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Biomedical subjects

H E Morgan

Publications and source records attributed to H E Morgan.

At least 73 records · Page 4Linked to original sources
PubMed1983

Insulin effects on protein synthesis are independent of glucose and energy metabolism.

Protein synthesis was accelerated in rat hearts that were provided insulin compared with provision of glucose or pyruvate alone or a mixture of glucose and pyruvate. The faster synthetic rates were accompanied by a reduction in numbers of ribosomal subunits, indicating that peptide chain initiation was accelerated relative to elongation/termination. In hearts supplied glucose, 65% of the maximal effect on protein synthesis was achieved by addition of 1.7 X 10(-10) M insulin, but significant effects on glucose uptake as well as on tissue contents of glucose 6-phosphate and creatine phosphate were obtained only with 7 X 10(-10) M insulin. Addition of glucose to perfusates containing pyruvate did not accelerate protein synthesis, although the glucose 6-phosphate content was raised. Similarly, the stimulatory effects of insulin on protein synthesis in hearts supplied pyruvate did not depend on changes in glucose 6-phosphate content, creatine phosphate/creatine, ATP/ADP, or adenylate energy charge. These studies indicate that insulin accelerated peptide-chain initiation and protein synthesis in rat heart by mechanisms independent of the hormone's effect on glucose or energy metabolism.

Adenine Nucleotides↗
PubMed1983

Effects of diabetes on cardiac lysosomes and protein degradation.

Rates of proteolysis by hearts obtained from alloxan diabetic rats and perfused as working preparations with buffer simulating control sera were accelerated 30% above identically perfused control hearts. The total homogenate activities of cathepsin D and beta-N-acetylglucosaminidase, assayed in the presence of Triton X-100, decreased 15-35% in diabetic heart, but the activities of these lysosomal enzymes assayable in the absence of detergent were unchanged in the diabetic tissue. The effects of diabetes were examined further by centrifugation of particulate fractions from subtilisin-treated hearts of control and diabetic rats on polyvinylpyrrolidone-coated colloidal silica (Percoll) gradients. Two species of lysosomes were resolved on the basis of their densities. Both dense and buoyant lysosomes accumulated radioactivity when hearts were exposed to [14C]phenylalanine methyl ester. Dense lysosomes (1.06-1.09 g/ml) sedimented with mitochondria while buoyant lysosomes banded with Golgi and sarcolemmal particles (1.02-1.03 g/ml). When particulate fractions of hearts from diabetic animals were layered on the Percoll gradients, total activities of beta-N-acetylglucosaminidase and cathepsin D were decreased from control in buoyant lysosomes, but unchanged in dense lysosomes. These results demonstrated that the increase in proteolysis in the diabetic heart was associated with decreased total activity and latency of cathepsin D and beta-N-acetylglucosaminidase and an increased proportion of dense lysosomes in the particulate fraction.

Acetylglucosaminidase↗
PubMed1981

Protein degradation and synthesis during recovery from myocardial ischemia.

Rates of synthesis and degradation of heart protein were measured during 30 or 60 min of myocardial ischemia and during the 30 or 60 min following these ischemic periods. During ischemia, rates of protein synthesis and degradation were reduced. Resumption of control rates of coronary flow after 30 min of ischemia resulted in complete restoration of creatine phosphate and partial recovery of ATP (75%), developed pressure (79%), and cardiac output (80%). After 60 min of ischemia, restoration of flow completely restored creatine phosphate but resulted in poor recovery of ATP (57%), developed pressure (26%), and cardiac output (63%). During the recovery phase, rates of protein synthesis and degradation of protein to free amino acids were the same as in hearts that had been perfused for a comparable period as working aerobic preparations. These findings were consistent with inhibition of an initial step in proteolysis during the period of ischemia followed by return to control rates of degradation when oxygen delivery and energy levels were restored.

Adenosine Triphosphate↗
PubMed1981

Use of aromatic amino acids as monitors of protein turnover.

Phenylalanine and tyrosine were metabolized by the perfused rat heart via a mitochondrial aminotransferase. When L-[alanyl-2,3-3H]phenylalanine and L-[alanyl-2,3-3H]tyrosine were used, release of 3H2O was progressive over 2 h of perfusion. Metabolism of L-[U-14C]phenylalanine to 14CO2 or production of 3H2O from L-[ring-2,6-3H]phenylalanine or L-[ring-2,6-3H]tyrosine was not detected. Although 3H2O production from L-[alanyl-2,3-3H]phenylalanine was rapid, net production of phenylpyruvate or other metabolites of phenylalanine was negligible. As a result, use of aromatic amino acids as monitors of protein turnover in heart muscle was validated. Production of 3H2O from L-[alanyl-2,3-3H]phenylalanine was catalyzed by a mitochondrial enzyme, which is thought to be aspartate aminotransferase (EC 2.6.1.1). The rate of 3H2O production by both intact and detergent-treated mitochondria exceeded that of phenylpyruvate by a factor of 10 and occurred in the absence of alpha-ketoglutarate. These data provide an explanation for the production of 3H2O from L-[alanyl-2,3-3H]phenylalanine by perfused rat heart without the concomitant production of [3H]phenylpyruvate.

Aerobiosis↗
PubMed1981

Carbohydrate metabolism in isolated, working newborn pig heart.

Metabolic activity of the newborn pig heart was observed by means of a preparation that allowed isolated hearts to perform a physiologic work load. A 10-min period of retrograde aortic perfusion was followed by 60 min of recirculating perfusion in which bicarbonate buffer was infused into the right atrium and ejected from both ventricles at measured pressures and flow rates. The buffer was supplemented with either glucose (10 mM), lactate (20 mM), or pyruvate (20 mM), or was unsupplemented. Pressure development and ventricular outputs were stable through 60 min of perfusion with glucose, pyruvate, or lactate supplementation. Myocardial high-energy phosphate and glycogen contents were also stable. In hearts perfused without substrate supplementation, mechanical performance deteriorated after 30 min. Rates of substrate uptake and oxygen consumption indicated that either glucose, lactate, or pyruvate could serve as a primary source of metabolic energy. Minimal lactate production was observed when either glucose or pyruvate were present. These findings indicate that, despite recent emergence from the relatively hypoxic intrauterine environment, the well-oxygenated newborn pig heart did not depend on anaerobic metabolism of glucose for energy production at physiologic work loads.

Adenosine Triphosphate↗
PubMed1980

Measurement of changes in high-energy phosphates in the cardiac cycle using gated 31P nuclear magnetic renonance.

Levels of the high-energy phosphate-containing compounds, ATP and creatine phosphate, and of inorganic phosphate (Pi) were measured as a function of position in the cardiac cycle. Measurements were made on isolated, perfused, working rat hearts through the use of gated 31P nuclear magnetic resonance spectroscopy. Levels of ATP and creatine phosphate were found to vary during the cardiac cycle and were maximal at minimal aortic pressure and minimal at maximal aortic pressure. Pi varied inversely with the high-energy phosphates.

Adenosine Triphosphate↗
PubMed1980

Regulation of protein synthesis and degradation during in vitro cardiac work.

Cardiac work increased protein synthesis in hearts supplied glucose (mixture 1), glucose-insulin-glucagon-lactate-beta-hydroxybutyrate (mixture 2) or palmitate-beta-hydroxybutyrate-glucose (mixture 3). In hearts provided mixture 1, acceleration of synthesis involved increased rates of peptide chain initiation. In these hearts intracellular concentrations of 5 amino acids decreased and 13 others were unchanged, indicating that faster protein synthesis did not depend on increased amino acid availability. In hearts supplied mixtures 2, 3, or 4 (lactate-glucose-insulin), intracellular concentrations of branched-chain amino acids were decreased by work, whereas intracellular levels of some acidic and neutral amino acids increased. Protein degradation was decreased by work in hearts supplied mixtures 1 and 2, but not mixtures 3 and 4. In hearts provided mixture 1, nitrogen balance was negative, but less so in working preparations. Nitrogen balance was zero or positive in working hearts provided mixtures 2 and 4. These studies indicated that in hearts supplied some, but not all, of the substrate mixtures, cardiac work maintained efficiently of protein synthesis and inhibited protein degradation. An improved method for perfusion of working hearts with albumin-containing buffer is described.

Amino Acids↗
PubMed1980

Effects of diabetes on protein turnover in cardiac muscle.

Effects of alloxan diabetes of 10-day duration on protein turnover were investigated in hearts perfused with buffers simulating control and diabetic sera. Diabetes produced a 30% inhibition of protein synthesis in hearts perfused as Langendorff or working preparations. This reduction was attributable to a 20% fall in RNA concentration and a 10% decrease in efficiency of protein synthesis. Determination of RNA in ribosomal subunits indicated that the reduction in efficiency that was observed with diabetes may be due to an inhibition of polypeptide chain elongation/termination. Pharmacological levels of insulin (25 mU/ml) and cardiac work stimulated protein synthesis in both control and diabetic hearts. Effects of diabetes and insulin on protein synthesis in isolated heart muscle cells were similar to those found in whole heart. Diabetes increased protein degradation in hearts perfused with buffer similating diabetic serum and under conditions of cardiac work. Insulin (25 mU/ml) decreased protein degradation in both control and diabetic hearts. These studies indicate that long-term diabetes produces a greater negative nitrogen balance that, in contrast to control hearts, cannot be normalized by pharmacological levels of insulin or by cardiac work.

Amino Acids↗
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

A role for leucine in regulation of protein turnover in working rat hearts.

Effect of leucine on protein turnover was examined in perfused hearts provided with 1 (0.2 mM) or 5 times (1 mM) plasma levels of leucine and normal plasma levels of other amino acids. When hearts were perfused as Langendorff or working preparations with buffer that contained 15 mM glucose, protein degradation was 2-3 times faster than protein synthesis. As a result, the heart was in marked negative nitrogen balance. Addition of 1 mM leucine significantly improved the nitrogen balance (24-33%) by stimulating protein synthesis in Langendorff preparations (25%) and inhibiting protein degradation in both preparations (14-29%). The stimulatory effect of leucine on protein synthesis was associated with a reduction in levels of ribosomal subunits. In hearts supplied physiological levels of glucose, lactate, beta-hydroxybutyrate, insulin, and glucagon, protein synthesis was more nearly equal to protein degradation. Provision of 1 mM leucine stimulated protein synthesis only in Langendorff preparations (32%) but did not have a significant effect on protein degradation in either preparation. Although leucine did not have a significant effect on either protein synthesis or degradation in working hearts, nitrogen balance became positive with addition of 1 mM leucine. These results suggest that leucine may exert an effect on myocardial nitrogen balance in vivo under conditions that elevate plasma leucine concentrations.

Animals↗
PubMed1980

Effects of glucocorticoids on peptide chain initiation in heart and skeletal muscle.

Treatment of rats for 5 days with cortisone acetate reduced synthesis of skeletal muscle protein by 56% compared to untreated controls, but had no effect on protein synthesis in heart. The reduction in synthesis in skeletal muscle was accounted for by both a loss of tissue RNA and development of a block in peptide-chain initiation. Activity of an eIF-2-like initiation factor decreased in psoas muscle of hormone-treated rats in proportion to the loss of RNA. Peptide-chain initiation, RNA content, and initiation factor activity were unaffected in heart muscle. In skeletal muscle of rats treated for 4 hr with dexamethasone, peptide-chain initiation was inhibited, whereas tissue RNA content and initiation factor activity were unchanged. These experiments suggested that total activity of eIF-2 did not always correlate with the rate of initiation, but that there did appear to be a relationship between initiation factor activity and tissue RNA content. Purification of eIF-2 from bovine heart muscle was undertaken in order to directly investigate the mechanism by which glucocorticoids modify eIF-2-activity and control peptide-chain initiation.

Animals↗
PubMed1980

Inhibition of protein degradation in the energy-poor heart.

Hypoxia and anoxia were induced in isolated perfused rat hearts by reduction of perfusate oxygen. Ischemia was produced by restricting coronary flow in hearts working against high resistance. Protein degradation, estimated from release of phenylalanine into the perfusate in the presence of cycloheximide, was inhibited in both anoxic and ischemia as compared to aerobic hearts. The effect of ischemia was greater than that of anoxia. A similar inhibitory effect was observed in energy-poor hearts when insulin was present in the perfusate. Other experiments indicated that the effects of energy depletion were exerted at a step early in the degradative pathway, since peptide products of partial proteolysis did not accumulate. A graded reduction in perfusate oxygen tension (hypoxia) led to a significant inhibition of proteolysis with unaltered tissue levels of nucleotides and creatine phosphate. Protein degradation was inhibited in aerobic and anoxic hearts exposed to increasing extracellular levels of hydrogen ions and lactate, suggesting that reduced proteolysis in hearts that are provided limited oxygen may result from accumulation of metabolites as well as from energy depletion per se.

Adenosine Triphosphate↗
PubMed1979

Effect of leucine and metabolites of branched chain amino acids on protein turnover in heart.

Leucine, but not isoleucine or valine, inhibited protein degradation and accelerated protein synthesis in hearts perfused with buffer that contained glucose (15 mM) and normal plasma levels of other amino acids, except for the branched chain compounds. Products of leucine, isoleucine, and valine metabolism also inhibited protein degradation and stimulated protein synthesis. These compounds included the transamination and decarboxylation products, as well as acetate, acetoacetate, and propionate. In some, but not all instances, inhibition of degradation and acceleration of synthesis were accompanied by an increase in intracellular leucine. When insulin was added to the perfusate, the rate of degradation was reduced by 40%, but addition of leucine was ineffective in the presence of the hormone. Insulin, leucine (2 mM) and a mixture of branched chain amino acids at normal plasma levels increased latency of cathepsin D in hearts that were perfused with buffer containing glucose. A combination of leucine and insulin increased latency more than either substance alone. These studies indicate that leucine as well as a variety of substrates that are oxidized in the citric acid cycle are involved in regulation of protein turnover in heart muscle.

Amino Acids↗