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Direct intra-renal perfusion of inosine was found to protect the canine kidney from 90 min of warm ischaemia. Significantly lower (P less than 0.01) serum creatinine levels were found 24 and 72 h post-operatively in an inosine treated group (N = 12) when compared to a control group (N = 5). Histological examination of the pre-treated kidneys confirmed the protective effect of inosine.
Intravenous, renal artery, and intraperitoneal administration of inosine at dosages of 100 to 200 mg/kg, 160 mg/kg, and 200 mg/kg, respectively, in the dog and rat was used to test its efficacy in preventing ischemic damage after 60 min of warm ischemia in an in situ solitary renal model. No improvement of renal function as compared with a control and a conventional mannitol/furosemide treatment group was detected. Rather, inosine at dosages of greater than or equal to 160 mg/kg resulted in significantly impaired renal function in the experimental groups of the dog model; no improvement was observed in the rat model. These results suggest that the use of inosine in human renal surgery and preservation should be approached cautiously.
Two complementary 24 base single stranded oligonucleotides containing randomly located inosine residues were synthesized in vitro. Once annealed, the two oligonucleotides were cloned into derivatives of ColE1 and transformed into Escherichia coli. Sequence analysis of 157 clones yielded 305 mutations. The pattern of the mutations revealed the following: (1) The frequency of inosine induced mutations was significantly less than predicted from its content in the oligonucleotides; (2) Inosine incorporation resulted almost exclusively in base changes to guanine; (3) The mutation distribution is biased towards A/T to G/C substitutions; (4) There were reproducible position biases; and (5) There was a reproducible strand bias which was independent of the cassette orientation with respect to the plasmid origin of replication.
The induction of generalized tonic-clinic seizures in mice by the methylxanthine stimulant caffeine is described. These seizures are indistinguishable in quality from those induced by pentylenetetrazol (PTZ), and pretreatment with low doses of caffeine potentiates PTZ-induced seizures. Benzodiazepines inhibit caffeine-induced seizures with a rank order potency that parallels their affinities for the central nervous system (CNS) benzodiazepine receptor in vitro. Inosine, a purine that has recently been shown to be a competitive inhibitor of [3H] diazepam binding in vitro, antagonizes caffeine-induced seizures, while 7-methyl-inosine, a purine that lacks receptor binding inhibitory activity, has no effect on seizures. Since the benzodiazepines, inosine, caffeine, and pentylenetetrazol all competitively inhibit [3H] diazepam binding and have marked effects on inducing or antagonizing seizures, further study of this receptor-ligand system may provide additional insights that concern possible biochemical mechanisms of seizures.
Theoretically, inosine analogues should act as effective inhibitors of tumor cell proliferation and viral replication. To acquire a broad spectrum of new candidate inosine analogues, a rapid, facile, quantitative and stereoselective method for deaminating potential antitumor and antiviral adenine analogues previously synthesized in our laboratory was developed. A novel 5'-adenylic acid deaminase, with relaxed substrate requirements, from Aspergillus species was utilized to deaminate four hexofuranosyladenine nucleosides and five adenine nucleoside dialdehydes to their corresponding inosine analogues. The fastest rates of deamination for the hexofuranosyl nucleosides were for the compounds where the vicinal hydroxyl groups on the sugars are oriented in the erythro configuration. For rapid deamination of the adenine nucleoside dialdehydes, the R configuration at the proximal carbon atom is preferred, while the nature of the group on the distal carbon atom has no significant effect on the rate or extent of deamination.
The effect of uridine and inosine on capillary permeability in the rat was investigated. Uridine produced a significant expansion of the albumin space which was accompanied by a significant increase in haematocrit indicating a leakage of water and proteins from the intra- to the extravascular compartment. This was attributed to a prominent constrictor effect of this substance on the post-capillary vessels. Inosine, on the contrary, produced an increase of the albumin space which was accompanied by a fall in haematocrit, indicating an expansion of the plasma volume. This was attributed to the vasodilator effect of inosine. It is suggested that these two substances may be involved in the control of the circulation.
Adenosine phosphorylase (EC 2.4.2.-) activity present in Sarcoma 180 cells grown in culture and in rat liver, is shown to be distinct from inosine-guanosine phosphorylase by several criteria: (a) treatment of Sarcoma 180 cell extract with p-chloromercuribenzoate inhibited the two activities to a different extent, (b) adenine selectively protected the adenosine phosphorylase activity of Sarcoma 180 and rat liver extract against heat inactivation, while hypoxanthine selectively protected inosine-guanosine phosphorylase activity, (c) at nearly saturating substrate concentrations and using Sarcoma 180 extract, the rates of ribosylation of a mixture of adenine + hypoxanthine or adenine + guanine, but not of hypoxanthine + guanine, were found to be almost equal to the sum of their individual rates as measured separately, (d) inosine selectively inhibited the ribosylation of hypoxanthine and guanine catalysed by Sarcoma 180 and rat liver extract while 2-chloroadenosine selectively inhibited the ribosylation of adenine and N6-furfuryladenine, (e) pH vs. activity curves were similar with hypoxanthine or guanine as the substrate but they were markedly different from the curve with adenine as the substrate. The potential role of adenosine phosphorylase activity in vivo is discussed.
1. Carbohydrate metabolism was studied in HT29 human colon cancer cells cultured in a glucose free medium supplemented with 2.8 mM inosine (HT29ino cells) in comparison with standard HT29 cells grown in the permanent presence of glucose (HT29Glc + cells) and with HT29Glc- cells which are adapted to grow permanently without glucose. 2. Inosine allows the standard cells to grow when glucose is lacking but surprisingly stops the growth of HT29Glc- cells. 3-mercaptopicolinate, an inhibitor of PEP-carboxykinase, does not hinder HT29ino cells to grow, which shows that gluconeogenesis from aspartate or pyruvate is not essential. It suggests that enough carbohydrate is supplied by the ribose moiety of inosine. 3. While standard HT29Glc + cells are highly glycolytic, it is not the case of HT29ino or HT29Glc- cells when glucose is given for few hours. When glucose is present for 24 hr or more, glycolytic rate increases in HT29ino cells and glycogen accumulates. 4. It is found that the pattern of enzymes activities related to carbohydrate metabolism in HT29ino cells is closer to that of HT29Glc + cells rather than to that of HT29Glc- cells. However, phosphofructokinase-1 activity, measured with saturating concentration of Fru-2,6-diP, is significantly lower in HT29ino cells. 5. Binding rate of hexokinase to mitochondria is similar in the three cell-lines. However, in HT29Glc- cells, bound hexokinase easily utilizes ATP generated by the mitochondria. By contrast, in HT29Glc+ and HT29ino cells, bound hexokinase is much more active with exogenous ATP, suggesting a functional defect in the mitochondria from these two latter cells.
High-resolution 1H nuclear magnetic resonance in H2O has been used to study the effect of sequence, conformation, environmental factors and base substituents on the exchange behavior of the hydrogen-bonded imino protons of guainine X cytosine and inosine X cytosine base-pairs in DNA, RNA, and DNA-RNA duplexes. The exchange rates were determined by measurement of the spin-lattice relaxation rates of the imino protons as a function of temperature. The exchange was not altered by the presence of high concentrations of salt, and the inability of phosphate to catalyze the exchange indicates that the exchange is limited by formation of a solvent-accessible "open" state. The exchange behavior depends on the duplex conformation and sequence. Exchange from the Z form polymers was orders of magnitude slower than the corresponding duplexes in the B conformation, and the A form RNA duplexes exchanged more slowly than the B form DNA polymers with the same sequence. The exchange behavior of the DNA-RNA hybrids was dependent on whether the purine or the pyrimidine strand contained the deoxyribose sugar. For both the guanine and inosine-containing duplexes, the homopolymer duplexes exchange more slowly than the more stable alternating copolymers. For the alternating duplexes, substitution of cytosine with 5-bromo- or 5-methylcytosine slowed the exchange and increased the activation energy for exchange. The inosine-containing duplexes exchanged more rapidly than the guanosine-containing duplexes, but both showed similar changes in exchange behavior in response to changes in sequence and base substituents. The activation energies for base-pair opening in B form DNA are correlated with the van der Waals contribution to the base-base interaction energy, suggesting that the purine base is partially unstacked in the open state. Using the relaxation measurements to set an upper limit on the exchange rate in poly(dG-dC) and the tritium exchange behavior at low temperature, we find that even though Z-DNA exchanges very slowly, the activation energy is similar to that observed in the A and B form duplexes, suggesting that exchange occurs from a similar open state.
A series of 15 single electroshocks administered through electrodes applied to the scalp of mice raised the threshold to pentylenetetrazol-induced seizures as determined by a tail vein infusion method. The same stimulus increased brain inosine and hypoxanthine. Phenytoin, which blocks the increase in inosine produced by this stimulus, reversed the elevation in threshold may be electroshock. The effect of electroshock on threshold may be mediated by inosine.
The influence of inosine (200 and 400 mg/kg i.p.) on adrenaline-induced myocardial necrosis in rats was studied. Adrenaline in a single dose (1 and 2 mg/kg s.c.) produced heart cell necrosis estimated by plasma activities of CPK-MB, CPK, blood lactates concentration and histopathological examination. In experimental groups inosine injected simultaneously and 10 minutes after adrenaline evoked significant suppression of CPK-MB and CPK enhancement measured 4 and 24 hours after adrenaline administration. The lower blood lactates concentration 4 hours after adrenaline injection was also found when preceded by inosine. Histopathological examination showed marked protection of the affected myocardium.
Inosine pranobex (InPx) could prove a valuable and innovative approach to the treatment of HIV-infected patients, since InPx administration has been shown in two multicenter trials to effectively delay the progression of HIV infection to overt AIDS. However, further studies are strongly required to optimize both the dosage of inosine pranobex and the administration schedules. Furthermore, clinical trials evaluating combination therapy of HIV infection with both InPx and zidovudine should ultimately provide an important advance in the management of HIV-infected patients. Our finding that concomitantly administered InPx to zidovudine-receiving patients increased the plasma levels of zidovudine as well as prolonged zidovudine mean half-life during InPx treatment suggests several potential advantages of the combination treatment with both InPx and zidovudine, such as a need for lower zidovudine dosage and a longer interval period between administering zidovudine to obtain sustained plasma levels as well as a potential to enhance residue immune function resulting from inosine pranobex treatment.
The effects of the complexes of inosine (Ino) analogues of isoprinosine on the immune response to sheep red blood cells (SRBC), in plaque-forming cells assay (PFC), in mice spleen, and on the Fc-dependent SRBC phagocytosis in mice peritoneal macrophages were investigated. Molar ratios of 1:3 of the complexes of inosine with N,N-dimethylaminopropanol-2-p-acetaminobenzoate (isoprinosine), and 8-thioinosine with N,N-dimethylaminopropanol-2-p-acetaminobenzoate (OSI-177), inosine with L-arginine butyrate (OSI-2655), and 8-thioinosine with L-arginine butyrate (OSI-3648) were administered. The administered doses were 0.5, 5 and 50 mg/kg body weight. The compound OSI-2655 exceeded isoprinosine in PFC stimulation and phagocytosis activation. The compound OSI-3648 exceeded isoprinosine only in PFC stimulation in the case of immunization with a suboptimal SRBC dose. OSI-3648 stimulated the immune response in PRC better than isoprinosine, OSI-177, or OSI-2655, and maintained the ability to stimulate capture, but lost the ability to stimulate destruction processes of captured SRBC. L-Arginine butyrate in the doses equivalent to its content in the complexes did not affect the number of PFC. L-Arginine butyrate was able to stimulate the processes of destruction but its stimulation degree was inferior to the compound OSI-2655.
The effect of inosine on adriamycin-induced cardiomyopathy was studied. Total adriamycin (ADR) dose of 25 mg/kg i.p. injected in 15 equal partial doses 3 times a week for five following weeks evoked fully developed cardiomyopathy in rats. Inosine 200 mg/kg i.p. injected 5 times a week parallel to ADR diminished ADR cardiotoxicity evaluated by electrocardiographic recordings and histopathological examination. Moreover lower cytostatic toxicity was observed as judged by less-expressed leucopenia and lower SGOT activities in inosine treated animals.
Four variants of yeast tRNA-Phe in which the anticodon and 3'-adjacent nucleotide (GmAAY) have been replaced by synthetic tetranucleotides NAAG (where N is each of the four canonical nucleosides G, C, U or A) are substrates for a yeast tRNA modification enzyme which catalyses the S-adenosyl-L-methionine dependent formations of Gm-34, Cm-34, Um-34, Am-34 and Im-34 (where Nm represents a 2'-O-methylnucleoside and I inosine). The kinetics of these nucleosides-34 2'-O-methylations reveal that yeast tRNA-Phe with G-34 (the natural substrate) is less efficiently modified than variants of the same tRNA containing U-34 and C-34. The formation of Am-34 in the tRNA containing A-34 was found to be particularly inefficient. However, in this tRNA, we observed the formation of I-34 followed by a 2'-O-methylation (giving rise to Im-34). In the yeast in vitro system described here, inosine formation is not dependent on the addition of any cofactor including hypoxanthine; the mechanism of inosine formation in yeast tRNA might therefore be distinct from that found in higher eukaryotes.
Reversible specific binding of [14C]inosine has been demonstrated in turbot (Scophthalmus maximus) buccal tissues rich in taste buds. A highly significant correlation was found for a series of nucleosides and nucleotides between their feeding stimulant activity and their ability to displace bound [14C]inosine. It is concluded that the binding of inosine is the first step in the gustatory process.
Haemodynamic effects of inosine were studied in intact dogs and subsequently in patients suffering from prolonged otherwise intractable cardiogenic shock. The nucleoside significantly improve myocardial performance in patients with an extremely low cardiac index by 63 +/- 29% as well as animals with no signs of haemodynamic deterioration, increasing cardiac output by 12.2 +/- 4.3%. These results suggest that inosine may become a promising inotropic agent. Further studies though are necessary to elucidate the mechanism of inosine action.
Salmonella enterica serovar Typhimurium normally salvage nucleobases and nucleosides by the action of nucleoside phosphorylases and phosphoribosyltransferases. In contrast to Escherichia coli, which catabolizes xanthosine by xanthosine phosphorylase (xapA), Salmonella cannot grow on xanthosine as the sole carbon and energy source. By functional complementation, we have isolated a nucleoside hydrolase (rihC) that can complement a xapA deletion in E. coli and we have overexpressed, purified and characterized this hydrolase. RihC is a heat stable homotetrameric enzyme with a molecular weight of 135 kDa that can hydrolyze xanthosine, inosine, adenosine and uridine with similar catalytic efficiency (k(cat)/Km=1 to 4 x 10(4) M(-1)s(-1)). Cytidine and guanosine is hydrolyzed with approximately 10-fold lower efficiency (k(cat)/Km=0.7 to 1.2 x 10(3) M(-1)s(-1)) while RihC is unable to hydrolyze the deoxyribonucleosides thymidine and deoxyinosine. The Km for all nucleosides except adenosine is in the mM range. The pH optimum is different for inosine and xanthosine and the hydrolytic capacity (k(cat)/Km) is 5-fold higher for xanthosine than for inosine at pH 6.0 while they are similar at pH 7.2, indicating that RihC most likely prefers the neutral form of xanthosine.