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PubMed1980

Nonmetabolically coupled coronary vasodilatation during inosine infusion in dogs.

Left ventricular contractile force (LVCF), dP/dt, arteriovenous oxygen difference [(a-v)O2], circumflex blood flow (CBF), and myocardial oxygen consumption (MVo2) were determined in dogs during intravenous infusion of inosine at various rates. LCVF and maximal dP/dt increased progressively with increasing infusion rates. CBF increased by 100% at the highest infusion rate, but (a-v)O2 was reduced by 30%. At each infusion rate the increase in MVo2 was only 40% the increase in CBF (P less than 0.05), indicating a nonmetabolically coupled vasodilatation. To further demonstrate this action, the effects of isoproterenol on CBF and (a-v)O2 were compared with those of inosine. During isoproterenol infusion, the increase in CB paralleled the increase in MVo2, and (a-v)O2 showed no change. Intracoronary infusion experiments showed that a 100% increase in flow was caused by an arterial inosine level of about 150 micro M. At inosine levels over 400 micro M, the increase in flow was equal to the maximal increase seen with adenosine infusion.

Animals↗

PubMed2001

Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease.

Peroxynitrite has been implicated in the pathogenesis of multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). Previously, we have shown that administration of uric acid (UA), a peroxynitrite scavenger, is therapeutic in EAE We have also shown that MS patients have lower levels of serum uric acid than healthy individuals or those with other neurological diseases. The aim of this investigation was therefore to raise serum UA levels in MS patients. Oral administration of UA failed to increase low serum UA levels, evidently due to its degradation by gastrointestinal bacteria. However, serum UA could be raised and maintained at elevated levels for a year and more without reported side-effects by oral administration of its precursor inosine. Three of 11 patients given inosine showed some evidence of clinical improvement and there was no sign of disease progression in the remaining patients. Gadolinium-enhanced lesions, observed in two patients before receiving inosine, could not be detected after either 10 or IS months inosine treatment These data provide evidence that serum UA levels can be readily manipulated and that the benefit of higher levels to individuals with MS should be studied further in greater number of patients.

Administration, Oral↗

PubMed1990

Identification of hypoxanthine and inosine in brain dialyzable fraction as stimulators for growth of porcine aortic endothelial cells in response to fibroblast growth factor in either dialyzed serum media or low serum media.

The rate of proliferation of porcine aortic endothelial cells (PAEC) in response to fibroblast growth factor (FGF) was largely retarded when incubated in Dulbecco's modified Eagle's medium (DMEM) supplemented with either 1% fetal bovine serum (FBS) or 10% dialyzed FBS in place of 10% FBS. Proliferation of endothelial cells in low serum media in response to FGF was enhanced to the level of media containing FGF plus 10% FBS by the addition of the dialyzable fraction from bovine brain homogenates. From the bovine brain dialyzable fraction, two active components were purified and identified as hypoxanthine and inosine. Either hypoxanthine or inosine, at a dose of 5 microM in DMEM with 1% FBS, maximally increased the incorporation of [3H]thymidine into DNA of PAEC in low serum media in the presence of FGF. However, no additive effect was observed when hypoxanthine and inosine were added simultaneously. The present data indicate that the proliferative action of FGF on PAEC can be potentiated by hypoxanthine and inosine.

Animals↗

PubMed1996

Efficacy of inosine pranobex oral therapy in subclinical human papillomavirus infection of the vulva: a randomized double-blinded placebo controlled study.

A randomized double-blind placebo controlled study was carried out to assess the efficacy of inosine pranobex (1 g orally 3 times a day for 6 weeks) in the treatment of symptomatic subclinical human papillomavirus infection of the vulva. In a series of 55 women, 22 patients in the inosine pranobex group and 24 patients in the placebo group were suitable for analysis. A total of 14 (63.5%) of the inosine pranobex treated patients and 4 (16.7%) of the placebo treated patients showed significant vulval epithelial morphological improvement (P = 0.005) at 2 months after initiation of treatment. Whereas 13 (59.1%) and 9 (37.5%) patients in the respective groups showed significant improvement in the severity of pruritus vulvae (P = 0.435). Twelve (66.7%) of 18 patients with morphological improvement compared to 10 (35.7%) of 28 patients with no morphological improvement experienced significant symptomatic alleviation of pruritus vulvae (P = 0.041). Similar results were seen at the second assessment 4 months after the initiation of treatment. Adverse drug reactions were reported by 2 patients in the treatment group and by 2 patients (skin rash) in the placebo group. These adverse reactions were mild and self limiting. It is concluded that inosine pranobex demonstrated a significant pharmacological activity in subclinical HPV infection of the vulva and should be considered an alternative treatment for the condition.

Administration, Oral↗

PubMed2006

Effects of xapA and guaA disruption on inosine accumulation in Escherichia coli.

A xapA-disrupted mutant was studied to minimize hypoxanthine production and to improve inosine productivity in mutants of Escherichia coli. The xapA-disrupted mutant accumulated 5.6 g/l of inosine from 40 g/l of glucose, while the parent strain accumulated 4.6 g/l. This result indicates that xapA is activated in xapA-positive inosine-producers and that xapA disruption might be useful for improving inosine productivity.

Escherichia coli↗

PubMed2006

Guanosine and inosine display antioxidant activity, protect DNA in vitro from oxidative damage induced by reactive oxygen species, and serve as radioprotectors in mice.

The effect of ribonucleosides on 8-oxoguanine formation in salmon sperm DNA dissolved in 1 mM phosphate buffer, pH 6.8, upon exposure to gamma rays was examined by ELISA using monoclonal antibodies against 8-oxoguanine. Nucleosides (1 mM) decreased the radiation-induced yield of 8-oxoguanine in the order Guo > Ino > Ado > Thd > Urd > Cyd. Guanosine and inosine considerably reduced deamination of cytosine in the DNA solutions upon heating for 24 h at 80 degrees C. The action of nucleosides on the heat-induced generation of reactive oxygen species in the phosphate buffer was studied. The concentration of hydrogen peroxide was measured by enhanced chemiluminescence in a peroxidase-luminol-p-iodophenol system; the hydroxyl radical formation was measured fluorometrically by the use of coumarin-3-carboxylic acid. Guanosine and inosine considerably decreased the heat-induced production of both hydrogen peroxide and OH radicals. Guanosine and inosine increased survival of mice after a lethal dose of radiation. They especially enhanced the survival of animals when were administered shortly after irradiation. The results indicate that guanosine and inosine, natural antioxidants, prevent oxidative damage to DNA, decrease the generation of ROS, and protect mice against gamma-radiation-induced death.

Animals↗

PubMed1978

Utilization of exogenous purine compounds in Bacillus cereus. Translocation of the ribose moiety of inosine.

Intact cells of Bacillus cereus catalyze the breakdown of exogenous AMP to hypoxanthine and ribose 1-phosphate through the successive action of 5'-nucleotidase, adenosine deaminase, and inosine phosphorylase. Inosine hydrolase was not detectable, even in crude extracts. Inosine phosphorylase causes a "translocation" of the ribose moiety (as ribose 1-phosphate) inside the cell, while hypoxanthine remains external. Even though the equilibrium of the phosphorolytic reaction favors nucleoside synthesis, exogenous inosine (as well as adenosine and AMP) is almost quantitatively transformed into external hypoxanthine, since ribose 1-phosphate is readily metabolized inside the cell. Most likely, the translocated ribose 1-phosphate enters the sugar phosphate shunt, via its prior conversion into ribose 5-phosphate, thus supplying the energy required for the subsequent uptake of hypoxanthine in B. cereus.

Adenosine Monophosphate↗

PubMedDate not supplied

[The biosynthesis of 2H-labelled inosine by Bacillus subtilis bacteria in a heavy-hydrogen medium].

We studied biosynthesis of the purine ribonucleoside inosine by the strain of Bacillus subtilis, which was adapted to deuterium through plating to individual colonies on 2% agar with 2H2O and subsequent selection. For growing the strain, a special heavy hydrogen medium with a high level of deuteration (89-90 at. % 2H) based on 2% hydrolyzate of the biomass of the methylotrophic Brevibacterium methylicum as a source of 2H-labeled growth substrates was obtained on 98 vol % 2H2O and 2 vol % [U-2H] methanol. We provide experimental data on the strain growth and accumulation of inosine in the culture medium. A study of the level of inosine deuteration using mass-spectroscopy of fast atoms has shown a polymorphism of deuterium incorporation in the molecule (isotope composition of inosine: 4 at. 2H, 20%; 5 at. 2H, 38%; 6 at. 2H, 28%; 7 at. 2H, 14%), deuterium being incorporated in the ribose and hypoxanthine fragments of the molecules.

Amino Acids↗

PubMedDate not supplied

Chemical assay for the antitumor agent inosine dialdehyde (NSC-118994) in biologic fluids.

Inosine dialdehyde, an antitumor agent highly active against several murine tumors, ispresently undergoing clinical trial for potential activity in man. To aid in the clinical evaluation of this drug, a chemical assay has been developed for the determination of concentrations of inosine dialdehyde in biologic fluids. The method involves reaction of inosine dialdehyde with phenylhydrazine in an acetic acid medium, followed by extraction of the product into ether and determining its absorbance at 378 nm. The reaction is specific for free inosine dialdehyde and will quantitate amounts as low as 1.0 mug.

Aldehydes↗

PubMed1976

Group translocation of the ribose moiety of inosine by vesicles of plasma membrane from T(3 cells transformed by Simian virus 40.

Plasma membrane vesicles are isolated from Simian virus 40-transformed Balb/c mouse 3T3 (SV-3T3) cells. These membrane vesicles contain no significant contamination by mitochondria, endoplasmic reticulum, or lysosomes as determined by marker enzyme analysis. The use of [U-14C] inosine as a transport substrate results in the accumulation of labeled ribose-1P as transport product by the plasma membrane vesicles. This suggests the action of purine nucleoside phosphorylase (the enzyme which mediates the phosphorolysis of inosine to ribose-1-P and hypoxanthine0 before, during, or after the transport step. Neither inosine nor significant amounts of hypoxanthine are found intravesicularly. The Km for inosine, the substrate in this reaction which leads to the accumulation of ribose-1-P by the plasma membrane vesicles, is 35 to 45 muM while the Vmax for ribose-1-P accumulation is 100 to 120 pmol/min/mg of plasma membrane protein...

Binding, Competitive↗

PubMed1991

Radioprotective effect of inosine and its enhancement by magnesium and global hypoxia.

The slight radioprotective action of inosine, when injected intraperitoneally to mice shortly before gamma-irradiation, can be enhanced by the administration of magnesium aspartate. This effect can be explained by the additivity of the vasodilatory actions of both agents. Inosine increases the radioprotective effectiveness of hypobaric hypoxia (10% O2), probably due to the additivity of the hypoxic effects in radiosensitive tissues. Acute hypoxic toxicity, however, is decreased by inosine administration. The cumulation of radioprotective effects of inosine and of its antihypoxic action in vitally important organs can have a favourable influence in hypoxic radiotherapy.

Animals↗

PubMed1988

[Effect of inosine after early infusion of contrykal and heparin in various hemodynamic types of acute myocardial ischemia].

In 79 experiments with a canine model of acute 2-hour myocardial ischemia, a positive affect of inosine was found on parameters of cardiac bioelectrical activity, contractile and hemodynamic functions in normal and hypodynamic circulation. In excessive myocardial hyperfunction, inosine infusion led to aggravation of ischemic signs in the ischemic lesion zone and only to its modest decrease in the adjacent and intact segments of the myocardium. During pre-infusion of contrykal and heparin followed by inosine administration, there was a considerable decrease in ischemia in all myocardial areas, as evidenced by ECG and electrograms, no matter what the hemodynamic type of acute myocardial ischemia. As this took place, a particularly marked inosine-induced improvement was seen in myocardial contractility and relaxation, total and intracardiac hemodynamic parameters.

Animals↗

PubMed1989

Effects of dialyzable leukocyte extracts (DLE) and inosine on stimulated lymphocytes.

The effects of dialyzable leukocyte extracts (DLE) on the lymphocytes were examined. The crude DLE suppressed the blast-formation of the PHA-stimulated lymphocytes and proliferation of the leukemic cell-lines but enhanced that of the fibroblastic cells. A certain fraction of the DLE caused the ATP level of the stimulated lymphocytes to rise, after incubation for 24 hours. The fraction was further purified and the inosine eluted from it. The inosine increased the ATP level and markedly enhanced the lymphocyte blast-formation and proliferation of the fibroblastic cells and leukemic cell-lines. It is suggested that when the DLE show some effects on the lymphocytes, the inosine contained in the DLE may show important effects. The effect of inosine was inhibited by other substances contained in the DLE, especially deoxynucleotides. These substances suppressed the blast-formation of the lymphocytes and the proliferation of the leukemic-cell lines. It remains to determine why the fibroblastic cells were not suppressed by them.

Adenosine Triphosphate↗

PubMed1988

Purine accumulation in human fat cell suspensions. Evidence that human adipocytes release inosine and hypoxanthine rather than adenosine.

Human adipocytes are of limited viability (7 +/- 2% release of lactate dehydrogenase/h) and contain active ectophosphatases which are capable of sequentially degrading ATP to adenosine. At densities of 30,000-40,000 cells/ml, human fat cell suspensions accumulated adenosine, inosine, and hypoxanthine, and their concentrations were 38 +/- 8, 120 +/- 10, and 31 +/- 7 nmol/liter after 3 h of incubation. Dipyridamole (10 mumol/liter), an inhibitor of nucleoside transport, caused a 5-7-fold increase in adenosine accumulation which was reduced by 85% on inhibition of ectophosphatases by beta-glycerophosphate and antibodies against ecto-5'-nucleotidase or alpha, beta-methylene 5'-adenosine diphosphate (10 mumol/liter), respectively, indicating that most of the adenosine is produced in the extracellular compartment. Accordingly, the spontaneous accumulation of adenosine was reduced beyond 5 nmol/liter on inhibition of ectophosphatase activities or removal of extracellular AMP by AMP deaminase (4 units/ml). Added adenosine (30 nmol/liter) disappeared until its concentration approached 5 nmol/liter. Isoproterenol (1 mumol/liter) had no effect on adenosine accumulation regardless whether purine production from extracellular sources was minimized or not. In contrast to adenosine, the concentrations of inosine and hypoxanthine displayed only a modest decrease (30-50%) on inhibition of ectophosphatase activities. In addition, isoproterenol caused a 2-3-fold increase in inosine and hypoxanthine production which was concentration-dependent and could be inhibited by propranolol. It is concluded that the adenosine that accumulates in human adipocyte suspensions is almost exclusively derived from adenine nucleotides which are released by leaking cells. By contrast, inosine and hypoxanthine are produced inside the cells, and the release of these latter purines appears to be linked to ATP turnover via adenylate cyclase.

Adenine Nucleotides↗

PubMed1983

Isoosmotic sucrose, adenine, inosine media for preservation of blood.

In order to manipulate red cells to remove additives and metabolites prior to transfusion after prolonged preservation, osmotic fragility must be depressed. In isoosmotic sucrose solutions, the osmotic hemolysis curve is shifted to the left (less fragile) within several hours at 37 degrees C and within several days at 4 degrees C. However, hyperosmolar solution induced hemolysis when 0.9% NaCl was added after preservation. In isoosmotic sucrose solutions, the order of effectiveness in maintaining intracellular ATP content was: adenine plus inosine greater than inosine alone greater than adenine alone greater than no addition. The same order was also seen in depression of the increase in osmotic fragility during storage for 8 weeks. Formation of too stable erythrocytes to osmotic fragility and accordingly too low filtrability was prevented by the addition of appropriate amounts of physiological saline. Media containing isotonic sucrose, adenine and inosine depressed the increase in osmotic fragility during preservation for 6 weeks at 4 degrees C. ATP and 2,3-DPG levels were also better maintained than in various media containing a small amount of adenine. This finding with the former which indicated that the media containing isoosmotic sucrose, adenine and inosine prolonged posttransfusional viability of rabbit cells very much, suggests that these media are worthy of further investigation, since excess metabolites can be easily removed before transfusion.

2,3-Diphosphoglycerate↗

PubMed1993

The effect of metipranolol and inosine on total hepatic ischemia of rats in vivo.

A protective effect of metipranolol on renal ischemia has recently been demonstrated in our laboratory. The aim of present work was to investigate the effect of this drug on a model of total hepatic ischemia. Inosine was chosen as a comparative agent. Metipranolol (1 mg.kg-1) or inosine (160 mg.kg-1) were given i.v. to rats 15 min prior to inducing of 30-min lasting hepatic ischemia. The animals were followed up for 90 min after the end of ischemia. Pretreatment with inosine almost removed the harmful effect of ischemia on bile flow. Pretreatment with metipranolol slightly minimized the post-ischemic bile flow fall, this effect having been statistically significant only at 30. min of postischemic period. Neither inosine, nor metipranolol administration influenced significantly the ALT or AST plasma activity 90 min after release of hepatic vessels occlusion.

Animals↗

PubMed1994

Guanosine-inosine-preferring nucleoside N-glycohydrolase from Crithidia fasciculata.

Protozoan parasites are incapable of de novo purine biosynthesis and obtain purines by salvage pathways. A nucleoside hydrolase which prefers inosine and uridine as substrates (IU-nucleoside hydrolase) has been characterized and implicated in purine salvage in Crithidia fasciculata (Parkin, D. W., Horenstein, B. A., Abdulah, D. R., Estupiñán, B., and Schramm, V. L. (1991) J. Biol. Chem. 31, 20658-20665). Treatment of C. fasciculata with inhibitors of the IU-nucleoside hydrolase did not prevent cell growth, suggesting alternative enzymes. A guanosine-inosine-preferring enzyme (GI-nucleoside hydrolase) has been purified from extracts of C. fasciculata and characterized. The enzyme is an oligomer of M(r) 38,500 subunits. The Vmax/Km for guanosine, inosine, and adenosine are 3.2 x 10(6), 6.2 x 10(6), and 9.8 M-1 S-1, respectively. Deoxynucleosides, nucleotides, and pyrimidine nucleosides are poor substrates. The pH profile for Km is independent of pH, whereas both Vmax and Vmax/Km demonstrate that a single protonated base, pKa 7.7 is required for activity. The transition state inhibitors of IU-nucleoside hydrolase, 1,4-dideoxy-1,4-imino-1-(S)-phenyl-D-ribitol (Horenstein, B. A., and Schramm, V. L. (1993) Biochemistry 32, 9917-9925) and p-nitrophenylriboamidrazone (Boutellier, M., Horenstein, B. A., Semenyaka, A., Schramm, V.L., and Ganem, B. (1994) Biochemistry 33, 3994-4000), are unexceptional inhibitors of the GI-nucleoside hydrolase. The enzyme is inhibited by 3-deazaadenosine and 2-iodoadenosine with Km/Ki values of 145 and 61, respectively. The results demonstrate that this previously uncharacterized enzyme has distinct structure, kinetic, and chemical mechanisms relative to IU-nucleoside hydrolase. Metabolic studies with labeled inosine as the sole purine source indicated that the GI-enzyme is efficient for purine salvage in vivo.

Animals↗

PubMedDate not supplied

[Effect of addition of bases and amino acids on inosine biosynthesis by mutants of Bacillus subtilis].

The relationship between the inosine biosynthesis by the Bacillus subtilis mutants VNII-genetika-265 and VNII-genetika-21 and the concentrations of adenine, guanine, uracile and amino acids was investigated. Adenine and guanine in high concentrations inhibited the inosine biosynthesis in both mutants. The mutant Gene-21 showed an increased requirement for adenine as compared with the mutant Gene-265. In the presence of uracile the pattern of the relationship between the inosine growth and biosynthesis and adenine in the mutane Gene-265 was similar to that in the mutant Gene-21. Excessive concentrations of histidine and tyrosine inhibited the inosine biosynthesis.

Adenine↗