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Biomedical subjects

J R Neely

Publications and source records attributed to J R Neely.

At least 55 records · Page 3Linked to original sources
PubMed1983

Cardiac function and myosin ATPase in diabetic rats treated with insulin, T3, and T4.

The effects of insulin, T4, and T3 treatment on cardiac function, myosin ATPase activity, and myosin isozyme distribution were studied in alloxan diabetic rats. Diabetes resulted in depressed peak ventricular pressure development, heart rate, and left ventricular +dP/dt. Myocardial Ca2+-activated myosin ATPase activity was reduced in association with lower serum levels of T3 and T4. The V1 isozyme of myosin decreased, and both V2 and V3 isozymes increased. Insulin treatment totally reversed the changes in function, serum thyroid hormones, and myosin ATPase activity. Treatment of diabetic animals with T4 (5 or 10 micrograms/day) prevented the decrease in myosin ATPase but did not prevent the changes in cardiac function, myosin isozymes, or serum T3 levels. Pharmacological doses of T3 (3 micrograms/day) that were adequate to maintain higher than normal serum T3 corrected the decrease in Ca2+-activated myosin ATPase and heart rate but only partially corrected the changes in pressure development and myosin isozyme distribution. Only when serum T3 was increased to four times normal was cardiac function corrected.

Adenosine Triphosphatases↗
PubMed1982

Rate-limiting step and control of coenzyme A synthesis in cardiac muscle.

Control of coenzyme A synthesis was studied in isolated, perfused rat hearts. Pantothenic acid (PA), coenzyme A, and intermediates in the the pathway were separated by high pressure liquid chromatography. The amount of 14C label in each of the metabolites was determined in tissue extracts when [14C]PA was supplied in the perfusate. The rate-controlling steps in the pathway were determined by measuring the net rate of [14C]PA flux through each of the reactions. The data indicated that the primary site of control in the pathway was the pantothenate kinase-catalyzed reaction, the first intracellular step in the conversion of PA to CoA. The rate of this reaction was inhibited by including glucose, pyruvate, fatty acids, or beta-hydroxybutyrate in the perfusate of isolated hearts. Pyruvate and beta-hydroxybutyrate caused a much greater inhibition than did glucose. Insulin was a strong inhibitor, but only in the presence of glucose. Insulin had no effect in hearts receiving either no substrate or palmitate as substrate. Collectively, these data indicated that an unknown tissue metabolite whose level changed with each of these substrates and insulin is a strong regulator of pantothenate kinase. Synthesis of CoA occurred in both the cytosolic and mitochondrial compartments. Accelerated mitochondrial CoA synthesis appeared to be dependent upon the production and accumulation of 4'-phosphopantotheine, which occurred only when pantothenate kinase was stimulated.

Animals↗
PubMed1982

Coenzyme A metabolism in pantothenic acid-deficient rats.

The pantothenic acid (PA) and coenzyme A (CoA) content of various organs of rats maintained on a PA-deficient diet were determined. The PA content of heart, kidney, gastrocnemius and testes of rats fed the PA-deficient diet was reduced by greater than 90%, and liver PA was reduced by 70%. However, these low PA levels were sufficient to maintain tissue CoA at control levels. Although CoA levels were maintained, the PA-deficient rats did not grow at normal rates suggesting that low PA may effect growth rate by mechanisms other than by depressed CoA. PA-deficient rats were subjected to fasting and alloxan-diabetes to determine if increased CoA synthesis occurred as in normal animals. Both fasting and diabetes resulted in elevations in myocardial and liver CoA, which were comparable in rats fed a PA-deficient diet or a regular diet. The source of the PA used for the increase in tissue CoA in PA-deficient rats has yet to be determined.

Animals↗
PubMed1982

Characterization of carnitine transport in isolated perfused adult rat hearts.

Carnitine transport was characterized in isolated perfused adult rat hearts. Carnitine uptake consisted of both a saturable (carrier-mediated) and nonsaturable (diffusion) component. Perfusion with 0.05 mM mersalyl acid, a sulfhydryl binding agent, inhibited the carrier-mediated transport but did not inhibit diffusion. The saturable transport system exhibited Michaelis-Menten kinetics with a maximum velocity of 154 nmol . g dry wt-1 . h-1 and an apparent Michaelis constant of 24 microM. D-carnitine competitively inhibited L-carnitine transport with an apparent inhibitor dissociation constant of 500 microM. Anoxia and K+ arrest resulted in only a slight inhibition of the saturable transport, suggesting that transport is not adenosine 5'-triphosphate (ATP) dependent. At physiological concentrations of extracellular carnitine (44 microM), total carnitine uptake rate was about 100 nmol . g dry wt-1 . h-1, 80% of which was by carrier-mediated transport. This rate of uptake would require about 60 h to replace the total cellular carnitine. Loss of tissue carnitine also appeared to be a slow process. These results suggest that carnitine is transported across the sarcolemma by both diffusion and carrier-mediated transport.

Animals↗
PubMed1982

A mechanism for reduced myocardial carnitine levels in diabetic animals.

The effects of substrates, fasting, and diabetes on carnitine transport into the myocardial cells were characterized in perfused adult rat hearts. Increasing the level of acetyl carnitine and decreasing the level of free carnitine by perfusion with various substrates did not alter the rate of carnitine transport. Carnitine transport was enhanced by the perfusion with palmitate. At low work, addition of 1.2 mM palmitate increased carnitine transport by 33%, whereas high work + 1.2 mM palmitate stimulated transport 60% over that of glucose-perfused hearts. The enhancement of carnitine transport correlated with a rise in tissue levels of long-chain acyl carnitine. When the level of long-chain acyl carnitine was increased prior to measurement of carnitine transport, the enhancement of uptake seen with palmitate as substrate was not observed. Carnitine transport in hearts from 48-h-fasted or diabetic animals was not different from transport in hearts of fed animals. Diabetes resulted in decreased tissue levels of carnitine. The decrease was observed after 48 h of severe diabetes and after several weeks of mild diabetes. In each case, low tissue levels of carnitine were associated with reduced serum carnitine. Serum carnitine decreased to a value near the Km for carnitine transport in diabetic animals. It is concluded that a decreased rate of transport due to lower serum carnitine may be responsible for reduced levels of carnitine seen in diabetic hearts.

Animals↗
PubMed1981

Effects of diabetes and fasting on pantothenic acid metabolism in rats.

The effects of fasting and diabetes on pantothenic acid (PA) metabolism were studied in rats. Tissue levels of PA and coenzyme A (CoA) and rates of [14C]PA uptake and incorporation into tissue CoA were determined. Both fasting and diabetes resulted in accelerated rates of [14C]PA uptake, higher tissue concentrations of PA, increased incorporation of [14C]PA into CoA, and elevated tissue concentrations of CoA in the liver. The concentration of PA in liver was near the Km of pantothenate kinase for PA in control animals, and increased PA uptake may, in part, account for the increased [14C]PA incorporation into CoA though an elevation in tissue PA levels. In cardiac muscle, increased [14C]PA incorporation into CoA and increased CoA levels were associated with reduced PA uptake and reduced tissue PA levels in both fasting and diabetic animals, suggesting that CoA synthesis is not controlled by substrate availability in this tissue. Uptake of [14C]PA by skeletal muscle was also reduced in diabetic animals. These data suggest that PA uptake by tissues is under metabolic or hormonal control. Decreased uptake by muscle and increased uptake by liver may represent a mechanism for shifting large body stores of PA present in muscle to the liver in which endogenous PA concentrations are normally low. In addition, both fasting and diabetes resulted in decreased urinary PA excretion, a finding that may represent a regulatory mechanism to conserve whole-body PA under these conditions.

Animals↗
PubMed1981

Regulation of coenzyme A synthesis in heart muscle: effects of diabetes and fasting.

Regulation of coenzyme A (CoA) synthesis was studied in the isolated perfused rat heart. Incorporation of [14C]pantothenic acid ([14C]PA) into CoA was determined to estimate rates of CoA synthesis. Although CoA levels were elevated in hearts removed from fasted and diabetic animals, in vitro rates of CoA synthesis were not elevated. The presence of 1.2 mM palmitate, 5 mM pyruvate, or 10 mM beta-hydroxybutyrate in the perfusate-reduced PA incorporation into CoA in control hearts by 40, 60, and 80%, respectively. Insulin (25 mU/ml) reduced incorporation by 90%. The alterations in CoA synthesis in hearts perfused with buffer containing palmitate, pyruvate, beta-hydroxybutyrate, and insulin were associated with no change in myocardial PA uptake. Data indicate that these substrates and insulin inhibit the first step in the pathway of CoA synthesis, pantothenate kinase. Because insulin is a strong inhibitor of CoA synthesis in vitro, decreased circulating levels of insulin in fasted and diabetic animals may account for the increased levels of CoA in vivo.

Alloxan↗
PubMed1981

Metabolic products and myocardial ischemia.

Metabolic products accumulate in ischemic myocardium secondary to reduced coronary flow, which prevents adequate washout of vascular spaces, and to reduced oxidative metabolism. The most notable products that accumulate are NADH, H+, lactate, CO2, long-chain acyl-CoA, and long-chain acyl carnitine. These products interfere with the production of ATP and the functioning of the myocardium. Glycolytic production of ATP is inhibited by accumulation of NADH, H+, and lactate. Mitochondrial and plasma membrane function may be altered by the acyl esters of CoA and carnitine. Mitochondrial membranes become structurally distorted and fragmented, and lipid-containing amorphous densities appear in the matrix. Structural alterations of mitochondria occur more frequently in hearts receiving high concentrations of fatty acids and correlate with high tissue levels of acyl esters of CoA and carnitine. Addition of acyl carnitine to mitochondria isolated from normal hearts results in nodulose-appearing cristae and fragmentation of mitochondrial membranes.

Acyl Coenzyme A↗
PubMed1980

Utilization of leucine by working rat heart.

Leucine provided substrate to partially support mechanical activity of working rat hearts; the beneficial effect on peak systolic pressure development was more marked as leucine concentration was increased to 10 mM. In Langendorff preparations that had been exposed to 5 mM [U-14C]leucine, the imposition of cardiac work was accompanied by a threefold increase in the rate of 14CO2 production within the first 30 s; however, the rate decreased 40% in the next 10 min. This transient acceleration of 14CO2 production was not observed when [1-14C]leucine was provided and appeared to be due to oxidation of a tissue pool of radioactive intermediates that was present after 10 min of Langendorff perfusion. Over a period of 1 h, oxidation of either [U-14C]- or [1-14C]leucine increased 25-40% in working compared to Langendorff preparations that were supplied 5 mM leucine and 11 mM glucose. In working hearts that were supplied a substrate and hormone mixture that simulated normal plasma and 1 mM leucine, a concentration found in the plasma of diabetic but not normal rats, leucine oxidation was accelerated 73% by work but amounted to only 3.3% of oxygen consumption.

Animals↗
PubMed1980

Energy metabolism during reperfusion following ischemia.

Insulin treatment of hearts during aerobic reperfusion following transient ischemia in the working rat heart preparation significantly improved the recovery of myocardial function. This improvement was reflected both by a shorter time required for the heart to resume beating, and to increase heart rate and peak systolic pressure after resumption of beating. The beneficial effects of insulin may be related to improved energy metabolism secondary to small increases in pyruvate production during the early phase of reperfusion. It was also associated with an increased rate of restoration of cellular K+. Pyruvate addition to the perfusate also improved resumption of spontaneous beating of the heart and restoration of normal rate and pressure development. This effect of pyruvate was also associated with increased cellular levels of K+. Both insulin and pyruvate may improve ATP production during the first few minutes of reperfusion when glycolysis and oxidation of fatty acids are inhibited, but ATP levels were not increased after 30 min of reperfusion.

Adenosine Triphosphate↗