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M F Vincent

Publications and source records attributed to M F Vincent.

At least 55 records · Page 3Linked to original sources
PubMed1991

Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes.

5-Amino-4-imidazolecarboxamide (AICA) riboside, the nucleoside corresponding to AICA ribotide (AICAR or ZMP), an intermediate of the de novo pathway of purine biosynthesis, was found to exert a dose-dependent inhibition on gluconeogenesis in isolated rat hepatocytes. Production of glucose from lactate-pyruvate mixtures was half-maximally inhibited by approximately 100 microM and completely suppressed by 500 microM AICA riboside. AICA riboside also inhibited the production of glucose from all other gluconeogenic precursors investigated, i.e., fructose, dihydroxyacetone, and L-proline. Measurements of intermediates of the glycolytic-gluconeogenic pathway showed that AICA riboside provoked elevations of triose phosphates and fructose-1,6-bisphosphate and decreases in fructose-6-phosphate and glucose-6-phosphate. The effects of AICA riboside persisted when the cells were washed 10 min after its addition but were suppressed by 5-iodotubercidin, an inhibitor of adenosine kinase. AICA riboside provoked a dose-dependent buildup of normally undetectable Z nucleotides. After 20 min of incubation with 500 microM AICA riboside, ZMP, ZTP, and ZDP reached 3, 0.3, and 0.1 mumol/g cells, respectively. Concentrations of ATP were not significantly modified by addition of up to 500 microM AICA riboside when the cells were incubated with lactate-pyruvate but decreased with fructose or dihydroxyacetone. The activity of rat liver fructose-1,6-bisphosphatase was inhibited by ZMP with an apparent Ki of 370 microM. It is concluded that AICA riboside exerts a suppressive effect on gluconeogenesis because it provokes an accumulation of ZMP, which inhibits fructose-1,6-bisphosphatase.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Kinase↗
PubMed1989

Stimulation by glycerate 2,3-bisphosphate: a common property of cytosolic IMP-GMP 5'-nucleotidase in rat and human tissues.

Glycerate 2,3-bisphosphate, a potent stimulator of the cytosolic 5'-nucleotidase which preferentially hydrolyzes IMP and GMP in human erythrocytes (Bontemps et al., 1988, Biochem. J. 250, 687-696), also stimulates the dephosphorylation of IMP in cytosol fractions of rat heart, liver, brain, kidney, spleen and erythrocytes, and of human polymorphonuclear leucocytes, mixed peripheral blood lymphocytes, platelets and fibroblasts. Depending on the cell type, stimulation by 5 mM glycerate 2,3-bisphosphate varied from 1.5- to 12-fold. Where investigated, glycerate 2,3-bisphosphate had an approx. 5-fold higher affinity for the enzyme than its other stimulator, ATP. These observations provide a useful tool to distinguish IMP-GMP 5'-nucleotidase from other 5'-nucleotidases, and suggest a common origin of the cytosolic IMP-GMP 5'-nucleotidase in various tissues.

2,3-Diphosphoglycerate↗
PubMed1989

Increase in phosphoribosyl pyrophosphate induced by ATP and Pi depletion in hepatocytes.

A series of compounds that induce depletion of ATP and Pi when added to isolated rat hepatocytes were found to cause a remarkable, although transient, elevation in the concentration of phosphoribosyl pyrophosphate (PRPP) in these cells. After the addition of 5 mM fructose, xylitol, tagatose, or D-xylulose, PRPP increased from a basal value of 6 +/- 1 nmol/g of cells to, respectively, 68 +/- 11, 42 +/- 11, 67 +/- 22, and 530 +/- 50 nmol/g of cells (means +/- SEM of 3-9 experiments). In each case, the increase in PRPP was preceded by a latency period of 5-10 min. PRPP reached maximal levels 15 min after the addition of fructose and 30 min after that of xylitol and D-xylulose, but continued to increase for as long as 60 min after the addition of tagatose. Most striking was that the increase in PRPP closely paralleled the restoration of intracellular Pi. Ribose 5-P increased about two- to fivefold after the addition of fructose, xylitol, and tagatose, and approximately 12-fold after D-xylulose. The mechanism by which ATP- and Pi-depleting compounds stimulate the activity of PRPP synthetase in isolated rat hepatocytes is discussed.

Adenosine Triphosphate↗
PubMed1989

D-xylulose-induced depletion of ATP and Pi in isolated rat hepatocytes.

Xylitol is known to cause hepatic ATP catabolism by inducing the trapping of Pi in the form of glycerol 3-P as a consequence of an increase in the NADH:NAD+ ratio, resulting from the oxidation of xylitol to D-xylulose. The question was therefore raised whether D-xylulose also depletes hepatic ATP. In isolated rat hepatocytes, 5 mM D-xylulose decreased ATP by 80% within 5 min compared to 40% with 5 mM xylitol. Intracellular Pi decreased by 70% within the same time interval with both compounds, but was restored three-fold faster with D-xylulose. The rate of utilization of D-xylulose reached 5 mumol.min-1.g-1 of cells, as compared with 1.5 for xylitol, indicating that reduction of xylitol into D-xylulose is a rate-limiting step in the metabolism of the polyol. D-Xylulose barely modified the concentration of glycerol 3-P but increased xylulose 5-P from 0.02 to 0.5 mumol/g within 5 min. The main cause of the ATP- and Pi-depleting effects of D-xylulose was found to be an accumulation of sedoheptulose 7-P from a basal value of 0.1 to 5 mumol/g of cells after 10 min. Ribose 5-P increased from 0.03 to 0.5 mumol/g at 5 min. Ribose 1-P also accumulated, albeit outside of the cells. This extracellular accumulation can be explained by the release of intracellular purine nucleoside phosphorylase from damaged hepatocytes acting on inosine that had diffused out of the cells. Smaller increases in the concentrations of sedoheptulose 7-P and pentose phosphates were recorded after incubations of the cells with xylitol.

Adenosine Triphosphate↗
PubMed1989

Pathways and control of adenine nucleotide catabolism in anoxic rat hepatocytes.

Studies are reviewed that show that in isolated rat hepatocytes subjected to anoxia, the catabolism of AMP, leading to uric acid instead of to allantoin in normoxia, proceeds almost exclusively by deamination of AMP followed by dephosphorylation of IMP. Adenosine, which is nearly undetectable in normoxic cell suspensions, accumulates to a slight extent in anoxia. The regulatory properties of liver AMP deaminase and cytosolic IMP-GMP 5'-nucleotidase were found to provide protective mechanisms for the hepatic adenine nucleotide pool in hypoxia.

5'-Nucleotidase↗
PubMed1988

Adenylosuccinase deficiency: an inborn error of purine nucleotide synthesis.

Clinical and biochemical data are presented on eight children with adenylosuccinase deficiency. This newly discovered inborn error of purine metabolism is characterized by an accumulation in body fluids of succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICA riboside), the dephosphorylated derivatives of the two substrates of adenylosuccinase. Six living children (three boys and three girls) and one deceased sibling displayed severe psychomotor retardation. Epilepsy was documented in five cases, autistic features in three, and growth retardation associated with muscular wasting in a brother and sister. In the cerebrospinal fluid, plasma and urine of these patients, the S-Ado/SAICA riboside ratio was between 1 and 2. In striking contrast, the eighth patient (a girl) was markedly less mentally retarded. Most noteworthy, the S-Ado/SAICA riboside ratio in her body fluids was around 5, suggesting that her milder psychomotor retardation was causally linked to this higher ratio. Adenylosuccinase deficiency was demonstrated in the liver of all seven living children, in the kidney of three patients in whom the enzymatic activity was measured, and in the muscle of three patients, including the two with muscular wasting. In fibroblasts of the six severely retarded patients, adenylosuccinase activity was reduced to approximately 40% of normal; in the patient with the higher S-Ado/SAICA riboside ratio, it reached only 6% of normal. The clinical heterogeneity of adenylosuccinase deficiency justifies systematic screening for the enzyme defect in unexplained neurological disease.

Adenylosuccinate Lyase↗
PubMed1988

Cytosolic purine 5'-nucleotidases of rat liver and human red blood cells: regulatory properties and role in AMP dephosphorylation.

Of the various species of cellular 5'-nucleotidases, membranous, lysosomal and cytosolic, only the latter are likely to play a role in the physiologic dephosphorylation of the 5'-nucleoside monophosphates present in the cytoplasm. The necessity to preserve cellular ATP renders a strict control of the dephosphorylation as well as of the deamination of AMP mandatory, because both nucleotides are maintained in equilibrium by adenylate kinase. Our studies of cytosolic purine 5'-nucleotidases purified from rat liver and from human erythrocytes, reviewed in this presentation, have shown that both display complex kinetic properties. Both enzymes have markedly higher affinities for IMP and for GMP than for AMP. In addition, they are stimulated by nucleoside triphosphates, among them ATP and GTP, and inhibited by Pi. The erythrocytic purine 5'-nucleotidase is also stimulated by glycerate 2,3-bisphosphate. It could thus be expected that under conditions of ATP and GTP breakdown, particularly when accompanied by an increase in Pi, the dephosphorylation of AMP would be curtailed. To verify this hypothesis, experiments were performed with isolated rat hepatocytes and with human red blood cells. The rate of dephosphorylation of AMP was measured by following time-wise the production of adenosine in the presence of coformycin (or deoxycoformycin) and 5-iodotubercidin. The coformycins inhibit the deamination of adenosine into inosine by adenosine deaminase, and 5-iodotubercidin inhibits the recycling of adenosine into AMP by adenosine kinase. Upon induction of ATP catabolism by the addition of fructose to isolated rat hepatocytes, the dephosphorylation of AMP was nearly completely suppressed. In accordance with these results, the activity of the rat liver cytosolic 5'-nucleotidase, assayed in the presence of concentrations of substrate and effectors mimicking those measured in intact cells following the addition of fructose, was decreased as compared to control conditions. In hepatocytes in which ATP catabolism was induced by suppression of oxygen, the rate of dephosphorylation of AMP increased about 3-fold. However, in contradiction with these data, the activity of the cytosolic 5'-nucleotidase, measured under conditions mimicking anoxia, decreased markedly. In human erythrocytes, dephosphorylation of AMP did not occur under physiologic conditions, but proceeded when ATP catabolism was induced by glucose lack or by alkalinization. The rate of dephosphorylation of AMP was 3-fold higher during glucose deprivation than under alkaline conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Monophosphate↗
PubMed1987

Myocardial protection by intracoronary nicardipine administration during percutaneous transluminal coronary angioplasty.

To determine if the calcium antagonist nicardipine protects the myocardium against ischemia, myocardial lactate, hypoxanthine and prostanoid function was studied in 12 patients during percutaneous transluminal coronary angioplasty (PTCA). Values were obtained before balloon inflation and during 4 minutes after deflation. Intracoronary injection of 0.2 mg of nicardipine distal to the stenosis was done randomly before the first or second inflation; the other inflation served as a control. One minute after deflation, coronary sinus flow levels were similar during the nicardipine and control procedure (161 +/- 61 vs 159 +/- 72 ml/min); lactate (-9 +/- 21% vs -17 +/- 21%, p less than 0.025) and hypoxanthine production (-107 +/- 85% vs -218 +/- 153%, p less than 0.05) were less severe after nicardipine pretreatment than after control. All patients reverted to lactate extraction 4 minutes after inflation plus nicardipine infusion, whereas lactate was still produced 4 minutes after control inflation. No significant changes in thromboxane B2 or prostacyclin levels were observed in the coronary sinus 1 minute after inflation, but higher arterial thromboxane B2 values were observed after control inflation than after inflation with nicardipine infusion (median values 169 vs 78 pg/ml, p less than 0.05). In conclusion, intracoronary infusion of nicardipine reduced signs of ischemia and alterations in prostanoid handling after coronary occlusion. The mechanisms of myocardial protection appeared unrelated to coronary sinus blood flow changes or to a systemic effect of nicardipine.

Angina Pectoris↗
PubMed1985

Effects of nicardipine on coronary blood flow, left ventricular inotropic state and myocardial metabolism in patients with angina pectoris.

The effects of intravenous nicardipine (2.5 mg) on the left ventricular (LV) inotropic state, LV metabolism, and coronary haemodynamics were analysed in 22 patients with angina pectoris. Measurements were made at fixed heart rate (atrial pacing), under basal state, and during a cold pressor test. After nicardipine, coronary blood flow and oxygen content in the coronary sinus increased significantly. The indices of inotropic state increased slightly, and the rate of isovolumic LV pressure fall improved. Myocardial oxygen consumption was unchanged despite the significant reduction in pressure-rate product, but LV lactate uptake increased, particularly during the cold pressor test. When nicardipine was administered after propranolol, the indices of inotropic state were unaffected. The lack of direct effect of nicardipine on LV inotropic state was further confirmed by intracoronary injection of 0.1 and 0.2 mg in a separate group of 10 patients. It is concluded that the nicardipine-induced coronary dilatation seems to improve perfusion and aerobic metabolism in areas with chronic ischaemia, resulting in reduced lactate production and augmented oxygen consumption.

Adrenergic beta-Antagonists↗
PubMed1985

[Role of adrenergic beta receptor partial agonists in left ventricular failure of ischemic origin. Value of xamoterol (ICI 118,587, Corwin)].

The ideal sympathomimetic derivative should possess the positive inotropic and relaxing effects of catecholamines whilst remaining free of their side-effects. Theoretically, such properties could be present in beta 1-adrenoceptor partial agonists. Xamoterol (ICI 118,587, Corwin; ISA 43 p. 100) seems to be the most promising beta 1 partial agonist. The aim of the study was to determine if the beneficial effects of Xamoterol were maintained during long term administration. Xamoterol (200 mg twice dialy) was administered to 14 patients with anterior myocardial infarction and moderate heart failure (class II-III NYHA). After 3 months' therapy, left ventricular function improved as indicated by reduction in left ventricular (LV) end-diastolic pressure (23 +/- 5 to 16 +/- 5 mm Hg; P less than 0.0005), LV end-diastolic volume (153 to 140 ml/m2; P less than 0.05) and in LV end-systolic volume especially in 11 patients with a control end-systolic volume less than 100 ml/m2 (- 15 p. 100; P less than 0.05). LV inotropic state was also enhanced as indicated by 21 p. 100 increases in EMax, the maximal LV pressure/volume ratio (P less than 0.02) and 20 p. 100 increases in the ratio end-systolic stress/ end-systolic volume (P less than 0.02). Myocardial oxygen consumption was unchanged, global lactate extraction fraction increased from 20 +/- 18 to 33 +/- 14 p. 100 (P less than 0.05) and LV alanine release was reduced (-1.7 to -0.2 muMol/min; P less than 0.05). The rate of LV pressure fall accelerated from 57 to 52 ms (P less than 0.05) and the mean diastolic wall stress was reduced by 35 p. 100 (P less than 0.05), reflecting the improvement in LV relaxation and diastolic function. Thus, the beneficial effects of Xamoterol were maintained after prolonged therapy particularly in patients with class II-III heart failure; patients in class IV benefited less from this therapy. No tachyphylaxis or side-effects were observed.

Administration, Oral↗
PubMed1984

Effects of nicardipine and nisoldipine on myocardial metabolism, coronary blood flow and oxygen supply in angina pectoris.

The effects of the calcium antagonists nicardipine and nisoldipine on left ventricular (LV) metabolism were analyzed in 32 patients with angina pectoris. Measurements were made at a fixed heart rate under the basal state and during a cold pressor test (CPT). After administration of the drugs, coronary blood flow increased significantly and the mean aortic pressure decreased by 10% (p less than 0.01) in the basal state and by 11% (p less than 0.01) during CPT. Despite the reduction in pressure-rate product, myocardial oxygen consumption was unchanged in the basal state (18 +/- 4 vs 19 +/- 4 ml/min, difference not significant) and during CPT (21 +/- 5 vs 21 +/- 5 ml/min, difference not significant); this discrepancy between a reduced pressure-rate product and an unchanged oxygen consumption was also noted when nicardipine was given after propranolol (0.1 mg/kg; 12 patients). Both agents also increased LV lactate uptake, particularly during CPT (+13 mumol/min, p less than 0.05 vs control CPT) and reduced LV glutamine production. In 10 patients in whom 14C-lactate was infused, the chemical LV lactate extraction ratio increased more than the 14C-lactate extraction ratio after administration of the drugs, indicating a reduction in LV lactate production. The data are consistent with the hypothesis that nicardipine and nisoldipine improve perfusion and aerobic metabolism in chronically ischemic areas, resulting in an augmented oxygen consumption and in a reduced lactate production.

Aged↗
PubMed1984

Metabolism of hypoxanthine in isolated rat hepatocytes.

The hepatic metabolism of hypoxanthine was investigated by studying both the fate of labelled hypoxanthine, added at micromolar concentrations to isolated rat hepatocyte suspensions, and the kinetic properties of purified hypoxanthine/guanine phosphoribosyltransferase from rat liver. More than 80% of hypoxanthine was oxidized towards allantoin; less than 5% of the label was incorporated into the purine mononucleotides, and a similar proportion appeared transiently in inosine. The maximal velocity of oxidation (approx. 750nmol/min per g of cells) was in close agreement with the known activity of xanthine oxidase in liver extracts. In contrast, the maximal velocity of the incorporation of labelled hypoxanthine into mononucleotides reached only 30nmol/min per g of cells, compared with an activity of hypoxanthine/guanine phosphoribosyltransferase, measured at substrate concentrations analogous to those prevailing intracellularly, of 500nmol/min per g of cells. Hypoxanthine incorporation into the mononucleotides was decreased by allopurinol, anoxia and ethanol, despite inhibition of its oxidation under these conditions; it was increased by incubation of the cells in supraphysiological concentrations of Pi. Allopurinol and anoxia decreased the concentration of phosphoribosyl pyrophosphate inside the cells by respectively 40 and 60%, ethanol had no effect on the concentration of this metabolite and Pi increased its concentration up to 10-fold. The kinetic study of purified hypoxanthine/guanine phosphoribosyltransferase showed that a mixture of ATP, IMP, GMP and GTP, at the concentrations prevailing in the liver cell, decreased the V max. of the enzyme 6-fold, increased its Km for hypoxanthine from 1 to 4 microM and its Km for phosphoribosyl pyrophosphate from 2.5 to 25 microM. In the presence of 5 microM-hypoxanthine and 2.5 microM-phosphoribosyl pyrophosphate, the mixture of nucleotides inhibited the activity of purified hypoxanthine/guanine phosphoribosyltransferase by 95%. It is concluded that this inhibition results in a limited participation of hypoxanthine/guanine phosphoribosyltransferase in the control of the production of allantoin by the liver.

Allopurinol↗