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Biomedical subjects

A L Shug

Publications and source records attributed to A L Shug.

At least 19 recordsLinked to original sources
PubMed1992

Protection of the ischemic diabetic heart by L-propionylcarnitine therapy.

Diabetics suffer from an increased incidence of myocardial infarction and are less likely to survive an ischemic insult. Since L-propionylcarnitine (LPC) has been shown to protect against ischemic/reperfusion injury, we hypothesized that LPC may be of even greater benefit to the diabetic heart. Diabetes was induced by i.v. streptozotocin, 60 mg/kg; duration: 12 wks. The chronic effect of LPC was determined by daily i.p. injections (100 mg/kg) for 8 wks. The acute effects of LPC were determined by adding it to the perfusion medium (5 mM) of control and diabetic hearts. Initial cardiac contractile performance of isolated perfused working hearts was assessed by varying left atrial filling pressure. Hearts were then subjected to 90 min of low flow global ischemia followed by 30 min reperfusion. Chronic LPC treatment had no effect on initial cardiac performance in either control or diabetic hearts. Acute addition of LPC to the perfusion medium enhanced pump performance of control hearts, but had no effect in diabetic hearts. Both acute and chronic LPC significantly improved the ability of control and diabetic hearts to recover cardiac contractile performance after ischemia and reperfusion, however, chronic treatment was more effective in diabetic hearts.

Animals↗
PubMed1992

The effect of enteral carnitine administration in humans.

We previously determined that the L-carnitine uptake by human duodenal tissue occurs by both active (KT 558 mumol/L) and passive mechanisms. The effects of enteral carnitine was studied in humans. A hamburger meal (345 mumol total carnitine) induced peak jejunal fluid free (unesterified) and short-chain acylcarnitine concentrations (SCAC) of 209 and 130 mumol/L, respectively. Plasma carnitine concentrations and the percent renal reabsorption remained unchanged. By contrast, a pharmacologic dose of free carnitine (25,298 mumol) raised peak intraluminal free and SCAC to 20,660 and 4204 mumol/L. Plasma total carnitine concentrations doubled to 93 mumol/L, and the percent renal reabsorption of free and SCAC declined to 76% and 52%, respectively. In triple-lumen perfusions, 200 mumol carnitine/L was absorbed at 484 nmol.min-1.30 cm-1 jejunum, a rate sufficient for prandial but not pharmacologic assimilation. Our findings indicate that absorption of physiologic and pharmacologic amounts of carnitine occurs predominantly by active transport and passive diffusion, respectively.

Absorption↗
PubMed1991

Myocardial L-carnitine deficiency in a family of dogs with dilated cardiomyopathy.

Dilated cardiomyopathy in a family of dogs was found to be associated with decreased myocardial L-carnitine concentrations, when compared with those in control dogs. In 2 affected dogs, treatment with high doses of L-carnitine was associated with increased myocardial L-carnitine concentration and greatly improved health and myocardial function. Withdrawal of L-carnitine supplementation from these dogs resulted in development of myocardial dysfunction and clinical signs of dilated cardiomyopathy.

Animals↗
PubMed1990

Defective myocardial carnitine metabolism in congestive heart failure secondary to dilated cardiomyopathy and to coronary, hypertensive and valvular heart diseases.

Reduced myocardial carnitine concentrations in the explanted heart and elevated plasma levels have been found in patients undergoing heart transplant for end-stage congestive heart failure (CHF). To evaluate a possible loss of myocardial carnitine in less severe stages of CHF, total myocardial carnitine levels were compared in right ventricular endomyocardial biopsies from 28 patients with mild, moderate and severe dilated cardiomyopathy, 8 patients with CHF of different origin and 13 normal control subjects. If possible, free myocardial carnitine and free and total plasma carnitine were also determined. For the first time, myocardial carnitine levels have been measured in endomyocardial biopsies from 13 normal human hearts (control values: 9.9 +/- 0.8 nmol/mg noncollagen protein). In comparison with these control values, total myocardial carnitine was significantly reduced in patients with dilated cardiomyopathy (6.1 +/- 0.5 nmol/mg noncollagen protein, p less than 0.0001), and CHF of other origins (6.6 +/- 1.1 nmol/mg noncollagen protein, p less than 0.02). Free myocardial carnitine concentrations in dilated cardiomyopathy (4.6 +/- 0.4 nmol/mg noncollagen protein) and CHF of different origin (4.4 +/- 0.5 nmol/mg noncollagen protein) were also significantly different from control values (control values: 9.7 +/- 0.7 nmol/mg noncollagen protein, p less than 0.0001 and p less than 0.005 for both groups). The loss of free and total myocardial carnitine was comparable in dilated cardiomyopathy and CHF due to other diseases. In contrast, plasma free and total carnitine levels in the CHF patients were significantly elevated (67 +/- 5.5 mumol/liter, control values 41 +/- 3.7 mumol/liter, p less than 0.005). Alterations in myocardial carnitine metabolism represent nonspecific biochemical markers in CHF with yet unknown consequences for myocardial function.

Adult↗
PubMed1990

Metabolic alterations in end-stage and less severe heart failure--myocardial carnitine decrease.

Severe tissue carnitine deficiency impairs fatty acid oxidation. In explanted hearts from patients with end stage heart failure a 57% carnitine decrease was found in comparison with healthy donor hearts (p less than 0.05). The reduction of myocardial carnitine levels affected all areas of the explanted hearts to a comparable extent. Carnitine decreases in patients with dilated cardiomyopathy or coronary artery disease were similar. Endomyocardial biopsies from patients with less severe heart failure due to cardiomyopathy (n = 28) or other myocardial diseases (n = 8) showed a 42% decrease of total myocardial carnitine (in nmol/mg non-collagen protein) in comparison with biopsies from patients with normal cardiac function (controls) (heart failure: 5.7, confidence interval 4.2-7.0; controls 9.3, confidence interval 7.6-12.0, p less than 0.005). Free myocardial carnitine in heart failure was also different from controls (heart failure: 4.2, confidence interval 3.7-5.3; controls 10.3, confidence interval 7.5-12.2, p less than 0.001). The decrease of free and total myocardial carnitine was comparable in dilated cardiomyopathy and heart failure due to other diseases. Alterations in myocardial carnitine content represent therefore non-specific biochemical markers in heart failure with yet unknown consequences for myocardial function.

Adult↗
PubMed1989

Fatal rhabdomyolysis following influenza infection in a girl with familial carnitine palmityl transferase deficiency.

Severe rhabdomyolysis following an influenza B infection developed in a previously well 13-year-old girl. There was no history of trauma. Her course was complicated by episodes of severe hyperkalemia, hypocalcemia, hyperphosphatemia, and myoglobinuria. Renal failure, hypertension, and life-threatening arrhythmias developed; she died. Muscle biopsy revealed that this girl had carnitine palmityl transferase deficiency. An asymptomatic sister was demonstrated to have the same disorder. Although carnitine palmityl transferase deficiency is usually associated with mild bouts of rhabdomyolysis that become apparent only in adulthood, severe forms of this disorder may be seen in children. Life-threatening rhabdomyolysis and myoglobinuria may follow any infection associated with decreased intake. If carnitine palmityl transferase deficiency is diagnosed in a proband, other siblings should be evaluated so that proper preventative measures can be undertaken to help prevent the development of symptoms in susceptible individuals who have not been recognized to have the disease.

Acute Kidney Injury↗
PubMed1988

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.

Animals↗
PubMed1988

Ketogenic effects of carnitine in patients with muscular dystrophy and cytochrome oxidase deficiency.

The effects of a single oral dose of carnitine on fasting-induced ketosis was investigated in four normal individuals, five patients with muscular dystrophy, and one patient with a generalized cytochrome c oxidase deficiency. Plasma carnitine, free fatty acids, glucose, insulin, and glucagon were also measured. Normal individuals showed an average 0.09 mM increase in blood beta-hydroxybutyrate concentration during a 12- to 18-hr period of fasting and carnitine administration did not affect this response (average: 0.12 mM). Muscular dystrophy patients showed a greater fasting-induced elevation in beta-hydroxybutyrate (average 0.29 mM) and carnitine administration greatly enhanced this ketogenic response (average 0.84 mM). The cytochrome c oxidase deficient patient showed an even larger increase in beta-hydroxybutyrate with fasting (1.67 mM) and carnitine further augmented this ketotic effect (3.78 mM). Plasma free fatty acids were also elevated in patients that showed enhanced ketosis. Plasma glucagon concentration did not change, but insulin levels decreased during the 12- to 18-hr period of fasting; no major differences were found between controls and patients. These results indicate that some patients with muscular dystrophy and cytochrome c oxidase deficiency are more prone to develop ketosis than normal individuals and that carnitine administration enhances this response. Since both muscular dystrophy patients and the patient with cytochrome c oxidase deficiency had similar ketogenic responses, the data suggest that ketone body utilization may be impaired in these patients. The ability of L-carnitine to be ketogenic should be considered in the treatment of these patients.

Adult↗
PubMed1987

High-performance liquid chromatography of coenzyme A esters formed by transesterification of short-chain acylcarnitines: diagnosis of acidemias by urinary analysis.

A protocol for the identification and estimation of short-chain esters of carnitine is described; it is useful for the diagnosis of acidemias. By this method, carnitine esters in urine are converted to coenzyme A esters enzymatically with carnitine acetyltransferase (CAT): short-chain acylcarnitine + CoA cat in equilibrium short-chain acyl-CoA + carnitine. The coenzyme A esters are separated by high-performance liquid chromatography using a radial compression system with a C8 Radial-Pak cartridge and a mobile phase containing 0.025 M tetraethylammonium phosphate in a linear gradient of 1 to 50% methanol. Coenzyme A esters are quantitated by integrator determination of the area under the 254-nm absorption peaks. Enzymatic conversion approaches 100% for acetyl and propionyl esters except in the presence of high levels of free carnitine, which lowers the proportion of ester as acyl-CoA at equilibrium. However, since acidemia patients produce urine low in free carnitine, this problem is minimized. The method is rapid and simple and identifies propionic, methylmalonic, and isovaleric acidemias.

Acidosis↗
PubMed1987

Modulation of adenine nucleotide translocase activity during myocardial ischemia.

Preliminary studies have shown that high levels of free fatty acids, which elevate LCACAE and lower levels of free carnitine, are much more harmful to the heart after repeated periods of ischemia and reperfusion than after exposure to continuous ischemia and reperfusion. These observations appear to support our hypothesis that LCACAE inhibition of the mitochondrial ANT during ischemia potentiates free radical mediated damage to the inner mitochondrial membrane during reperfusion. These and related findings by others have led us to hypothesize that the mechanisms of ischemic injury to the heart involve the following sequence of events: (1) exposure to high levels of FFA during ischemia and reperfusion results in permanently elevated LCACAE and low free carnitine levels; (2) LCACAE-ANT binding increases and ANT activity decreases; (3) mitochondrial swelling occurs because of decreased ADP/ATP transport and oxidative phosphorylation; (4) complex III activity is altered (superoxide formation increases), and swelling of mitochondrial membranes exposes C = C bonds that are required for lipid peroxidation, which can lead to inner mitochondrial membrane damage. We further hypothesize that LCACAE-ANT inhibition-induced free radical damage causes the loss of mitochondrial matrix components (22), eventually leading to lesions of the sarcolemmal membrane and cell necrosis (22). Studies now in progress support this hypothesis and indicate that inhibition of ANT in isolated rat heart mitochondria by carboxyatractyloside or palmitoyl CoA stimulates free radical formation, probably at the complex III loci.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

[Carnitine metabolism--changes in the end stage of dilated cardiomyopathy and ischemic heart muscle disease].

Biochemical analyses from endomyocardial biopsies indicate that cardiac energy metabolism is altered in patients with end-stage cardiac failure. Myocardial energy production is predominantly based on fatty acid oxidation. Carnitine, a naturally occurring compound, plays an essential role in fatty acid oxidation by carrying long-chain fatty acids into the mitochondrial matrix where they undergo beta-oxidation. In experimental animals, myocardial carnitine deficiency may cause cardiomyopathies which are reversible with carnitine substitution. Rare human diseases, as systemic carnitine deficiency, are associated with impaired cardiac function. We therefore investigated carnitine metabolism in patients with cardiac failure. Plasma and myocardial carnitine levels were measured in 55 patients undergoing cardiac transplantation because of end-stage cardiac failure based on dilated cardiomyopathy (DC, n = 30) or coronary artery disease (CAD, n = 22). Elevated plasma carnitine levels (controls: 49 +/- 12 microM; DC: 82 +/- 38 microM; p less than 0.001, CAD: 86.9 +/- 21.6 microM; p less than 0.05) were found in both patient groups (Fig. 1). Plasma carnitine did not correlate with creatinine (Fig. 2). Compared to controls, myocardial carnitine levels were significantly reduced: DC: 5.9 +/- 1.45 nmol/mg NCP; CAD: 5.84 +/- 1.84 nmol/mg NCP; controls: 15.6 +/- 5.4 nmol/mg NCP (Fig. 3). No correlation between myocardial and plasma levels was found (Fig. 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiomyopathy, Dilated↗
PubMed1987

Free radical-mediated damage during myocardial ischemia and reperfusion and protection by carnitine esters.

Ischemic injury may be exacerbated by readmission of oxygen into the myocardium, probably due to the formation of free radicals and their interaction with membrane lipids. We tested the hypothesis that ischemic myocardial damage is potentiated during reperfusion with excess free fatty acids in the globally ischemic rat heart, and in parallel studies, we investigated the protective effects of carnitine derivatives. Intermittent ischemia, i.e. three 20 min periods of ischemia followed by 10 min reperfusion each, was induced in isolated working rat hearts perfused with either glucose (11 mM) alone or glucose with palmitate (11 mM and 1.2 mM). The ischemic coronary flow was reduced to 1.1 ml/min in a low-flow group and equalled 0 ml/min in a no-flow group. Loss of functional recovery in the low-flow and no-flow group was more pronounced when palmitate was present in the perfusate. This was associated with increased levels of long-chain acyl-CoA esters in the palmitate perfused hearts. Malondialdehyde, an indicator of free radical formation, was elevated in both low-flow and no-flow groups when either substrate was used. We therefore suggest that free radical formation contributes to myocardial injury in intermittent ischemia. The mechanism of free radical formation and their sites of action have not yet been completely elucidated - the peroxidation of membrane lipids is probably involved, particularly in the presence of high palmitate. The protective effect of the carnitine derivatives D-propionylcarnitine, L-propionylcarnitine and propionylcarnitine taurine amide was studied in the no-flow hearts (Table 2).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Protection from adriamycin-induced cardiomyopathy in rats.

The use of adriamycin, one of the most potent antineoplastic agents available causes a dose dependent cardiomyopathy. Carnitine does play a central role in myocardial metabolism by controlling fatty acid oxidation and the acetyl-CoA pool. Protective effects of carnitine have been described in different myocardial diseases. We therefore investigated whether chronic carnitine administration could protect from adriamycin-induced cardiomyopathy. As the rat has proved to be an effective model for adriamycin-induced cardiomyopathy, we studied four groups of rats, treated for 6 weeks according to the following protocols: group (I) adriamycin i.v. and carnitine i.p. (II) adriamycin i.v. and NaCl i.p. (III) NaCl i.v. and i.p. (IV) NaCl i.v. and carnitine i.p. After 6 weeks of treatment, hearts were studied in an isolated working rat heart system. Adriamycin/NaCl treated hearts produced reduced cardiac output and left ventricular systolic pressure compared to controls (NaCl/CaCl, group III) or to adriamycin/carnitine treated hearts (Fig. 1-3 and Table 1). The myocardial carnitine content in non-perfused hearts was not influenced by adriamycin therapy, and muscle, kidney and liver carnitine levels were unchanged. However, total plasma carnitine in the adriamycin/NaCl group was significantly elevated, based on increased carnitine esters. Histological changes like degeneration, vacuolization, interstitial edema, fibrosis and mitochondrial damage were pronounced in the adriamycin group but were almost lacking in the carnitine-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Protection of the ischemic myocardium by propionylcarnitine taurine amide. Comparison with other carnitine derivatives.

The cardioprotective effect of the two synthetic carnitine derivatives, propionylcarnitine taurine amide (PCTA) and butyrylcarnitine taurine amide (BCTA), were studied in isolated perfused rat hearts. The protective effects of PCTA and BCTA were compared with those of chemically similar compounds, which have already been investigated in part and reported on; i.e. propionylcarnitine, carnitine, taurine and the combination of propionylcarnitine and taurine. The addition of either PCTA or BCTA significantly improved the recovery of cardiac function of ischemic reperfused hearts. PCTA (0.5 mM) treated hearts regained 75%, 91% and 89% of their preischemic values for cardiac output, left ventricular pressure and dp/dt after 90 min ischemia and 15 min reperfusion. These parameters of cardiac function remained impaired in control hearts which recovered only 38% of the initial preischemic cardiac output, 73% of initial intraventricular developed pressure and 64% of initial positive dp/dt. The cardioprotective effects of PCTA, BCTA and propionylcarnitine were in the same range. However, PCTA and BCTA acted in 20-fold lower molar concentrations compared to propionylcarnitine. Carnitine (11 mM), taurine (11 mM) as well as the combination of propionylcarnitine and taurine at low concentrations had no cardioprotective effect in these experiments. Myocardial adenosine triphosphate (ATP) and creatine phosphate (CP) concentrations were significantly higher in the PCTA or BCTA treated hearts than in controls, and lactate levels were reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Carnitine protection against adriamycin-induced cardiomyopathy in rats.

The effects of chronic adriamycin toxicity on myocardial carnitine content and contractile function were studied in rats, along with potential protective effects of L-carnitine administration. Cardiomyopathy was induced over a 6- to 7-week period by weekly intravenous injections of adriamycin, 2 mg/kg. In vivo myocardial tissue levels of carnitine were not significantly changed by adriamycin, but plasma levels were elevated. Cardiac output was depressed in isolated perfused hearts from adriamycin-treated rats perfused with 11 mM glucose. In a second experiment, 4-week-old male rats were divided into four groups: saline-treated control, L-carnitine-treated control, saline-treated adriamycin, and L-carnitine-treated adriamycin. L-Carnitine was given intraperitoneally each day at a dose of 500 mg/kg. Myocardial histology and ultrastructure were analyzed. Cardiac performance was determined in hearts perfused with 1.2 mM palmitate and 5.5 mM glucose. Hearts from saline-treated adriamycin rats showed histopathological changes and a significantly diminished cardiac output at various preloads when compared to saline-treated controls. Daily intraperitoneal L-carnitine reduced histopathological alterations and improved cardiac performance.

Animals↗
PubMed1986

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.

Adult↗
PubMed1986

Protection of the ischaemic myocardium by L-propionylcarnitine: effects on the recovery of cardiac output after ischaemia and reperfusion, carnitine transport, and fatty acid oxidation.

The effects of L-propionylcarnitine on the recovery of cardiac contractile performance after global ischaemia and reperfusion were studied in isolated perfused rat hearts. The addition of either 5.5 or 11 mmol X litre-1 L-propionylcarnitine significantly improved the recovery of cardiac output, left ventricular pressure, and dP/dt after 90 min of ischaemia and 15 min of reperfusion. Myocardial adenosine triphosphate and creatine phosphate concentrations were significantly higher in the L-propionylcarnitine treated hearts than in controls, but the concentrations of long chain acyl carnitine and coenzyme A were unaffected. The protecting effects of L-propionylcarnitine were compared with those of L-carnitine and L-acetylcarnitine. A 11 mmol X litre-1 dose of L-propionylcarnitine and L-acetylcarnitine significantly improved the recovery of cardiac output after 90 min of ischaemia and 15 min of reperfusion, but L-carnitine did not. L-Propionylcarnitine was the most protective agent. The effects of these derivatives on L-3H-carnitine transport and 14C-palmitate oxidation were also measured. All of these derivatives competitively inhibited L-3H-carnitine transport in isolated cardiac myocytes, but L-propionylcarnitine was the most potent. Carnitine and L-propionylcarnitine stimulated palmitate oxidation in the homogenate, whereas L-acetylcarnitine inhibited it. In myocytes only L-propionylcarnitine affected palmitate oxidation. These data show that L-propionylcarnitine protects the ischaemic myocardium. Its protection is greater than that for L-carnitine or L-acetylcarnitine, and the difference in effectiveness may relate to the rate of transport into the cells and the effects on fatty acid utilisation.

Acetylcarnitine↗