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PubMed1987

Interaction of metabolism of aspartate and inosine and energy state of malignant cells.

1. Oxidation of glutamine in Ehrlich ascites-carcinoma cells results in a large accumulation of aspartate. 2. The addition of inosine causes a marked decrease in aspartate production from glutamine. This may be related to the resynthesis of AMP from aspartate and IMP, the latter being produced from inosine via the salvage pathway for purine nucleotides. In accordance with this assumption, a significant production of lactate was observed, which comes probably from the ribose moiety of inosine. Since lactate is known to inhibit production of aspartate from glutamine, this may explain the effect of inosine. 3. Addition of glutamine together with inosine increased cellular ATP content. This was not the case if glutamine or inosine was present separately or if inosine was added together with lactate, pyruvate or glucose. The effect did not occur if amino-oxyacetate, an inhibitor of transaminases, was added. These findings suggested again that production of aspartate is important for resynthesis of ATP from IMP via the purine nucleotide cycle. 4. If the cells were exposed to prolonged anaerobic incubation, addition of glutamine and inosine markedly increased O2 uptake and [ATP], suggesting the crucial importance of aspartate production by glutamine oxidation for the recovery of energy metabolism in the cells.

Adenosine Triphosphate↗
PubMed2002

Effect of inosine on the plasma concentration of uridine and purine bases.

To examine whether inosine increases the plasma concentration of uridine, 20 mg/kg body weight of inosine was orally administered to 5 healthy subjects. The plasma concentration of uridine was increased by 1.25-fold (P <.05), while that of hypoxanthine, xanthine, and uric acid was increased by 1.26-fold (P <.01), 1.26-fold (P <.01), and 1.2-fold (P <.05), respectively, 2.5 hours after the oral administration of inosine. In addition, the 1-hour urinary excretion of uridine was increased by 1.17-fold (P <.05) and that of hypoxanthine, xanthine, and uric acid by 1.38-fold (P <.05), 1.4-fold (P <.05), and 1.4-fold (P <.05) between 2 and 3 hours after the administration of inosine. We also conducted an in vitro study with Mahlavu cells and found that the addition of inosine (50 micromol/L) inhibited a decrease in the concentration of uridine in medium originally containing 50 micromol/L uridine. Further, we demonstrated that the apparent Km and Vmax values for Na-independent uridine transport were 67.0 +/- 4.3 micromol/L and 7.0 +/- 0.3 pmol/mg protein/s, respectively, and the Ki value of inosine for Na-independent uridine transport was 45.1 +/- 12.1 micromol/L. These results suggest that inosine inhibits uridine uptake via the nucleoside transport pathway, and administered inosine is converted to purine bases (uric acid, hypoxanthine, and xanthine) in the intestine and liver, before entering the systemic circulation via the hepatic vein.

Adult↗
PubMed2005

Inosine infusion prevents mortality in endotoxic shock.

BACKGROUND: Substances that inhibit Na/K ATPase activity appear in plasma during severe septic shock causing Na and fluid to move into cells and K to move out, resulting in cell swelling and an elevation of plasma K. These changes contribute to the morbidity of sepsis. Recently, we reported that inosine and other purine nucleosides stimulate Na/K ATPase activity, prolong survival in hemorrhagic shock, and lower the plasma potassium in that condition. Here, we determine whether inosine prolongs survival in lipopolysaccharide-induced sepsis shock. METHODS: Pentobarbital-anesthetized rats underwent cannulation of a femoral artery and vein, and lipopolysaccharide was injected by intravenous bolus (10 mg/kg). Rats were than resuscitated (5 mL/hr) with inosine (5 mmol/L) in saline, saline alone, inosine with S-4-nitrobenzyl-6-thioinosine (NBTI, 10 micromol/L, an equilibrative nucleoside transporter blocker), NBTI alone, or no resuscitation. RESULTS: Inosine significantly and dramatically prolongs survival of rats in endotoxic shock as compared with saline resuscitation or to no resuscitation. Furthermore, resuscitation with NBTI (10 micromol/L) prevented prolonged survival with inosine. CONCLUSION: Inosine prevents mortality in lipopolysaccharide-induced septic shock in rats. The mechanism of action must be intracellular, as blockers of the equilibrative nucleoside transporter prevented prolonged survival with inosine.

Animals↗
PubMedDate not supplied

Effect of inosine on seizures induced with pentylenetetrazole, bicuculline, or picrotoxin.

The effect in mice of inosine administered subcutaneously on the threshold of seizures induced with pentylenetetrazole (PTZ), bicuculline, and picrotoxin was studied, and brain inosine levels were measured. Following inosine, 1,000 mg/kg, the threshold to PTZ was increased at 10-30 min after injection as determined by a tail vein infusion method. Bicuculline and picrotoxin thresholds were significantly elevated only at 5 min. The time to the first myoclonic jerk after intraperitoneal administration of each of these convulsants was significantly prolonged by the lowest dose of inosine tested (250 mg/kg for PTZ, 100 mg/kg for bicuculline, and 500 mg/kg for picrotoxin). Inosine was given subcutaneously 10 min before the convulsant. The mean control brain inosine concentration was 2.9 microM. After subcutaneous inosine, 1,000, 500, and 250 mg/kg, the highest levels reached were 14.4, 7.9, and 4.3 microM, respectively. It is concluded that micromolar concentrations of inosine in brain are antiepileptic.

Animals↗
PubMed1989

Effect of inosine on pial arterioles: potentiation of adenosine-induced vasodilation.

We examined the cerebral vasoactivity of inosine and its effect on pial arteriolar vasodilation induced by adenosine. Pial circulation was observed through cranial windows implanted in rats anesthetized with halothane. No significant change in venous or arteriolar diameter was apparent when inosine (10(-6) to 10(-3) M) was superfused. In contrast, adenosine in concentrations of 10(-7) and 10(-6) M dilated pial arterioles by 9.0 +/- 1.2 and 17.7 +/- 1.7%, respectively. Addition of 10(-5) M inosine had no effect, whereas 10(-4) M inosine enhanced the vasodilation induced by 10(-7) M adenosine to 19.4 +/- 1.7% and that by 10(-6) M adenosine to 23.3 +/- 2.3%. When theophylline (5 X 10(-5) M) was perfused together with 10(-7) M adenosine and 10(-4) M inosine, the vasodilation was almost completely abolished. The present study indicates that inosine alone does not affect pial vessel diameter but potentiates the response of pial arterioles to exogenous adenosine. This potentiating action of inosine may be attributed to an increase in perivascular adenosine and may be explained by the action of inosine as an adenosine uptake inhibitor.

Adenosine↗
PubMed1990

Inosine transiently decreases coronary flow but potentiates vasodilation by adenosine.

To test whether inosine interferes with the action of adenosine, we investigated the effects of intracoronary administration of inosine, adenosine, 8-phenyltheophylline, and adenosine deaminase on isolated rat heart. Inosine did not change heart rate or developed tension but increased the effluent adenosine concentration. Inosine also decreased exogenous adenosine uptake and breakdown. After the start of the inosine infusion (20 microM), a transient 30% decrease of coronary flow took place within 0.5 min. The nucleoside caused sustained vasodilation, dependent on the concentration (30-400 microM). After the infusion we observed a transient vasodilation. A nonvasoactive inosine concentration (10 microM) combined with an adenosine concentration that increased flow by 60% (0.1 microM) raised vasodilation by another 60%. Infusion of adenosine, adenosine deaminase, or 8-phenyltheopylline did not influence the inosine-induced transient decrease of flow, suggesting that this decrease is independent of adenosine and its receptor. We conclude that inosine 1) potentiates the vasodilation induced by adenosine and 2) is a coronary vasodilator but probably also a vasoconstrictor.

Adenosine↗
PubMed1996

Inosine-induced vasoconstriction is mediated by histamine and thromboxane derived from mast cells.

Mast cell degranulation has been shown to release products that cause arteriolar constriction. We previously reported that two nucleosides, adenosine and inosine, cause vasoconstriction of isolated hamster cheek pouch arterioles by stimulating degranulation of periarteriolar mast cells. The objectives of the present study were to characterize the nucleoside-dependent vasoconstriction in vivo and to determine the mediator or mediators responsible. We examined the vasomotor effect of inosine on arterioles in the cheek pouches of anesthetized hamsters (70 mg/kg pentobarbital sodium) in the control situation and in the presence of receptor antagonists for histamine (H1), thromboxane A2 (Tx), and leukotrienes (LT). Most experiments were carried out using inosine applied once locally via micropipette to arterioles and observing the subsequent response. Over a range of inosine concentrations from 10(-5) to 10(-3) M in the pipette, we observed a dose-dependent increase in the incidence and magnitude of constriction. In addition, mast cell staining with ruthenium red was observed after stimulation with inosine, an indication of mast cell degranulation. Neither the H1, Tx, nor LT antagonist alone had a significant effect on the vasomotor response to inosine. However, combined H1 and Tx blockade significantly reduced the incidence and magnitude of inosine-induced constriction. These data establish that inosine-induced constriction occurs in vivo and support the role of mast cells in this response. Furthermore they suggest that multiple mediators, primarily histamine and thromboxane, are responsible for the observed constriction.

Animals↗
PubMed2005

Inosine reduces ischemic brain injury in rats.

BACKGROUND AND PURPOSE: Purinergic nucleoside inosine elicits protection and regeneration during various injuries. The purpose of this study was to examine the protective effects of inosine against cerebral ischemia. METHODS: Adult Sprague-Dawley rats were anesthetized. Inosine, hypoxathine, or vehicle was administered intracerebroventricularly before transient right middle cerebral artery occlusion (MCAo). Animals were placed in behavioral chambers 2 days to 2 weeks after MCAo and then euthanized for tri-phenyl-tetrazolium chloride staining. Glutamate release was measured by microdialysis/high-performance liquid chromatography, and single-unit action potentials were recorded from neurons in the parietal cortex. RESULTS: Stroke animals receiving inosine pretreatment demonstrated a higher level of locomotor activity and less cerebral infarction. Intracerebroventricular administration of the same dose of hypoxanthine did not confer protection. Coadministration of selective A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1, 4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS1191) significantly reduced inosine-mediated protection. Inosine did not alter basal glutamate release, nor did it reduce ischemia-evoked glutamate overflow from cerebral cortex. However, inosine antagonized glutamate-induced electrophysiological excitation in cerebral cortical neurons. CONCLUSIONS: Inosine inhibits glutamate postsynaptic responses and reduces cerebral infarction. Its protective effect against ischemia/reperfusion-related insults may involve activation of adenosine A3 receptors.

Animals↗
PubMed2005

Effects of edd and pgi disruptions on inosine accumulation in Escherichia coli.

Using an inosine-producing mutant of Escherichia coli, the contributions of the central carbon metabolism for overproducing inosine were investigated. Sodium gluconate instead of glucose was tested as a carbon source to increase the supply of ribose-5-phosphate through the oxidative pentose phosphate pathway. The edd (6-phosphogluconate dehydrase gene)-disrupted mutant accumulated 2.5 g/l of inosine from 48 g/l of sodium gluconate, compared with 1.4 g/l of inosine in the edd wild strain. The rpe (ribulose phosphate 3-epimerase gene)-disrupted mutant resulted in low cell growth and low inosine production on glucose and on gluconate. The disruption of pgi (glucose-6-phosphate isomerase gene) was effective for increasing the accumulation of inosine from glucose but resulted in low cell growth. The pgi-disrupted mutant accumulated 3.7 g/l of inosine from 40 g/l of glucose when 8 g/l of yeast extract was added to the medium. Furthermore, to improve effective utilization of adenine, the yicP (adenine deaminase gene)-disrupted mutant was evaluated. It showed higher inosine accumulation, of 3.7 g/l, than that of 2.8 g/l in the yicP wild strain when 4 g/l of yeast extract was added to the medium.

Adenine↗
PubMed1985

Effects of inosine on cardiac adenine nucleotide metabolism in rats.

Inosine was administered as a continuous intravenous infusion (100 mg/kg per hr) in rats treated with isoproterenol (25 mg/kg, s.c.). After 24 hr, the isoproterenol-induced decline in myocardial ATP and total adenine nucleotides was attenuated by inosine. Infusion of ribose (100 mg/kg per hr) had a similar cardioprotective influence. The effect of inosine may have been due to the incorporation into cardiac adenine nucleotides of the degradation products of inosine, either of the ribose moiety via the de novo synthesis pathway or of hypoxanthine via the salvage pathway utilizing 5-phosphoribosyl-1-pyrophosphate. To decide this, [8-(14)C]inosine was injected intravenously 4 hr after administration of isoproterenol. Its incorporation into myocardial adenine nucleotides was enhanced. Furthermore, the effect of inosine on the de novo synthesis of adenine nucleotides in normal and isoproterenol-stimulated hearts was studied and compared to that of ribose. The normal rate was attenuated and the isoproterenol-elicited increase was reduced by inosine. In contrast, ribose stimulated adenine nucleotide biosynthesis in the control rat heart and potentiated the isoproterenol-induced enhancement. These results indicate that the effect of inosine is not due to the metabolism of ribose-1-phosphate via the pentose phosphate and the de novo synthesis pathways, but rather to the 5-phosphoribosyl-1-pyrophosphate-dependent salvage of hypoxanthine. Obviously, this pathway is of such a magnitude that the isoproterenol-evoked decline in myocardial adenine nucleotide levels is attenuated.

Adenine Nucleotides↗
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↗
PubMed1993

Effects of inosine on adenosine-induced coronary vasodilation in the open chest dog.

The effects of inosine (CAS 58-63-9) on adenosine-induced coronary vasodilation were studied in open-chest dogs. Inosine and hypoxanthine were infused into the coronary artery at a rate to obtain respective calculated coronary plasma concentrations of 10(-5) mol/l, and the dose-coronary flow response of adenosine was recorded with and without inosine or hypoxanthine infusion. When the maximum coronary dilation was obtained, 10 ml of 2 x 10(-3) mol/l 8-phenyltheophylline (8-PT) solution was injected into the femoral vein. Additionally, adenosine deaminase activity was measured in vitro in the presence of various concentrations of either inosine or hypoxanthine. It was found that inosine, but not hypoxanthine, intensified the coronary vasodilatory effect of adenosine, which was abolished by 8-PT injection: EC50 of adenosine was reduced from 10(-5.43) mol/l to 10(-5.90) mol/l by inosine. Inosine and hypoxanthine did not affect adenosine deaminase activity at concentrations of 10(-4) mol/l or less. These findings indicate that inosine intensifies the coronary vasoactivity of adenosine, independent of inhibition of adenosine deaminase activity.

Adenosine↗
PubMed1994

Enhancement of proliferation in cultures of Chinook salmon embryo cells by interactions between inosine and bovine sera.

The influence of inosine on DNA synthesis by Chinook salmon embryo cells (CHSE-214) was investigated because previously cell number was shown to increase from six- to thirtyfold if inosine was added to the basal medium (L-15) supplemented with either dialyzed fetal bovine serum (dFBS), calf serum (CS), or dCS. Relative to L-15, 3H-thymidine incorporation was inhibited by these sera alone but elevated in nondialyzed (intact) FBS. Inosine at 10 microM stimulated 3H-thymidine incorporation from ten- to seventyfold in dFBS, CS, and dCS but was only slightly stimulatory in FBS and in L-15 alone. As well as inosine, hypoxanthine, cIMP, IMP, IDP, and ITP were just as stimulatory, but the nonsalvageable purines (xanthine, xanthosine, and XMP) were not. The stimulatory action of inosine was highest in low density cultures. Dipyridamole and S-(p-nitrobenzyl)-6-thioinosine (NBTI), inhibitors of facilitated nonconcentrative nucleoside transport, did not completely block the enhancement of cell number by inosine and by themselves increased proliferation in CS and dCS. Overall, these results suggest that exogenous inosine promoted CHSE-214 proliferation by overcoming factors in the nondialyzable fraction of sera that led to purine loss and by raising intracellular purine nucleotides to levels necessary for cells to respond to growth factors in the nondialyzable fraction of sera.

Animals↗
PubMed2004

Inosine stimulates chemotaxis, Ca2+-transients and actin polymerization in immature human dendritic cells via a pertussis toxin-sensitive mechanism independent of adenosine receptors.

Inosine is an endogenous purine nucleoside, which is formed by adenosine deaminidase during adenosine breakdown and is released into the extracellular space from the sympathetic nervous system or injured cells. Here, we studied the biological activity of inosine on human dendritic cells (DC), which are specialized antigen presenting cells characterized by their ability to migrate from the blood to peripheral tissues, and then to secondary lymphoid organs where they initiate adaptive immune responses. In immature DC, inosine concentration-dependently stimulated Ca(2+)-transients, actin polymerization, and chemotaxis. Experiments with adenosine receptor antagonists and pertussis toxin (PTX) as well as desensitization studies suggested that the activity of inosine was mediated by a G protein-coupled receptor pathway independent of adenosine receptors. DC, induced to mature by lipopolysaccharide, lost their ability to respond towards inosine with these activities. Moreover, inosine did neither influence membrane expression of CD54, CD80, CD83, CD86, HLA-DR, and MHC class I molecules nor modulated secretion of interleukin (IL)-12, IL-10, and tumor necrosis factor alpha in immature and lipopolysaccharide-matured DC. In aggregate, our study indicates that inosine may be involved in the trafficking control system of immature DC, and mediates its chemotactic activity by a PTX-sensitive mechanism independent of adenosine receptors.

Actins↗
PubMed2001

Inosine attenuates tourniquet-induced skeletal muscle reperfusion injury.

BACKGROUND: Adenosine attenuates skeletal muscle reperfusion injury, but its short half-life in vivo limits potential therapeutic benefits. The aim of this study was to ascertain whether inosine, a stable adenosine metabolite, modulates skeletal muscle reperfusion injury. MATERIALS AND METHODS: C57BL/6 mice were randomized (8-10 per group) to six groups: time controls; inosine (100 mg/kg) before anesthesia; 2 h of bilateral tourniquet hindlimb ischemia; I/R (2 h of bilateral tourniquet hindlimb ischemia, 3 h of reperfusion); inosine (100 mg/kg) before I/R; drug vehicle before I/R. Serum tumor necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-2 were measured before ischemia and at the end of reperfusion. Tissue edema was determined by wet/dry weight ratios. Tissue leucosequestration was assessed by the myeloperoxidase (MPO) content. RESULTS: At the end of reperfusion, inosine pretreatment resulted in lower MPO levels in muscle (P = 0.02) and lung (P = 0.0002) than saline pretreatment. Similarly, muscle (P = 0.04) and lung (P = 0.02) wet/dry ratios were significantly reduced with inosine but not with saline pretreatment. At the end of reperfusion, serum proinflammatory cytokine levels (TNF-alpha and MIP-2) were significantly reduced (P < 0.05) compared to preischemia levels following inosine pretreatment but not saline pretreatment. Ischemia alone did not alter any of the parameters assessed. CONCLUSIONS: These findings demonstrate that pretreatment with inosine attenuates the local and systemic proinflammatory responses associated with skeletal muscle reperfusion injury.

Animals↗
PubMed1981

Anticonvulsant doses of inosine result in brain levels sufficient to inhibit [3H] diazepam binding.

Several purines have been shown to be competitive inhibitors of [3H] diazepam binding. Inosine has also been shown to have benzodiazepine-like neurophysiologic, pharmacologic and behavioral effects, and to partially inhibit caffeine-induced seizures in mice. Using presumptive therapeutic doses of inosine, levels were determined in mouse brain at various times following injection. Inosine and hypoxanthine concentrations in brain increased several fold following inosine administration, indicating that inosine permeated the blood-brain barrier. The levels of inosine and hypoxanthine attained in brain were sufficient to inhibit by more than 50% the GABA-stimulated [3H] diazepam binding. These data suggest that the anticonvulsant properties of inosine are related to its interaction with the benzodiazepine receptor.

Animals↗
PubMed1987

Inosine partially mimics the effects of glucose on ionic fluxes, electrical activity, and insulin release in mouse pancreatic B-cells.

The purine ribonucleoside inosine is known to be metabolized in islet cells (its ribose moiety feeds into the pentose-phosphate cycle) and stimulate insulin release, but the mechanisms of this stimulation have not been established. These were investigated with mouse islets. In the absence of glucose, 5 mM inosine decreased 86Rb+ efflux from islet cells, depolarized the B-cell membrane, induced electrical activity (slow waves of membrane potential with bursts of spikes on the plateau), accelerated 45Ca2+ efflux and stimulated insulin release with the same efficiency as 10 mM glucose. Raising the concentration of inosine to 20 mM only had a slight further effect and, in particular, failed to cause persistent depolarization of the B-cell membrane. The electrical activity triggered by inosine was blocked by cobalt, and the stimulation of 45Ca2+ efflux and insulin release was abolished in a Ca2+-free medium. The effects of 10 mM glucose on electrical activity, 45Ca2+ efflux and insulin release were augmented by as little as 0.5 mM inosine. All effects of inosine were abolished by an inhibitor of nucleoside transport (nitrobenzylthioguanosine) and markedly impaired by inhibitors of nucleoside phosphorylase (formycin B) or of glycolysis (iodoacetate). In conclusion, inosine metabolism in B-cells induces insulin release by triggering the same sequence of events as glucose metabolism: a decrease of K+ permeability of the B-cell membrane, leading to depolarization and activation of voltage-dependent Ca channels.

Animals↗
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↗