparatus with palmitate as the only perfused substrate. These findings indicate that tissue levels of carnitine in heart and skeletal muscle are maintained $\text{in vivo}$ by an exchange transport mechanism. It is postulated that the depletion of L-carnitine from these tissues occurs by an exchange of the D- and L-isomer across the cell membrane. The technique may be useful for estimating the levels of carnitine required for fatty acid oxidation and normal cardiac and skeletal muscle function; however, interpretation of such tests may be complicated by the inhibitory effects of the D-isomer upon carnitine transferase enzymes.     

In vivo and in vitro intervention with L-carnitine prevents abnormal energy metabolism in isolated diabetic rat heart: chemical and phosphorus-31 NMR evidence

The beneficial effects of in vivo injections (200 mg/kg, twice daily) or in vitro perfusion (5.0 mM) of L-carnitine on an intrinsic abnormality in energy metabolism was investigated in isolated, perfused diabetic rat heart. Hearts were aerobically perfused for 60 min with elevated fatty acid substrate to simulate diabetic conditions. Phosphorus-31 nuclear magnetic resonance spectroscopy revealed a temporal decline in myocardial ATP levels (to approx 82%) during perfusion of diabetic hearts, but not in control hearts. This reduction was prevented by prior treatment in vivo with L-carnitine or by providing L-carnitine acutely in the perfusion medium. Chemical analysis of tissue extracts indicated that L-carnitine injections were effective in replenishing the decrease in total myocardial carnitine content which was present in diabetic hearts and in preventing the accumulation of long chain fatty acyl CoA. Perfusion with L-carnitine also attenuated the elevation of long chain fatty acyl CoA in diabetic hearts. This study gives additional support to the hypothesis that decreases in ATP which occur in the isolated, perfused diabetic heart are correlated with a concomitant elevation in long chain fatty acyl CoA, a known inhibitor of adenine nucleotide translocase. In the presence of elevated exogenous fatty acids, a primary deficiency in the total myocardial carnitine pool would result in elevations in tissue concentrations of long chain fatty acyl CoA since carnitine is a required carrier for transport of fatty acids into mitochondria. Replenishment of the carnitine in vivo was shown to be sufficient to prevent subsequent alteration in long chain fatty acyl CoA and ATP in isolated perfused diabetic hearts despite the burden of elevated fatty acid substrates.     

Carnitine and deoxycarnitine concentration in rat tissues and urine after their administration

Administration of L-carnitine to rats was followed by an increase of deoxycarnitine in urine. Conversely, administration of deoxycarnitine caused an increase of carnitine. The latter treatment also produced a transient but significant diminution of L-carnitine in heart, skeletal muscle and kidney, but not in liver and plasma. Administration of D-carnitine to rats previously loaded with deoxycarnitine significantly depleted the elevated deoxycarnitine concentration in skeletal muscle and kidney while increasing it in plasma. These results suggest that the tissue exchange between L-carnitine and deoxycarnitine, already demonstrated in vitro, occurs also in vivo.     

Metabolic changes induced by maximal exercise in human subjects following L-carnitine administration

In double-blind cross-over experiments, ten moderately trained male subjects were submitted to two bouts of maximal cycle ergometer exercise separated by a 3 day interval. Each subject was randomly given either L-carnitine (2 g) or placebo orally 1 h before the beginning of each exercise session. At rest L-carnitine supplementation resulted in an increase of plasma-free carnitine without a change in acid-soluble carnitine esters. Treatment with L-carnitine induced a significant post-exercise decrease of plasma lactate and pyruvate and a concurrent increase of acetylcarnitine. The determination of the individual carnitine esters in urine collected for 24 h after the placebo exercise trial revealed a decrease of acetyl carnitine and a parallel increase of a C4 carnitine ester, probably isobutyrylcarnitine. Conversely, acetylcarnitine was strongly increased and C4 compounds were almost suppressed in the L-carnitine loading trial. These results suggest that L-carnitine administration prior to high-intensity exercise stimulates pyruvate dehydrogenase activity, thus diverting pyruvate from lactate to acetylcarnitine formation.     

Effect of malonyl-CoA on the kinetics and substrate cooperativity of membrane-bound carnitine palmitoyltransferase of rat heart mitochondria

The effect of malonyl-CoA on the kinetic parameters of carnitine palmitoyltransferase (outer) the outer form of carnitine palmitoyltransferase (palmitoyl-CoA: L-carnitine O-palmitoyltransferase, EC 2.3.1.21) from rat heart mitochondria was investigated using a kinetic analyzer in the absence of bovine serum albumin with non-swelling conditions and decanoyl-CoA as the cosubstrate. The K0.5 for decanoyl-CoA is 3 microM for heart mitochondria from both fed and fasted rats. Membrane-bound carnitine palmitoyltransferase (outer) shows substrate cooperativity for both carnitine and acyl-CoA, similar to that exhibited by the enzyme purified from bovine heart mitochondria. The Hill coefficient for decanoyl-CoA varied from 1.5 to 2.0, depending on the method of assay and the preparation of mitochondria. Malonyl-CoA increased the K0.5 for decanoyl-CoA with no apparent increase in sigmoidicity or Vmax. With 20 microM malonyl-CoA and a Hill coefficient of n = 2.1, the K0.5 for decanoyl-CoA increased to 185 microM. Carnitine palmitoyltransferase (outer) from fed rats had an apparent Ki for malonyl-CoA of 0.3 microM, while that from 48-h-fasted rats was 2.5 microM. The kinetics with L-carnitine were variable: for different preparations of mitochondria, the K0.5 ranged from 0.2 to 0.7 mM and the Hill coefficient varied from 1.2 to 1.8. When an isotope forward assay was used to determine the effect of malonyl-CoA on carnitine palmitoyltransferase (outer) activity of heart mitochondria from fed and fasted animals, the difference was much less than that obtained using a continuous rate assay. Carnitine palmitoyltransferase (outer) was less sensitive to malonyl-CoA at low compared to high carnitine concentrations, particularly with mitochondria from fasted animals. The data show that carnitine palmitoyltransferase (outer) exhibits substrate cooperativity for both acyl-CoA and L-carnitine in its native state. The data show that membrane-bound carnitine palmitoyltransferase (outer) like carnitine palmitoyltransferase purified from heart mitochondria exhibits substrate cooperativity indicative of allosteric enzymes and indicate that malonyl-CoA acts like a negative allosteric modifier by shifting the acyl-CoA saturation to the right. A slow form of membrane-bound carnitine palmitoyltransferase (outer) was not detected, and thus, like purified carnitine palmitoyltransferase, substrate-induced hysteretic behavior is not the cause of the positive substrate cooperativity.     

Effects of L-carnitine on mechanical recovery of isolated rat hearts in relation to the perfusion with glucose and palmitate

The purpose of this study was to investigate the effects of L-carnitine on the hemodynamic parameters of Langendorff hearts. Isolated rat hearts were perfused with various solutions containing high or low concentrations of fatty acids, additional glucose or no glucose, and L-carnitine or no L-carnitine. The most interesting part of the experiments was the behaviour of the hearts in the reperfusion period after no-flow ischemia of 20 min. The results were: (1) With glucose and high fatty acid concentrations the hearts showed an improved recovery of the left ventricular functions in the reperfusion period compared with low fatty acid concentrations. Without glucose the left ventricular pressure is much lower in the reperfusion period. (2) Addition of L-carnitine improved the recovery of the ischemically damaged hearts. This improvement is especially impressive at low fatty acid concentrations. L-carnitine addition at high fatty acid concentrations but without glucose strongly improved reperfusion behaviour. (3) The coronary flow is increased by 2 experimental conditions: (i) perfusion at low levels of fatty acids, carnitine and with glucose and (ii) high levels of fatty acids and carnitine but without glucose. These findings suggest that supplementation of L-carnitine has a beneficial effect on the isolated heart under various conditions, and possibly on specific human heart diseases.     

Plasma carnitine levels as a marker of impaired left ventricular functions

L-Carnitine plays a role in the utilization of fatty acids and glucose in the myocardium. Previous studies have indicated carnitine deficiency in patients with congestive heart failure. However, the extent of altered carnitine metabolism and left ventricular function is not fully determined. This study is designed to determine if plasma L-carnitine levels can serve as a marker for impaired left ventricular function in patients with congestive heart failure.To test this hypothesis, plasma and urinary levels of L-carnitine were measured in 30 patients with congestive heart failure (CHF) and in 10 control subjects. CHF was due to dilated cardiomyopathy (DCM) and rheumatic heart disease (RHD). Cardiac functions such as percentage of fractional shortening (%FS), ejection fraction (EF), left ventricular mass index (LVMI), were determined by echocardiography. All patients and control subjects had normal renal functions.Plasma carnitine was significantly higher in patients with DCM (37.05 ± 7.62, p < 0.0001) and with RHD (47.2 ± 8.04, p < 0.0001) vs. the control subjects (14.4 ± 5.30 mg/L). Urinary carnitine was significantly higher in DCM (49.13 ± 14.11, p < 0.0001) and in RHD 43.53 ± 15.5, p < 0.0001), than the control (25.1 ± 5.78 mg/L). Plasma carnitine level correlated significantly with impaired left ventricular systolic functions in these patients: %FS < 25% (r = -0.38 and p = 0.038), EF < 0.55 (r = -0.502 and p = 0.005) and LMVI > 124 gm/m² (r = 0.436, and p = 0.016). These data suggest that elevated plasma and urinary carnitine levels in patients with CHF could serve as a marker for myocardial damage and impaired left ventricular functions.     

Absorption of D- and L-carnitine by the intestine and kidney tubule in the rat

The process by which L- and D-carnitine are absorbed was investigated using the live rat and the isolated vascularly perfused intestine. A lumenal dose of 2-6 nmol in the perfused intestine resulted in less than 5% transport of either isomer to the perfusate in 30 min. The L-isomer was taken up by the intestinal tissue about twice as rapidly as the D-isomer by both the perfused intestine (52.8% and 21.6%, respectively) and the live animal (80% and 50%, respectively) in 30 min. After 1 h 90% of the L-carnitine had accumulated in the intestinal tissue and was released to the circulation over the next several hours. Accumulation of D-carnitine reached a maximum of 80% in 2 h and release to the circulations was similar to that of L-carnitine. Uptake of both L-[14C]carnitine and acetyl-L-[14C]carnitine was more rapid in the upper jejunal segment than in other portions of the small intestine. Acetylation occurred in all segments, resulting in nearly 50% conversion to this derivative in 5 min. Increasing the dose of L-carnitine reduced the percent acetylation. The uptake of both isomers was a saturable process and high concentrations of D-carnitine, acetyl-L-carnitine and trimethylaminobutyrate inhibited L-carnitine uptake. In the live animal after 5 h, the distribution of isotope from L-[14C]carnitine and D-[3H]carnitine differed primarily in the muscle where 29.5% of the L-carnitine and 5.3% of the D-carnitine was found and in the urine where 2.9% of the L-carnitine and 7.1% of the D-carnitine was found. The renal threshold for L-carnitine was 80 microM and for D-carnitine 30 microM, in the isolated perfused kidney. Approx. 40% of the L-carnitine but none of the D-carnitine excreted in the urine was acetylated. L-Carnitine and D-carnitine competed for tubular reabsorption.     

Respiratory chain enzymes in muscle of endurance athletes: effect of L-carnitine.

The effects of L-carnitine on respiratory chain enzymes in muscle of long distance runners were studied in 14 athletes. These subjects received placebo or L-carnitine (2 g orally b.i.d.) during a 4-week period of training. Athletes receiving L-carnitine showed a significant increase (p < 0.01) in the activities of rotenone-sensitive NADH cytochrome c reductase, succinate cytochrome c reductase and cytochrome oxidase. In contrast, succinate dehydrogenase and citrate synthase were unchanged. No significant changes were observed after placebo administration. The levels of both total and free carnitine from athletes receiving placebo were significantly decreased (p < 0.01) after treatment. By contrast, total and free carnitine levels were markedly increased (p < 0.01) after supplementation with L-carnitine. Our results suggest that L-carnitine induces an increase of the respiratory chain enzyme activities in muscle, probably by mechanisms involving mitochondrial DNA.     

The effect of oral L-carnitine supplementation on the muscle and plasma concentrations in the Thoroughbred horse

1. L-carnitine was administered orally to thoroughbred horses for 58 days. 2. Acceptability and effects on plasma, muscle and urine concentration were studied. 3. Ten-60 g/day (as 2-3 doses) was acceptable with no deleterious effects. 4. One x 10 g L-carnitine significantly raised the plasma-free carnitine concentration (7 hr post) from 21.2 to 31.8 mumol/l; 2 x 30 g increased the mean to 36.5 mumol/l. 5. Plasma acetylcarnitine increased from approximately 1 to 5.5 mumol/l (7 hr post) on 2 x 30 g/day. 6. Muscle total carnitine was unchanged over 58 days. 7. Urinary output accounted for 3.5-7.5% of added carnitine, indicating low intestinal absorption.     

Interacting effects of L-carnitine and malonyl-CoA on rat liver carnitine palmitoyltransferase.

Malonyl-CoA significantly increased the Km for L-carnitine of overt carnitine palmitoyltransferase in liver mitochondria from fed rats. This effect was observed when the molar palmitoyl-CoA/albumin concentration ratio was low (0.125-1.0), but not when it was higher (2.0). In the absence of malonyl-CoA, the Km for L-carnitine increased with increasing palmitoyl-CoA/albumin ratios. Malonyl-CoA did not increase the Km for L-carnitine in liver mitochondria from 24h-starved rats or in heart mitochondria from fed animals. The Km for L-carnitine of the latent form of carnitine palmitoyltransferase was 3-4 times that for the overt form of the enzyme. At low ratios of palmitoyl-CoA/albumin (0.5), the concentration of malonyl-CoA causing a 50% inhibition of overt carnitine palmitoyltransferase activity was decreased by 30% when assays with liver mitochondria from fed rats were performed at 100 microM-instead of 400 microM-carnitine. Such a decrease was not observed with liver mitochondria from starved animals. L-Carnitine displaced [14C]malonyl-CoA from liver mitochondrial binding sites. D-Carnitine was without effect. L-Carnitine did not displace [14C]malonyl-CoA from heart mitochondria. It is concluded that, under appropriate conditions, malonyl-CoA may decrease the effectiveness of L-carnitine as a substrate for the enzyme and that L-carnitine may decrease the effectiveness of malonyl-CoA to regulate the enzyme.     

Characteristics of L-carnitine import into heart cells

L-carnitine is an essential cofactor for the transport of fatty acids across the mitochondrial membranes. L-carnitine can be provided by food products or biosynthesized in the liver. After intestinal absorption or hepatic biosynthesis, L-carnitine is transferred to organs whose metabolism is dependent upon fatty acid oxidation, such as the skeletal muscle and the heart. The intracellular transport of L-carnitine into the cell requires specific transporters and today, several of these have been characterized. Most of them belong to the solute carrier family. Heart is one of the major target for carnitine transport and use, however basic properties of carnitine uptake by heart cells have never been studied. In this paper, the transport of L-carnitine by rat heart explants has been examined and the kinetic properties of this transport determined and compared to data obtained in skeletal muscle explants. As in muscle, L-carnitine uptake by heart cells was shown to be dependent on sodium and was inhibited by L-carnitine analogues. Molecules known to interact with the skeletal muscle L-carnitine transport were studied in the heart. While trimethyl hydrazinium propionate (THP) was shown to fully inhibit the L-carnitine uptake by muscle cells, it remained inefficient in inhibiting the L-carnitine uptake by heart cells. On the other hand, compounds such as verapamil and AZT were both able to inhibit both the skeletal muscle and the cardiac uptake of L-carnitine. These data suggested that the muscle and heart systems for L-carnitine uptake exhibited different systems of regulation and these results have to be taken in consideration while administrating those compounds that can alter l-carnitine uptake in the muscle and the heart and can lead to damage to these tissues.     

Sigmoid kinetics of purified beef heart mitochondrial carnitine palmitoyltransferase. Effect of pH and malonyl-CoA

The kinetics of purified beef heart mitochondrial carnitine palmitoyltransferase have been extensively investigated with a semiautomated system and the computer program TANKIN and shown to be sigmoidal with both acyl-CoA and L-carnitine. In contrast, Michaelis-Menten kinetics were found with carnitine octanoyltransferase. The catalytic activity of carnitine palmitoyltransferase is strongly pH dependent. The K0.5 and Vmax are both greater at lower pH. The K0.5 for palmitoyl-CoA is 1.9 and 24.2 microM at pH 8 and 6, respectively. The K0.5 for L-carnitine is 0.2 and 2.9 mM at pH 8 and 6, respectively. Malonyl-CoA (20-600 microM) had no effect on the kinetic parameters for palmitoyl-CoA at both saturating and subsaturating levels of L-carnitine. We conclude that malonyl-CoA is not a competitive inhibitor of carnitine palmitoyltransferase. The purified enzyme contained 18.9 mol of bound phospholipid/mol of enzyme which were identified as cardiolipin, phosphatidylethanolamine, and phosphatidylcholine by thin-layer chromatography. The data are consistent with the conclusion that native carnitine palmitoyltransferase exhibits different catalytic properties on either side of the inner membrane of mitochondria due to its non-Michaelis-Menten kinetic behavior, which can be affected by pH differences and differences in membrane environment.     

Effects of SM-20550, a selective Na+-H+ exchange inhibitor,on the ion transport of myocardial mitochondria

The study investigated the influence of L-carnitine on the formation of malondialdehyde, an indicator of lipid peroxidation, in isolated Langendorff rat hearts. Earlier investigations of hemodynamic parameters and the recovery of ATP and creatine phosphate, carried out by means of ³¹P-NMR spectroscopy, had demonstrated that, depending on the composition of the perfusates (content of glucose, fatty acids, and carnitine), quite strong differences may occur in the reperfusion period after ischemia.In order to determine a possible relationship between these differences and the addition of carnitine, the study investigated whether carnitine penetrated into the tissue during the experiments, and whether it was able to reduce the concentration of detrimental substances. The concentrations of free and total carnitine as well as the malondialdehyde content as an indicator of ischemia/reperfusion damage were determined in different parts of the cardiac tissue as follows: After the Langendorff-experiments the hearts were dissected, homogenized and reconditioned; then carnitine and malondialdehyde were determined. The study included 63 hearts, which were divided into 8 different perfusion groups.Carnitine concentrations in heart tissue perfused with L-carnitine were much higher than those of the controls. Since exogenous L-carnitine and formed esters could be found in the tissue after the experiment, they must have permeated the cellular membrane rapidly. The concentrations of malondialdehyde behaved in an inverted way; as expected they were lower in carnitine-perfused hearts. The favourable effects of L-carnitine, expressed both by improved cardiac dynamics and ATP and CrP recovery in the reperfusion period, are obviously due to the fact that L-carnitine reduces ischemic damage.     

L-Carnitine dissimilation in the gastrointestinal tract of the rat

Results of previous studies in this laboratory and others have suggested that L-carnitine is degraded in the gastrointestinal tract of the rat, perhaps by the action of indigenous flora. L-[methyl-14C]Carnitine was administered to rats either orally or intravenously in doses of 86 nmol or 124 mumol, and expired air, 48-h urine and fecal collections, and selected tissues at 48 h after isotope administration were examined for radiolabeled carnitine and metabolites. Urine and feces of rats receiving oral L-[methyl-14C]carnitine consistently contained two radiolabeled metabolites which were identified as trimethylamine N-oxide (primarily in urine) and gamma-butyrobetaine (primarily in feces). In these rats, these metabolites accounted for up to 23% and 31% of the administered dose, respectively. By contrast, for rats receiving intravenous L-[methyl-14C]carnitine or germ-free rats receiving the isotope orally or intravenously, virtually all of the radioactivity recovered was in the form of carnitine. Analyses for 14CO2 and [14C]trimethylamine in expired air revealed little or no (less than 0.1% of dose) conversion to these compounds, regardless of size of dose or route of administration. Results of this study demonstrate conclusively that L-carnitine is degraded in the gastrointestinal tract of the rat and that indigenous flora are responsible for these transformations.     

The influence of diet and carnitine supplementation on plasma carnitine, cholesterol and triglyceride in WHHL (Watanabe-heritable hyperlipidemic), Netherland dwarf and New Zealand rabbits (Oryctolagus cuniculus)

1. Plasma carnitine levels in the spontaneously (endogenously) hyperlipidemic Watanabe (WHHL) rabbit are approximately 2-fold higher (P less than 0.001) than in normal rabbits of the New Zealand (NZ) or Netherland Dwarf (NDw) breeds. 2. Plasma carnitine levels in WHHL (44 +/- 3 nmol/ml) can be approximated in NZ and NDw which are rendered exogenously hyperlipidemic by supplementation of the stock chow diet with cholesterol and peanut oil. 3. The induction of endogenous hyperlipidemia in NZ by feeding a sucrose casein rich diet results in a biphasic response of plasma carnitine (elevation followed by normalization). 4. Plasma carnitine in WHHL is readily elevated by supplemental L-carnitine and the elevation is associated with a reduction in plasma triglyceride which shows differences in individual response time; plasma cholesterol is unaffected by supplemental L-carnitine.     

Fatty acid oxidation and related gene expression in heart depleted of carnitine by mildronate treatment in the rat

The metabolic and genic effects induced by a 20-fold lowering of carnitine content in the heart were studied in mildronate-treated rats. In the perfused heart, the proportion of palmitate taken up then oxidized was 5-10% lower, while the triacylglycerol (TAG) formation was 100% greater than in controls. The treatment was shown to increase the maximal capacity of heart homogenates to oxidize palmitate, the mRNA level of carnitine palmitoyltransferase I (CPT-I) isoforms, the specific activity of CPT-I in subsarcolemmal mitochondria and the total carnitine content of isolated mitochondria. Concomitantly, the increased mRNA expression of lipoprotein lipase, fatty acid translocase and enzymes of TAG synthesis was associated with a 5- and 2-times increase in serum TAG and free fatty acid contents, respectively. The compartmentation of carnitine at its main functional location was expected to allow the increased CPT-I activity to ensure in vivo correct fatty acid oxidation rates. All the inductions related to fatty acid transport, oxidation and esterification most likely stem from the abundance of blood lipids providing cardiomyocytes with more fatty acids.     

Effects of L-carnitine and its derivatives on postischemic cardiac function,ventricular fibrillation and necrotic and apoptotic cardiomyocyte death in isolated rat hearts

The study aimed to examine whether L-carnitine and its derivatives, acetyl-L-carnitine and propionyl-L-carnitine, were equally effective and able to improve postischemic cardiac function, reduce the incidence of reperfusion-induced ventricular fibrillation, infarct size, and apoptotic cell death in ischemic/reperfused isolated rat hearts. There are several studies indicating that L-carnitine, a naturally occurring amino acid and an essential cofactor, can improve mechanical function and substrate metabolism not only in hypertrophied or failing myocardium but also in ischemic/reperfused hearts. The effects of L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine, on the recovery of heart function, incidence of reperfusion-induced ventricular fibrillation (VF), infarct size, and apoptotic cell death after 30 min ischemia followed by 120 min reperfusion were studied in isolated working rat hearts. Hearts were perfused with various concentrations of L-carnitine (0.5 and 5 mM), acetyl-L-carnitine (0.5 and 5 mM), and propionyl-L-carnitine (0.05, 0.5, and 5 mM), respectively, for 10 min before the induction of ischemia. Postischemic recovery of CF, AF, and LVDP was significantly improved in all groups perfused with 5 mM of L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine. Significant postischemic ventricular recovery was noticed in the hearts perfused with 0.5 mM of propionyl-L-carnitine, but not with the same concentration of L-carnitine or L-acetyl carnitine. The incidence of reperfusion VF was reduced from its control value of 90 to 10% (p < 0.05) in hearts perfused with 5 mM of propionyl-L-carnitine only. Other doses of various carnitines failed to reduce the incidence of VF. The protection in CF, AF, LVDP, and VF reflected in a reduction in infarct size and apoptotic cell death in hearts treated with various concentrations of carnitine derivatives. The difference between effectiveness of various carnitines on the recovery of postischemic myocardium may be explained by different membrane permeability properties of carnitine and its derivatives.