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At least 19 recordsLinked to original sources
PubMed1976

Inosine-stimulated insulin release and metabolism of inosine in isolated mouse pancreatic islets.

Inosine is a potent primary stimulus of insulin secretion from isolated mouse islets. The inosine-induced insulin secretion was totally depressed during starvation, but was completely restored by the addition of 5 mM-caffeine to the medium and partially restored by the addition of 5 mM-glucose. Mannoheptulose (3 mg/ml) potentiated the effect of 10 mM-inosine in islets from fed mice. The mechanism of the stimulatory effect of inosine was further investigated, and it was demonstrated that pancreatic islets contain a nucleoside phosphorylase capable of converting inosine into hypoxanthine and ribose 1-phosphate. Inosine at 10 mM concentration increased the lactate production and the content of ATP, glucose 6-phosphate (fructose 1,6-diphosphate + triose phosphates) and cyclic AMP in islets from fed mice. In islets from starved mice inosine-induced lactate production was decreased and no change in the concentration of cyclic AMP could be demonstrated, whereas the concentration of ATP and glucose 6-phosphate rose. Inosine (10 mM) induced a higher concentration of (fructose 1,6-diphosphate + triose phosphates) in islets from starved mice than in islets from fed mice suggesting that in starvation the activities of glyceraldehyde 3-phosphate dehydrogenase or other enzymes below this step in glycolysis are decreased. Formation of glucose from inosine was negligible. Inosine had no direct effect on adenylate cyclase activity in islet homogenates. The observed changes in insulin secretion and islet metabolism mimic what is seen when glucose and glyceraldehyde stimulate insulin secretion, and as neither ribose nor hypoxanthine-stimulated insulin release, the results are interpreted as supporting the substrate-site hypothesis for glucose-induced insulin secretion according to which glucose has to be metabolized in the beta-cells before secretion is initiated.

Adenosine Triphosphate↗
PubMed1975

Enzymatic formation of inosine 3',5'-monophosphate and of 2'-deoxyguanosine 3',5'-monophosphate. Inosinate and deoxyguanylate cyclase activity.

Enzymes in particulate fractions from sea urchin sperm and in soluble fractions from rat lung were shown to catalyze the formation of inosine 3',5'-monophosphate (cyclic IMP) and of 2'-deoxyguanosine 3',5'-monophosphate (cyclic dGMP) from ITP and dGTP, respectively. With sea urchin sperm particulate fractions, Mn2+ was an essential metal cofactor for inosinate, deoxyguanylate, guanylate and adenylate cyclase activities. Heat-inactivation studies differentiated inosinate and deoxyguanylate cyclase activities from adenylate cyclase, but indicated an association of these activities with guanylate cyclase. Preincubation of sea urchin sperm particulate fractions with trypsin altered in a very similar manner guanylate, inosinate, and deoxyguanylate cyclase activities, and various metals and metal-nucleotide combinations protected the three cyclase activities to comparable degrees against trypsin. The relative guanylate, deoxyguanylate and inosinate cyclase activities at 0.1 mM nucleoside triphosphate were 1.0, 0.5 and 0.08, respectively. With these three cyclase activities, plots of reciprocal velocities against reciprocal Mn2+-nucleoside triphosphate concentrations were concave upward, suggesting positive homotropic effects. With rat lung soluble preparations, relative guanylate, deoxyguanylate, inosinate and adenylate cyclase activities at 0.09 mM nucleoside triphosphate were 1.0, 1.7, 0.1 and 0, respectively. MnGTP was a competitive inhibitor of deoxyguanylate cyclase activity (Ki equals 12.2 muM) and MndGTP was a competitive inhibitor of guanylate cyclase activity (Ki equals 16.2 muM). Inhibition studies using ITP were not conducted. When soluble fractions from rat lung were applied to Bio-Gel A 1.5 m columns, elution profiles of guanylate, deoxyguanylate and inosinate cyclase activities were similar. These results suggest that deoxyguanylate, guanylate and inosinate cyclase activities reside within the same protein molecule.

Adenosine Triphosphate↗
PubMedDate not supplied

[Study of inosine transformation into 5'-inosinic acid by the culture of Pseudomonas trifoli].

The transformation of inosine into 5'-inosine acid by Pseudomonas trifolii cells was studied. The synthesis of 5'-inosine acid can be performed by both live intact and dry cells. The effectiveness of inosine phosphorylation depends on the ratio of the inosine and phosphate donor concentrations and the amount of cells. The temperature and pH effect on activity of nucleoside phosphotransferase, phosphomonoesterase and 5'-nucleotidase has been studied. The influence of surface active substances and metal ions on the synthesis of 5'-inosine acid has been investigated. Optimal conditions for the inosine transformation by the above culture have been established.

Cations, Divalent↗
PubMed1977

Factors affecting inosinate synthesis and inosine triphosphate accumulation in human erythrocytes.

Measurements of rates of inosinate synthesis from radioactive hypoxanthine by human erythrocytes show a large degree of individual variation. Rates of inosinate synthesis also vary with the pH and phosphate concentration of the incubation medium. This may be due to changes in the rate of phosphoribosyl pyrophosphate synthesis, and the stimulatory effect of phosphate on this process seems to be more important than the inhibitory effect of 2,3-diphodphoglycerate. The rate of inosinate synthesis, and especially the extent of accumulation of inosine triphosphate, increase disproportionately with time of incubation up to at least 24 h. Storage of erythrocytes also tends to increase inosinate synthesis and inosine triphosphate accumulation.

Anaerobiosis↗
PubMed1976

Inhibition of ribonucleotide reductase activity and nucleic acid synthesis in tumor cells by the dialdehyde derivatives of inosine (NSC 118994) and inosinic acid.

Periodate-oxidized inosine (Inox; NSC 118994) and periodate-oxidized 5'-inosinic acid (PI-IMP) were prepared and studied for their effects on ribonucleotide reductase activity in partially purified extracts from Ehrlich tumor cells and on nucleic acid synthesis in intact tumor cells in culture. Ribonucleotide reductase activity in cell-free extracts from Ehrlich tumor cells was inhibited by Inox and PI-IMP. PI-IMP was more inhibitory to the reductase activity than was Inox. Furthermore, the inhibition of ribonucleotide reductase activity by Inox and PI-IMP was greater for cytidine-5'-diphosphate reductase activity than for adenosine-5'-diphosphate reductase activity. The ribonucleotide reductase activity in cell-free extracts prepared from Ehrlich tumor cells treated with Inox or PI-IMP in culture was decreased compared with the activity in the extracts from untreated cells. Incorporation of labeled cytidine into the RNA and DNA of Ehrlich tumor cells in culture was inhibited by both Inox and PI-IMP. The conversion of cytidine to deoxycytidine nucleotides in the acid-soluble pool was likewise inhibited. These data indicate that Inox and PI-IMP inhibit the ribonucleotide reductase step as one of the sites of action of these compounds. However, the inhibition of RNA synthesis indicates that there must be additional sites of action of these nucleoside analogs.

Aldehydes↗
PubMed1978

Radical formation in single crystals of hypoxanthine.HCl.H2O, inosine, and the disodium salt of 5'-inosine-monophosphate.

Radical formation in single crystals of hypoxanthine.HCl.H2O, inosine and Na2-5'-IMP.(7.5 H2O) by X-irradiation has been studied using electron-spin-resonance spectroscopy at 9.5 and 35 GHz. In all crystals both H-addition radicals at position C2 and C8 of the purine ring are found. The coupling constants of these two radicals are different and depend strongly on the protonation state of the base. INDO-calculations indicate that the C8-radical is protonated at O6. In Na2-5'-IMP OH-addition radicals at position C2 of the purine ring are formed. Electron adduct radicals are found in the neutral and the N7-protonated base after X-irradiation at 77 K. In Na2-5'-IMP no electron adduct is formed but a radical which probably is the cation. In hypoxanthine.HCl.H2O a radical could be observed after X-irradiation at 77 K, which results from addition of a Cl- to the nitrogen N1.

Electron Spin Resonance Spectroscopy↗
PubMed1976

Regulation of purine nucleotide synthesis. Effects of inosine on normal and hypoxantine-guanine phosphoribosyltransferase-deficient fibroblasts.

Incubation of normal and hypoxanthine-guanine phosphoribosyltransferase-deficient (mutant) human fibroblasts with inosine results in increased intracellular concentration of 5-phosphoribosyl 1-pyrophosphate (PP-ribose-P). The magnitude of this increase is dependent on the concentration of the nucleoside and results from donation of the ribose moiety of inosine to the ribosyl phosphate moiety of PP-ribose-P through ribose phosphate intermediates. During incubation, rates of purine nucleotide synthesis de novo, estimated by incorporation of (14C) formate into formylglycinamide ribotide, are diminished in both normal and mutant cells: 5 mM inosine inhibits purine synthesis by 60-80% in normal cells and 2-20% in hypoxanthine-guanine phosphoribosyltransferase-deficient cells. The rates of purine synthesis in both normal and mutant cells are increased, however, during incubation with methylene blue at concentrations (50-100 muM) which result in more modest increases in ribose 5-phosphate and PP-ribose-P concentrations than are observed with inosine. Saturation of the PP-ribose-P amidotransferase reaction by PP-ribose-P does not appear, therefore, to explain the failure of increased PP-ribose-P concentration to stimulate the rate of purine synthesis in either type of fibroblast during incubation with inosine. Although the dissociation between PP-ribose-P concentration and the rate of purine nucleotide synthesis in normal fibroblasts incubated with inosine may be explained at least in part by an accompanying increase in intracellular concentrations of purine nucleotide feedback inhibitors, purine nucleotide concentrations are unchanged in mutant cells during incubation with inosine; these cells, in addition, show minimal (less than 3% of normal) incorporation of labeled hypoxanthine or the hypoxanthine moiety of inosine into purine nucleotides. The effect of inosine on purine synthesis de novo in hypoxanthine-guanine phosphoribosyltransferase-deficient fibroblasts is not explained in full by consideration of the concentrations of purine nucleotides and of PP-ribose-P, the factors frequently invoked as antagonistic regulators controlling the rate of this process.

Adult↗
PubMed1977

Positive inotropic response to inosine in the in situ canine heart.

Effects of inosine on left ventricular contractile force, circumflex blood flow, heart rate, and arterial pressure were investigated in mongrel dogs. Infusion of 50 ml of 10, 25, or 50 mM inosine into the right atrium over 5 min produced arterial blood inosine concentrations of 20-120 microM. Infusion of inosine concentrations of 10 mM or greater produced statistically significant increases in contractile force and circumflex blood flow (P less than 0.05). The increases in contractile force and circumflex blood flow caused by 50 inosine were approximately 40% and 110%, respectively. No statistically significant increases in heart rate or arterial pressure were observed during infusion of inosine at any concentration. Administration of propranolol (2 mg/kg) in no way altered the effects of inosine on contractile force or circumflex blood flow. Thus, the present study suggests that inosine in concentrations which may be produced in the myocardium during stressful conditions causes a substantial effect on the inotropic state of the heart and that the effects of inosine are not mediated through adrenergic mechanisms.

Animals↗
PubMed1977

Inosine uptake by cultured fibroblasts from normal and purine nucleoside phosphorylase-deficient humans.

Purine nucleoside phosphorylase-deficient cultured human fibroblasts accumulate inosine from the medium at 60% of the rate in wild type cells when the extracellular inosine concentration is 10 micronM and 30% of the normal rate when inosine is present at 100 micronM. When 10 micronM inosine is present, uridine but not hypoxanthine inhibits the accumulation of inosine. There exist two transport systems for inosine. One is shared with pyrimidine ribonucleosides and is the predominant one at 10 micronM inosine; the other is purine nucleoside phosphorylase-dependent and prevails at 100 micronM inosine.

Biological Transport↗
PubMedDate not supplied

The effect of nitroglycerin on myocardial release of inosine, hypoxanthine and lactate during pacing-induced angina.

The efficacy of nitroglycerin as an antianginal drug has been evaluated by calculation of myocardial extraction and production values of lactate and the adenosine triphosphate (ATP) catabolites inosine and hypoxanthine. Coronary venous and arterial blood was sampled at rest, during pacing-induced angina and 4--6 min after nitroglycerin at identical paced heart rates for enzymatic assay of inosine and hypoxanthine after separation by column chromatography and for determination of lactate. Sublingual nitroglycerin given to 10 patients with coronary artery disease decreased coronary venous lactate values from 1175 +/- 320 mumol/l during pacing-induced angina to 950 +/- 240 mumol/l (p less than 0.05). The calculated myocardial lactate production during angina (-31 +/- 19%) diminished after nitroglycerin (-1.7 +/- 22%) (p less than 0.0025). Coronary venous inosine values during angina (1275 +/- 865 nmol/l) decreased after nitroglycerin (795 +/- 555 nmol/l) (p = n.s.), the arterial values (885 +/- 610 nmol/l) increased (960 +/- 580 nmol/l) (p = n.s.), the myocardial inosine release (-26 +/- 20%) changed to extraction values (19 +/- 19%) (p less than 0.0005). Coronary venous hypoxanthine values during angina (1540 +/- 1035 nmol/l) were reduced (1110 +/- 675 nmol/l) (p = n.s.); the arterial values (1625 +/- 1050 nmol/l) decreased (1510 +/- 935 nmol/l) (p = n.s.), the myocardial hypoxanthine extraction (0.3 +/- 29%) with a wide individual variability increased after nitroglycerin (24 +/- 13%) (p less than 0.025). The myocardial release of inosine and lactate during severe angina with significant positive correlation (r = 0.66, p less than 0.0025) demonstrates that anaerobic glycolysis is accompanied by ATP breakdown. The unchanged myocardial inosine and hypoxanthine extraction after nitroglycerin indicates that nitroglycerin is capable of attenuating this effect. In spite of reduced mean myocardial lactate production after nitroglycerin ischemic myocardial energy deficiency may be less marked. Thus, the enhanced myocardial inosine uptake may be one factor contributing the beneficial effects of nitroglycerin including the improvement of myocardial oxygen balance.

Angina Pectoris↗
PubMedDate not supplied

Blood storage XXIII: 2,3-DPG maintenance for six weeks in a CPD-adenine-inosine preservative with and without methylene blue.

In a pilot study the optimal concentration of inosine for 2,3-DPG maintenance in a CPD-adenine (0.25 mM) preservative was confirmed to be at lease 10 mM. In these experiments, 2,3-DPG maintenance was nearly normal for six weeks of storage in CPD-adenine-inosine (10 mM) preservative with or without methylene blue. The control preservative lacking inosine showed a statistically significant decrease in 2,3-DPG concentrations after the 3rd week. Finally, 2,3-DPG levels were significantly better maintained in CPD-adenine preservatives that contained 15 mM concentrations of inosine, whether methylene blue was present or not (10(-6)M), compared to CPD-adenine-inosine preservatives that contained 5 mM inosine, with or without methylene blue. The methylene blue effect, while it can be demonstrated in most experiments to help the red blood cell maintain 2,3-DPG during prolonged blood storage, is judges to be a slight value. However, inosine is of great value in maintaining 2,3-DPG for prolonged (five to six weeks) liquid storage.

Adenine↗
PubMed1976

Germination of unactivated spores of Bacillus cereus T. Effect of preincubation with L-alanine or inosine on the subsequent germination.

Heat-activated spores of Bacillus cereus T germinate rapidly in the presence of L-alanine alone or inosine alone. In contrast, unactivated spores can not germinate in the presence of either germinant alone but rapidly in the presence of both germinants. The highest level of cooperative action of L-alanine and inosine on the germination was observed when they were present in a ratio 1:1. Preincubations of unactivated spores with L-alanine or inosine had opposite effects on the subsequent germination in the presence of both germinants: preincubation with L-alanine stimulated the initiation of subsequent germination, while preincubation with inosine inhibited it. These results suggest that germination of unactivated spores initiated by L-alanine and inosine includes two steps, the first initiated by L-alanine and the second prompted by inosine. The effect of preincubation of unactivated spores with L-alanine was not diminished by washings. The pH dependence of the preincubation of unactivated spores was not so marked as that of the subsequent germination in the presence of inosine.

Alanine↗
PubMed1979

The protective action of inosine on isolated arteries in hypoxia.

1 The pressor responses to injected noradrenaline (NA) of isolated perfused femoral or renal arteries of the rabbit were studied.2 Vascular smooth muscle is relatively resistant to hypoxia. A combination of hypoxia and dinitrophenol (DNP) respiratory uncoupling was necessary to abolish the pressor response to NA. Loss of the pressor response was assumed to result from decreased capacity of arteries to form adenosine 5'-triphosphate (ATP). Reperfusion of the hypoxic arteries with oxygenated medium resulted in recovery of the pressor response to NA.3 Inclusion of inosine (10 mM) in the hypoxic perfusion medium increased significantly the rate and extent of post-hypoxic recovery of the pressor response to NA.4 Whereas the presence of inosine in the hypoxic perfusion medium aided post-hypoxic recovery, inosine had no direct action on the pressor dose response to NA. Therefore, the action of inosine was protective as opposed to direct.5 The protective action of inosine did not involve potentiation of NA binding to NA-adrenoceptor sites (the equilibrium coefficient, K(eq) for NA-receptor interaction was unaltered by hypoxia and/or inosine).6 The results are discussed in terms of a presumptive mechanism whereby inosine is believed to act by maintaining intracellular adenine nucleotide concentrations in hypoxia.

Adenine Nucleotides↗
PubMed1975

The potentiation of the activity of adenosine on coronary blood flow, blood pressure and heart rate by inosine in the dog.

The activity of adenosine and inosine on coronary blood flow and arterial blood pressure was investigated in anaesthetized and thoracotomized dogs. The following results were obtained. 1. Individual adenosine administration caused an increase in coronary blood flow. However, this adenosine activity was significantly strengthened when the same dose of adenosine was applied simultaneously with inosine in doses of 3.2, 5.6 and 10.0 mg/kg body weight i.v. The duration of the effect of adenosine on the coronary blood flow was also potentiated by inosine. 2. The hypotensive effect resulting from 0.2 mg adenosine/kg i.v. was significantly strengthened by simultaneous inosine application (3.2, 5.6 and 10.0 mg/kg i.v.). The activities on the blood pressure of increments in the individual adenosine dosages (0.2, 0.4 and 0.6 mg/kg i.v.) were significantly potentiated by 10 mg inosine/kg body weight i.v. 3. The heart rate was not modified by 0.2 mg adenosine/kg i.v. However, the same adenosine dosage plus inosine (3.2, 5.6 and 10.0 mg/kg i.v.) applied simultaneously led to bradycardia. Increasing adenosine doses (0.2, 0.4 and 0.6 mg/kg i.v.) applied simultaneously with inosine (10.0 mg/kg body weight i.v.) led to a dose dependent retardation of the heart rate. 4. The possible reasons for the potentiation of the effect of adenosine by inosine were discussed.

Adenosine↗
PubMed1976

Effects of uridine and inosine on glucose metabolism in skeletal muscle and activated lipolysis in adipose tissue.

In a first series of experiments, the effects of uridine and inosine on glucose metabolism in rat diaphragm muscle incubated in Krebs-bicarbonate buffer were studied. Uridine in concentrations of 10(-4) to 10(-6) M stimulated the uptake of glucose and increased the content of glycogen, but had no effect on the production of lactate. When diaphragm muscles were incubated in the buffer without glucose, uridine (10(-4)-10(-6) M) had no effects on the content of glycogen and on the production of lactate. On the other hand, inosine in concentrations of 10(-4) to 10(-6) M stimulated the uptake of glucose and the production of lactate, but had no effect on the content of glycogen in the muscle. In a second series of experiments, uridine (10(-4)-10(-5) M) and inosine (10(-4)-10(-7) M) inhibited the relase of glycerol from isolated rat epididymal adipose tissue in Krebs-bicarbonate buffer. Uridine and inosine in concentrations of 10(-4) M inhibited the epinephrine (10(-5) M)-, the norepinephrine (10(-5) M)- and the theophylline (10(-3) M)-stimulated lipolysis. Dibutyryl 3',5'-adenosine monophosphate-stimulated lipolysis was further activated in the presence of 10(-4) M uridine or inosine. Dose-response curves studies suggested that inosine, but not uridine, has a common receptor site with epinephrine in adipose tissue. These results demonstrated that both nucleosides stimulated the glucose uptake, but only uridine increased the synthesis of glycogen in the muscle. Both nucleosides also inhibited lipolysis in adipose tissue. The mechanism of antilipolytic action of these nucleosides is unknown, but one of the receptor sites for inosine might be adenylate cyclase.

Adipose Tissue↗
PubMed1979

Myocardial release of inosine, hypoxanthine and lactate during pacing-induced angina in humans with coronary artery disease.

The applicability of the adenosine triphosphate (ATP) catabolites, inosine and hypoxanthine as markers of myocardial ischemia in humans with coronary artery disease has been investigated. Inosine and hypoxanthine were assayed enzymatically after separation by a new column chromatographic method. The myocardial lactate extraction at rest (17 +/- 13%) changed to production values (-23 +/- 28%) during pacing-induced angina (P less than 0.0005). Coronary venous inosine values increased from 535 +/- 185 nmol/l at rest to 1030 +/- 740 nmol/l during angina (P less than 0.005), the arterial values amounted to 770 +/- 325 nmol/l and 805 +/- 515 nmol/l respectively (P, NS). The calculated myocardial uptake of inosine at rest (27 +/- 16%) changed to production values (-25 +/- 29%) during angina (P less than 0.0005). Coronary venous hypoxanthine increased from 1000 +/- 760 nmol/l at rest to 1235 +/- 800 nmol/l during angina (P, NS), the arterial values amounted to 1300 +/- 1040 nmol/l and 1235 +/- 800 nmol/l respectively (P, NS). The myocardial extraction changed from 20 +/- 18% at rest to -5.4 +/- 29% during angina (P less than 0.0025). The significant positive correlation (r = 0.61, P less than 0.0025) between myocardial release and uptake of inosine and lactate during severe angina demonstrates that anaerobic glycolysis is accompanied by ATP breakdown. During a second pacing period at less increased pressure--rate product after nitroglycerin, lactate production (-1.7 +/- 22%) already occurred whereas extraction of inosine (19 +/- 19%) and hypoxanthine (24 +/- 15%) did not change. In conclusion, lactate functions as a sensitive marker of myocardial ischemia and inosine is useful in detecting ischemic myocardial energy deficiency by the indication of insufficient glycolytic ATP supply.

Adenosine Triphosphate↗
PubMed1976

Latency of inosine-5'-diphosphatase in microsomes isolated from rat liver.

The latency of inosine-5'-diphosphatase has been studied in microsomes isolated from rat liver. The appearance of latent activity was the result of an increase in the Vmax of the enzyme. This was observed when assays were carried out in the presence of sodium deoxycholate, after microsomes were treated wtih phospholipase C, or at pH 10.3 and after microsomes were subjected to nitrogen cavitation. The apparent Km of inosine-5'-diphosphatase for IDP was unchanged when microsomes were treated with phospholipase C or at pH 10.3 after both these treatments approximately 85% of the enzyme remained bound to the membrane. In contrast, when microsomes were treated with phospholipase C or at pH 10.3 after both these treatments approximately 85% of the enzyme remained bound to the membrane. In contrast, when microsomes were treated with sodium deoxycholate or subjected to nitrogen cavitation, approximately 75% of the inosine-5'-diphosphatase activity was released from the membrane, and the apparent Km of the enzyme for IDP increased 4- and 2-fold, respectively. Microsomal cisternae were loaded with lead phosphate by incubation with glucose-6-P and Pb2+, and the release of this lead phosphate following the addition of EDTA to the medium was determined to estimate the permeability of the microsomal membrane. When microsomes were treated with sodium deoxycholate, phospholipase C, or at alkaline pH, the microsomal membrane became almost completely permeable to EDTA under conditions where there was little or no increase in the activity of inosine-5'-diphosphatase. Microsomes were treated at pH 10.3 and then adjusted slowly to pH 7.5. The activity of inosine-5'-diphosphatase decreased to the same activity observed in untreated preparations. The results seem of exclude the possibility that latent inosine-5'-diphosphatase activity is the result of an increased permeability of the membrane to IDP. They are, however, consistent with the presence of a noncompetitive inhibitor of the enzyme in the microsomal membrane.

Animals↗