Search PubMed⌕ Search

Biomedical subjects

J R Neely

Publications and source records attributed to J R Neely.

At least 73 records · Page 4Linked to original sources
PubMed1978

Coenzyme A and carnitine distribution in normal and ischemic hearts.

The distribution of coenzyme A and carnitine between the mitochondrial and cytosolic compartments was determined in rat heart ventricular muscle. The CoA and carnitine levels of homogenate, mitochondrial, and postmitochondrial fractions were determined in nonperfused hearts and in hearts that were perfused under control and ischemic conditions. Using the mitochondrial marker enzymes, citrate synthase and cytochrome c oxidase, the cellular content of mitochondrial protein was determined to be 53 +/- 1.0 (nonperfused), 53.5 +/- 1.5 (control), and 58.1 +/- 2.2 (ischemic) mg/g of wet heart muscle. These values were used to calculate the contribution of the CoA and carnitine located in the mitochondrial compartment to the total cellular levels of CoA and carnitine. Under both control and ischemic conditions, approximately 95% of the cellular CoA was mitochondrial. The percentage of the total cellular carnitine associated with the mitochondria increased from 8 to 9% in nonperfused and control hearts to 25% during ischemia, indicating that a net transfer of carnitine occurred from the cytosol to the mitochondrial matrix.

Animals↗
PubMed1978

Control of fatty acid metabolism in ischemic and hypoxic hearts.

The effects of whole heart ischemia on fatty acid metabolism were studied in the isolated, perfused rat heart. A reduction in coronary flow and oxygen consumption resulted in lower rates of palmitate uptake and oxidation to CO2. This decrease in metabolic rate was associated with increased tissue levels of long chain acyl coenzyme A and long chain acylcarnitine. Cellular levels of acetyl-CoA, acetylcarnitine, free CoA, and free carnitine decreased. These changes in CoA and its acyl derivatives indicate that beta oxidation became the limiting step in fatty acid metabolism. The rate of beta oxidation was probably limited by high levels of NADH and FADH2 secondary to a reduced supply of oxygen. Tissue levels of neutral lipids showed a slight increase durning ischemia, but incorporation of [U-14C]palmitate into lipid was not altered significantly. Although both substrates for lipid synthesis were present in higher concentrations during ischemia, compartmentalization of long chain acyl-CoA in the mitochondrial matrix and alpha-glycerol phosphate in the cytosol may have accounted for the relatively low rate of lipid synthesis.

Acetyl Coenzyme A↗
PubMed1978

Insulin therapy for depressed myocardial contractility after prolonged ischemia.

Insulin was administered to two patients whose diminished myocardial contractility made it difficult to terminate cardiopulmonary bypass. In both instances, bypass was successfully terminated shortly after the insulin injection. These clinical observations led to experiments under the controlled conditions provided by the isolated, working rat heart preparation. The recovery of contractility after 30 minutes of severe ischemia was assessed in all 11 control and 11 insulin-treated hearts. Myocardial performance, as judged by the product of heart rate and peak systolic blood pressure, was significantly greater in the insulin-treated hearts. These clinical observations and experimental findings suggest the need for more extensive study of the potential value of insulin in treating depressed contractility after prolonged myocardial ischemia.

Animals↗
PubMed1977

Fatty acid oxidation by isolated perfused working hearts of aged rats.

It has been reported that mitochondria isolated from hearts of old rats have lower respiratory activity than mitochondria from young rats. In order to determine the physiological correlates of these changes, the metabolism of hearts from young and old rats has been compared in a perfused working heart preparation. The oxidation of [14C]palmitate to 14CO2, oxygen consumption, and nucleotide levels were measured under different cardiac workloads. The hearts from old animals performed less cardiac work and utilized less oxygen and palmitate in proportion to tissue mass, but the ratio of oxygen consumed to pressure developed was unaltered. There was a small but significant decrease in cardiac efficiency expressed as the ratio between the rate of oxygen consumed and ventricular pressure development. Tissue levels of total carnitine and long-chain acylcarnitine derivatives were greatly reduced in the older heart without significant change in free CoA, acetyl-CoA, or long-chain acyl-CoA. The adenine nucleotide levels were not significantly different in the two groups. The results appear consistent with the in vitro studies on isolated mitochondria.

Acetyl Coenzyme A↗
PubMed1977

Integration of lipid utilization with Krebs cycle activity in muscle.

This essay illustrates the ways in which beta-oxidation and the citric acid cycle interact. These included: 1) competition for CoASH, 2) competition for NAD+, and 3) competition for FADH2 oxidation. By means of the above, the cell is able to maintain a precise coordination between the activation of fatty acids in the cytosol, beta-oxidation in the mitochondria, and the complete oxidation of acetyl-CoA to CO2 via the citric acid cycle throughout a wide range of energy demands and oxygen availability.

Animals↗
PubMed1976

Effects of excess glucose and insulin on glycolytic metabolism during experimental myocardial ischemia.

The selective metabolic effects of glucose and insulin were tested in an intact working swine heart preparation. Supplements of glucose (26.6 millimolar [mM] and insulin (0.025 units/ml) were provided to 18 hearts, 9 control hearts (coronary flow 151 ml/min) and 9 hearts rendered globally ischemic (coronary flow reduced from 167 to 85 ml/min). These hearts were compared with 14 additional hearts (6 control and 8 ischemic) given no supplements (glucose 8.6 mM, no excess insulin). In hearts without supplements, ischemic significantly decreased mechanical performance, myocardial oxygen consumption, fatty acid oxidation and tissue high energy phosphate stores. Glucose consumption was reduced from 133 micromoles (mumol)/hr per g (before ischemia) to 58 mumol/hr per g (P less than 0.05), presumably from inhibition at glyceraldehyde-3-phosphate dehydrogenase. Data for control hearts with excess glucose and insulin were similar to data in control hearts without supplements except that glucose consumption and glycolytic flux were increased. Ischemia in treated hearts, as compared with untreated ischemic hearts, effected similar significant decreases in myocardial oxygen consumption, fatty acid oxidation and high energy phosphate stores and resulted in greater reductions in mechanical performance and in 10 minutes' less average survival time. Glucose consumption was reduced from 483 (before ischemia) to 242 mumol/hr per g (P less than 0.005) and inhibition at glyceraldehyde-3-phosphate dehydrogenase was again noted. Thus, excess carbohydrate and insulin hormone, when infused directly into the ischemic myocardium, did not provide an efficacious increase in either glycolytic flux or energy production. These findings suggest that an alternative explanation for the reported efficacy of glucose-insulin-potassium infusions must be sought.

Animals↗
PubMed1976

Rate-limiting steps of carbohydrate and fatty acid metabolism in ischemic hearts.

Control of glycolysis and fatty acid oxidation in ischemic myocardium was studied in isolated working rat hearts. Coronary flow was reduced to the whole heart. In ischemic tissue, oxygen consumption, glycolysis and fatty acid oxidation all decreased in proportion to the restriction in coronary flow. Inhibition of glycolysis developed at the level of glyceraldehyde-3-phosphate dehydrogenase. Restricted flux through this step appeared to result from accumulation of lactate, H+ and NADH. The rate of glycolysis was inversely related to accumulation of lactate. Additions of high levels of lactate to the perfusate inhibited glycolysis in aerobic, anoxic and ischemic hearts. The mechanism of this effect of lactate in anaerobic hearts is unknown, but does not appear to be related to pH changes. Oxidation of fatty acids was restricted at the level of beta-oxidation and high levels of both long-chain acyl CoA and carnitine derivatives accumulated.

Adenosine Triphosphate↗
PubMed1976

Effects of treatment with pyruvate and tromethamine in experimental myocardial ischemia.

Failure of glycolysis to increase sufficiently to supply optimal levels of energy production in ischemic heart muscle is due in part to the cummulative restrainst of acidosis on rate-limiting enzymes, particularly glyceraldehyde-3-phosphate dehydrogenase. In an effort to modify this inhibition and salvage jeopardized myocardium, treatment with excess levels of pyruvate and tromethamine (Tris), designed to buffer intracellular hydrogen ion accumulations and improve the oxidation-reduction ratio, NAD+/NADH, was tested in 59 swine hearts in two separate preparations of global and regional ischemia. Global ischemia, per se, caused hemodynamic deterioration and shortened survival time (44.3 +/- 3.1 minutes). Myocardial oxygen consumption, fatty acid oxidation, and glucose uptake were all significantly (P less than 0.001) reduced as were estimates of glycolysis and tissue stores of creatine phosphate and ATP (P less than 0.01). Although treatment with Tris alone was inconclusive, administrations of pyruvate (40-50 mM) buffered with Tris (added directly into the coronary perfusate) effected an improvement in mechanical function and a significant prolongation in survival time (56.9 +/- 2.6 minutes. P less than 0.01). Glycogenolysis was enhanced and levels of key glycolytic intermediates were reduced, suggesting an acceleration of glycolytic flux. Excess levels of pyruvate (1.52 +/- 0.48 mumol/ml of coronary perfusate) provided added substrate for oxidation and led to a greater than 5-fold incrase in rates of pyruvate decarboxylation as compared to untreated ischemic hearts...

Animals↗
PubMed1976

Effects of mechanical activity and hormones on myocardial glucose and fatty acid utilization.

The effects of increased cardiac work on glycolysis, the citric acid cycle, and oxidation of fatty acids were studied in isolated rat hearts. Glycolysis was stimulated by increased work in heart perfused with glucose alone or with glucose, high levels of insulin, and low levels of palmitate. With glucose alone, stimulation was associated with a rapid decrease in phosphate potential and rapid activation of phosphofructokinase, but an apparently slower activation of glucose transport. With glucose, insulin, and palmitate present, stimulation of glucose utilization was rapid and correlated with activation of phosphofructokinase.

Animals↗
PubMed1975

Regulation of long chain fatty acid activation in heart muscle.

Regulation of fatty acid activation was studied in whole tissue homogenates of rat heart. The palmityl-CoA synthestase activity was proportional to the fatty acid to albumin ratio in the incubation medium with maximal activity occurring at a molar ratio of about 5. Fatty acyl-CoA synthetase activity was inhibited by products of the reaction (AMP, pyrophosphate, and palmityl-CoA). The apparent Ki for palmityl-CoA inhibition was 5 muM and this inhibition could be relieved by CoA-SH or albumin. The Km for CoA-SH in the absence of palmityl-CoA was 7 muM and was increased to 24 muM by addition of 8 muM palmityl-CoA. Cytosolic and mitochondrial levels of CoA-SH and carnitine were estimated in whole tissue homogenates of heart and liver. From 90 to 100% of whole tissue CoA was recovered in the mitochondrial fraction of heart muscle and it was estimated that the cytosolic concentration of free CoA-SH probably never exceeds its Km value for fatty acid activation in this tissue. Therefore, the rate of fatty acid activation would be expected to depend on the availability of CoA-SH in the cytosolic space. By adjusting the concentration of CoA-SH in the cytosol to the rate of acetyl-CoA oxidation, carnitineacetyl-CoA transferase may function in cardiac muscle to couple the rate of fatty acid activation in the cytosolic compartment to acetyl-CoA oxidation in the mitochondria. Approximately 30% of whole tissue CoA-SH was located in the cytosolic space in liver. Heart muscle has about twice as much carnitine as liver but in both tissues 100% of whole tissue carintine was located in the cytosolic space. The ratio of carnitine to CoA-SH in the cytosolic space was estimated to be about 100 in heart and 17 in liver. This high ratio in cardiac muscle may function to channel fatty acids toward oxidation rather than toward synthesis of complex lipids.

Acetyltransferases↗