The molecular order of synthesis and mobilization of glycogen in the perfused heart was studied by 13C NMR. By varying the glucose isotopomer ([1-13C]glucose or [2-13C]glucose) supplied to the heart, glycogen synthesized at different times during the perfusion was labeled at different carbon sites. Subsequently, the in situ mobilization of glycogen during ischemia was observed by detection of labeled lactate derived from glycolysis of the glucosyl monomers. When [1-13C]glucose was given initially in the perfusion and [2-13C]glucose was given second, [2-13C]lactate was detected first during ischemia and [3-13C]lactate second. This result, and the equivalent result when the glucose labels were given in the reverse order, demonstrates that glycogen synthesis and mobilization are ordered in the heart, where glycogen is found morphologically only as beta particles. Previous studies of glycogen synthesis and mobilization in liver and adipocytes [Devos, P., & Hers, H.-G. (1979) Eur. J. Biochem. 99, 161-167; Devos, P., & Hers, H.-G. (1980) Biochem. Biophys. Res. Commun. 95, 1031-1036] have suggested that the organization of beta particles into alpha particles was partially responsible for ordered synthesis and mobilization. The observations reported here for cardiac glycogen suggest that another mechanism is responsible. In addition to examining the ordered synthesis and mobilization of cardiac glycogen, we have selectively monitored the NMR properties of 13C-labeled glycogen synthesized early in the perfusion during further glycogen synthesis from a second, differently labeled substrate. During synthesis from the second labeled glucose monomer, the glycogen resonance from the first label decreased in integrated intensity and increased in line width.(ABSTRACT TRUNCATED AT 250 WORDS)
Tracer studies of pyrimidine biosynthesis in Lactobacillus leichmannii (ATCC 7830) indicated that, while aspartate is utilized in the usual manner, the guanido carbon of arginine, rather than carbon dioxide, is utilized as a pyrimidine precursor. The guanido carbon of arginine also contributes, to some extent, to the carbon dioxide pool utilized for purine biosynthesis. The enzyme of the first reaction leading from arginine to pyrimidines, arginine deiminase, was investigated in crude bacterial extracts. It was inhibited by thymidylic acid and purine ribonucleotides, and to a lesser extent by purine deoxynucleotides and deoxycytidylic acid. Under the assay conditions employed, a number of nucleotides had no effect on the enzyme activity of the aspartate transcarbamylase of L. leichmannii. Growth of the cells in media containing uracil, compared to growth in media without uracil, resulted in a fourto fivefold decrease in the concentrations of aspartate transcarbamylase and dihydroorotase and a twofold increase in the concentration of arginine deiminase, as estimated from specific enzyme activity in crude extracts of the cells. A small increase in specific enzyme activity of ornithine transcarbamylase and carbamate kinase was also observed in extracts obtained from cells grown on uracil. No appreciable change in concentration of any of the five enzymes studied was detected when the cells were grown in media containing thymidine or guanylic acid. A hypothetical scheme which suggests a relationship between the control of purine and pyrimidine biosynthesis in this bacterium and which is consistent with the experimental results obtained is presented.
The effects of 11.7 mM glucose, insulin, and potassium (GIK) on metabolism during ischemia were investigated in the perfused guinea pig heart using magnetic resonance spectroscopy. Intracellular metabolites, primarily glycogen and glutamate, were labeled with I3 C by addition of [l-13 C]glucose to the perfusate during a normoxk, preischemic period. 13C and 31 P NMR spectroscopy was used to observe the metabolism of "C-labeled metabolites simultaneously with high-energy phosphorus metabolites and pH. The extent of acidosis and the rate and amount of labeled lactate accumulation during ischemia were the same in control (3 mM glucose + insulin) and GIK-treated hearts. In contrast, the rate of labeled glycogen mobilization during ischemia in GIK-treated hearts was one third the rate observed in control hearts. These observations suggest that GIK decreased the rate of glycogenolysis during ischemia without affecting the rate of glycolysis. We propose that glucose contributed as a glycolytic substrate to a greater extent during ischemia in GIK-treated hearts than in hearts perfused with 3 mM glucose and insulin. The glycogen-sparing effect of GIK demonstrated in these studies could delay the onset of ischemic damage in a clinical setting by prolonging the availability of glycolytic substrate necessary for production of high-energy phosphate. (Circulation Research 1988;62:1065-1074 M yocardial ischemia is a common and important clinical problem. Although metabolism of the ischemic myocardium has been an area of active investigation for many years, the metabolic changes resulting from the inadequate oxygen and substrate supply and product removal associated with ischemia are incompletely understood. However, it is clear that one of the important metabolic events leading to cellular damage during ischemia is failure of the rate of energy production to meet the demands for energy utilization.Several therapeutic strategies have been introduced to alter cardiac metabolism during ischemia. A mixture of glucose, insulin, and potassium (GIK) was initially used 25 years ago as a means of eliminating the electrocardiographic abnormalities of myocardial infarction.1 Since that time GIK has been used in numerous studies of coronary artery occlusion in animals and man. Nearly all of the animal studies, using a variety of measures of recovery, have shown reduced infarct size and improved tissue metabolism.2 " 3 Studies in man have been less conclusive. Infusion of GIK in patients Received November 6, 1986; accepted January 6, 1988. with acute myocardial infarction has resulted in improved left ventricular function, 6 improved electrical stability, 7 clinical improvement, 8 and reduced mortality. 9 Other studies have found no reduction in mortality.l 0 " In patients with stable angina pectoris and coronary artery disease, administration of GIK, together with cardiac pacing, was beneficial in some studies 12 and detrimental in others.13M A better understanding of the metabolic action of GDC may explain many of these contradicto...
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