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PubMed1980

Inotropic and chronotropic responses to inosine in isolated and blood-perfused dog atria.

The effects of inosine on sinus rate and atrial contractile force were investigated using the isolated and blood-perfused canine atrium which was perfused with arterial blood from a donor dog. Injected inosine (100-3000 micrograms) consistently induced positive chronotropic and inotropic effects. However, the larger doses of inosine (1000 and 3000 micrograms) frequently produced slight and brief negative inotropic and chronotropic effects followed by long-lasting positive ones. Positive responses were not suppressed by treatment with propranolol. Negative responses were not inhibited by treatment with atropine. Adenosine-induced negative chronotropic and inotropic effects were potentiated by a continuous infusion of inosine at larger doses of 800-1000 micrograms/min. From these results, we concluded that inosine may have direct positive chronotropic and inotropic actions and that it potentiates adenosine-induced cardiac actions.

Acetylcholine↗
PubMed1991

Leishmania donovani: characteristics of adenosine and inosine transporters in promastigotes of two different strains.

The nucleoside transport characteristics of two strains of Leishmania donovani promastigotes were studied. Strain S1, growing in fully defined medium, and strain S2 (MHOM/ET/67/HA3) both transported adenosine and inosine, but only strain S1 transported uridine and thymidine. Competition studies in the presence of 100 microM of unlabeled adenosine, inosine, guanosine, 2'-deoxyadenosine, tubercidin, formycin B, 3'-deoxyinosine as well as uridine, thymidine and cytidine, with either 1 microM [3H]adenosine or [3H]inosine as permeant, were carried out. The inhibition profile with [3H]inosine as permeant was essentially identical in S1 and S2 promastigotes, indicating that the same inosine transporter was present in both strains. However, with [3H] adenosine as permeant, significant differences were noted between the two strains. Thus, only adenosine, 2'-deoxyadenosine, tubercidin, uridine, and thymidine were strongly inhibitory in S1 promastigotes, while essentially all nucleosides tested were effective in S2 promastigotes. This indicates that adenosine transport in S2 promastigotes seems to involve a transporter differing from that described for S1 promastigotes.

Adenosine↗
PubMed1994

3-isobutyl-1-methylxanthine decreases renal cortical interstitial levels of adenosine and inosine.

The purpose of this study was to test the hypothesis that endogenous cyclic AMP, via metabolism by phosphodiesterase, contributes to interstitial levels of adenosine in the renal cortex in vivo. This hypothesis was tested by determining the effects of 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, on renal cortical interstitial levels of adenosine and inosine. Changes in renal cortical interstitial adenosine and inosine levels were assessed in rats by implanting microdialysis probes into the renal cortex and measuring adenosine and inosine levels in the dialysate exiting the kidney using high performance liquid chromatography. When added to the dialysate entering the kidney at concentrations of 0.5, 1 and 2.5 mM, 3-isobutyl-1-methylxanthine significantly and dose-dependently decreased interstitial levels of both adenosine and inosine. The percentage changes from baseline of interstitial levels of adenosine and inosine were: -39 +/- 6% and -19 +/- 6%, respectively, with 0.5 mM 3-isobutyl-1-methylxanthine; -45 +/- 7% and -24 +/- 8%, respectively, with 1 mM 3-isobutyl-1-methylxanthine; and -56 +/- 12% and -38 +/- 8%, respectively, with 2.5 mM 3-isobutyl-1-methylxanthine. These data suggest that in the renal cortex, cyclic AMP metabolism via phosphodiesterase is an important source of renal interstitial adenosine.

1-Methyl-3-isobutylxanthine↗
PubMed1984

Influence of concomitant infusion of thymidine and inosine on methotrexate activity in normal and P388-bearing mice.

Combinations of thymidine and inosine (ranging from 0 to 7.5 mg/hr) were co-administered during a 72-hr continuous i.v. infusion of 3 micrograms/hr methotrexate in normal and P388 solid tumor-bearing DBA/2 mice. Methotrexate alone was lethal to all normal mice. Inosine at 1.0-7.5 mg/hr could reverse toxicity up to 100% while thymidine at 0.5-7.5 mg/hr was less effective (less than or equal to 86% survival). Combinations of the nucleosides averted toxicity more effectively than either compound alone and in a synergistic manner. From P388 tumor-bearing mice 27% survived methotrexate and eventually died of tumor. Co-infusion of thymidine or inosine decreased the percentage of toxic deaths and caused an increase in life span of more than 50% as compared to untreated tumor-bearing mice. However, the diminishing effect on survival with thymidine and inosine doses above 0.5 mg/hr indicated loss of the antitumor effect of methotrexate. This was also observed with combinations of the nucleosides. The influence of thymidine on the antitumor effect of methotrexate was compared in L1210- and P388-bearing mice (both in ascites) with 13 micrograms/hr methotrexate for 48 hr and 4 mg/hr thymidine for 96 hr. The increase in life span for L1210-bearing mice (8.6 days, 96%) was significantly longer than that with P388-bearing mice (6.1 days, 56%), probably due to biochemical differences between these tumors. It is concluded that co-administration of inosine and/or thymidine allows the use of methotrexate doses otherwise not tolerated, though with loss of anti-tumor effect. The choice of the tumor model may greatly influence the outcome of in-vivo studies on the modulation of methotrexate action by nucleosides.

Animals↗
PubMed2006

Inosine reduces microcirculatory disturbance and inflammatory organ damage in experimental acute pancreatitis in rats.

BACKGROUND: Despite improvement in the management of severe necrotizing pancreatitis, mortality remains high. Today, no specific treatment exists. Inflammatory cascades and microcirculatory disturbances play a key role in the pathogenesis of acute pancreatitis. The aim of the present study was to evaluate the effects of inosine, an immunomodulatory substance, on the severity of experimental necrotizing pancreatitis. METHODS: Severe necrotizing pancreatitis was induced in rats. Treatment groups received inosine either prophylactically or therapeutically. Pancreatic injury was evaluated by microcirculatory assessment and histology. RESULTS: Prophylactic inosine significantly attenuated pancreatic microcirculatory disturbances and morphologic injury in necrotizing pancreatitis. However, inosine treatment did not have any beneficial effects when applied therapeutically several hours after onset of the disease. CONCLUSIONS: Prophylactic inosine reduces microcirculatory and pancreatic injury in acute necrotizing pancreatitis. These effects should be assessed in the clinical setting of ERCP and pancreas transplantation.

Analysis of Variance↗
PubMed2001

Molecular dynamics of DNA quadruplex molecules containing inosine, 6-thioguanine and 6-thiopurine.

The ability of the four-stranded guanine (G)-DNA motif to incorporate nonstandard guanine analogue bases 6-oxopurine (inosine, I), 6-thioguanine (tG), and 6-thiopurine (tI) has been investigated using large-scale molecular dynamics simulations. The simulations suggest that a G-DNA stem can incorporate inosines without any marked effect on its structure and dynamics. The all-inosine quadruplex stem d(IIII)(4) shows identical dynamical properties as d(GGGG)(4) on the nanosecond time scale, with both molecular assemblies being stabilized by monovalent cations residing in the channel of the stem. However, simulations carried out in the absence of these cations show dramatic differences in the behavior of d(GGGG)(4) and d(IIII)(4). Whereas vacant d(GGGG)(4) shows large fluctuations but does not disintegrate, vacant d(IIII)(4) is completely disrupted within the first nanosecond. This is a consequence of the lack of the H-bonds involving the N2 amino group that is not present in inosine. This indicates that formation of the inosine quadruplex could involve entirely different intermediate structures than formation of the guanosine quadruplex, and early association of cations in this process appears to be inevitable. In the simulations, the incorporation of 6-thioguanine and 6-thiopurine sharply destabilizes four-stranded G-DNA structures, in close agreement with experimental data. The main reason is the size of the thiogroup leading to considerable steric conflicts and expelling the cations out of the channel of the quadruplex stem. The G-DNA stem can accommodate a single thioguanine base with minor perturbations. Incorporation of a thioguanine quartet layer is associated with a large destabilization of the G-DNA stem whereas the all-thioguanine quadruplex immediately collapses.

Biophysical Phenomena↗
PubMed2002

Inosine stimulates axon growth in vitro and in the adult CNS.

Unlike mammals, lower vertebrates can regenerate their optic nerves and certain other CNS pathways throughout life. To identify the molecular bases of this phenomenon, we developed a cell culture model and found that goldfish retinal ganglion cells will regenerate their axons in response to the purine nucleoside inosine. Inosine acts through a direct intracellular mechanism and induces many of the changes in gene expression that underlie regenerative growth in vivo, e.g., upregulation of GAP-43, T alpha-1 tubulin, and the cell-adhesion molecule, L1. N-kinase, a 47-49-kDa serine-threonine kinase, may mediate the effects of inosine and serve as part of the modular signal transduction pathway that controls axon growth. In vivo, inosine stimulates extensive axon growth in the mature rat corticospinal tract. Following unilateral transection of the corticospinal tract, inosine applied to the intact sensorimotor cortex stimulated layer 5 pyramidal cells to upregulate GAP-43 expression and to sprout axon collaterals. These collaterals crossed the midline at the level of the cervical enlargement and reinnervated regions whose normal connections had been served. Further understanding of the molecular changes that lie upstream and downstream of N-kinase may lead to new insights into the control of axon growth and to novel methods to improve functional outcome in patients with CNS injury.

Animals↗
PubMed1976

Enhanced preservation of the ischaemic kidney with inosine.

The function of rat kidneys subjected to 60 minutes of warm ischaemia at body-temperature was notably protected by the prior administration of the purine nucleoside inosine as a 40 mg/ml solution maintained at 37 degrees C. With direct intrarenal arterial perfusion of the kidney at the onset of ischaemia or with intraperitoneal (i.p.) injection 40 minutes before ischaemia, the plasma-creatinine at 24 hours was significantly lower (P less than 0-001) than that of untreated 60-minute-ischaemia controls and not significantly different from that of non-ischaemic unilateral-nephrectomy controls. Intravenous inosine 20 minutes beforehand also afforded significant (P less than 0-01) protection. 7-day survival was 100% in 30 inosine-pretreated rats and 65% in 45 rats with all other types of pre-treatment (P less than 0-001). Although i.p. adenosine was better (P less than 0-05) than no treatment, i.p. inosine was better (P less than 0-02) than i.p. adenosine. Allopurinol, phenoxybenzamine, A.T.P., or cyclic A.M.P. caused no improvement over controls. Kidneys perfused with inosine maintained higher purine-nucleotide levels during ischaemia and rapidly resynthesised A.T.P. when blood-flow was restored in vivo.

Adenosine↗
PubMed2003

Effects of inosine on axonal regeneration of axotomized retinal ganglion cells in adult rats.

Damage to the central nervous system (CNS) is always followed by an irreversible axon degeneration of injured neurons. The purine nucleoside inosine has been shown to induce neurons to regenerate axons in culture and in vivo. In the present study, we investigated the in vivo effects of inosine on the axon regeneration of axotomized retinal ganglion cells (RGCs) in adult rats, using the model of peripheral nerve (PN) grafting onto the ocular stump of the transected optic nerve. Animals were allowed to survive for 4 weeks after surgery with repeated intraperitoneal injections of inosine 1 day before PN grafting till they were killed. Treatment with inosine induced a significant increase (62%) in the number of FluroGold -labeled RGCs regrowing their axons into the PN graft, when compared with the control animals. The axon outgrowth-promoting effect of inosine in adult rodents may represent a potential clinical treatment for injured or degenerated CNS.

Age Factors↗
PubMed1976

Hemoglobin function in stored blood, XVII. Maintenance of red cell 2,3 DPG (function) and ATP (viability) for six weeks in ACD or CPD-adenine-inosine-methylene blue.

Blood preservatives containing adenine for six week storage have been prepared with inosine and methylene blue at various pH levels in order to maintain, 23-DPG levels for immediate oxygen transport upon transfusion. In one experiment, the adverse effect of a high pH on ATP maintenance was demonstrated in the presence of methylene blue and inosine. In this and other experiments it was clear that ATP was better maintained in low pH preservatives and DPG better maintained in higher pH preservatives. However, 2,3-DPG levels were kept from falling with CPD-adenine-inosine over a wide range of pH values. A CPD-adenine-inosine preservative at a pH 5.8 maintained normal DPG levels for three weeks of storage. A similar preservative but with a pH of 6.6 maintained normal DPG levels for 35 days of storage. It is suggested that if all blood bank units are going to have normal DPG levels for optimal oxygen transport at the time of transfusion then a CPD preservative with a higher pH and/or metabolic nutrients and regulators such as inosine or methylene blue would be required.

Adenine↗
PubMed1975

Heavy metal-nucleoside interactions. Binding of methylmercury(II) to inosine and catalysis of the isotopic exchange of the C-8 hydrogen studied by 1-H nuclear magnetic resonance and raman difference spectrophotometry.

Raman difference spectrophotometry reveals that CH3HgII binds quantitatively to N(1) of inosine at pH 8, substituting for the proton. When N(1) is saturated, binding occurs at a second site. Measurements of the 1-H nuclear magnetic resonance spectra of both inosine and of CH3Hg-II are in agreement with the N(1) binding and indicate that the second site for mercuriation is N(7). This second binding reaction is observed to increase the rate of exchange of the C(8) hydrogen with solvent, consistent with results observed for alkylation at N(7). Coordination of the electrophilic CH3Hg-II to N(7) increases the acidity of H(8), facilitating OHminus--catalyzed proton abstraction and reprotonation by themedium. For comparison, the reaction of CH3Hg-II with [8-2-H]inosine has been studied. Displacement of the N(1) hydrogen upon mercuriation of inosine causes a significant electron delocalization into the ring, increasing the basicity of N(7), and accounting for the synergic effect in metal binding observed originally by Simpson. In contrast, 1-methylinosine interacts only slightly with CH3Hg-II at pH 8. Coordination appears to be at N(7), since H(8) again is observed to exchange rapidly with solvent protons. In acidic solution, pH less than 2, binding to inosine is almost quantitative and exclusively to N(7). The behavior of CH3Hg-II is compared with that of Pt(II) and with Ni(II), Co(II), AND Zn(II). A brief comparison is made among ultraviolet absorption spectrophotometry, nuclear magnetic resonance (NMR), and Raman difference spectrophotometry for studying reactions of nucleosides and nucleotides.

Binding Sites↗
PubMed1987

Increases in cerebral cortical perfusate adenosine and inosine concentrations during hypoxia and ischemia.

The cerebral cortical cup technique was used to monitor changes in adenosine and inosine levels in the rat cerebral cortex during periods of hypoxia, anoxia, or hemorrhagic hypotension. Basal levels of adenosine and inosine in cortical perfusates stabilized within 10 min at concentrations of 30-50 and 75-130 nM, respectively. Comparable levels were observed in normal CSF collected from the cisterna magna. Reductions in the oxygen content of the inspired air (14, 12, 8, and 5% oxygen) resulted in increases in the adenosine and inosine levels in the cortical perfusates, the magnitude of the increase being progressively more pronounced with greater reductions in the oxygen content. Cerebral anoxia/ischemia, induced by 100% nitrogen inhalation, caused a rapid increase in the adenosine and inosine contents of the cortical perfusates. Hemorrhagic hypotension (46.1 +/- 1.7 mm Hg) of 5 min duration did not result in an elevated adenosine or inosine release. The results suggest that interstitial fluid adenosine levels are likely to be in the low nM range in the normoxic animal and are capable of rapid increases during hypoxic or anoxic episodes. The findings support the adenosine hypothesis of CBF regulation.

Adenosine↗
PubMed1982

Inosine metabolism in the rat.

1. Uptake and subsequent metabolism of purine and ribose moieties was monitored after intravenous administration of doubly labelled inosine. 2. More than 95% was cleared from the plasma within 5 min, and 99% within 20 min. 3. Approx. 50% of the 160 mumol total was rapidly incorporated into liver and kidney. Kidney removed the greatest amount (21 mumol/g wet wt.), about 10-fold more than heart, lung or liver. Lung and heart accounted for only 3%. These tissues then lost radioactivity during the remainder of the experiment. Radioactivity in the skeletal muscle, in contrast, increased from 8% of the injected dose at 5 min to 40% at 60 min. 4. In liver, kidney, heart and lung there was a significant difference in the fate of inosine. After initial incorporation of inosine, kidney predominantly lost inosine; heart preferentially lost purines; lung preferentially lost ribose radioactivity; and in liver the ribose radioactivity was rapidly lost, whereas purine was retained. Some of the ribose moiety was metabolized to glucose, presumably in the liver, and then released into the blood. Ribose radioactivity (probably as glucose) and radioactive hypoxanthine accumulated in skeletal muscle throughout the experiment. 5. Inosine caused a rapid and prolonged increase in the blood glucose content, from 6 to 15 mM in 60 min. This was accompanied by a small increase in plasma insulin. 6. It is concluded that the purine and ribose radioactivity lost from the kidney, liver and other tissues becomes incorporated into skeletal muscle.

Animals↗
PubMed1979

Inosine, an endogenous ligand of the brain benzodiazepine receptor, antagonizes pentylenetetrazole-evoked seizures.

Partially purified extracts of bovine brain were previously found to inhibit competitively the binding of [3H]-diazepam to rat brain synaptosomal membranes. The purines inosine and hypoxanthine were subsequently identified as the compounds responsible for this inhibitory activity. Intracerebroventricular administration of inosine to mice of the C3H/HEN and NIH general purpose strains caused a dose- and time-dependent increase in the latency to clonicotonic seizures produced by intraperitoneal administration of the convulsant pentylenetetrazole. Intracerebroventricular administration of equimolar doses of 2'-deoxyinosine, which is more potent than inosine in inhibiting the binding of [3H]diazepam in vitro, significantly increased pentylenetetrazole-evoked seizure latency. In contrast, both 7-methylinosine and thymidine were ineffective in inhibiting the in vitro binding of [3H]diazepam and increasing the latency to pentylenetetrazole-induced seizures in vivo. These results suggest that endogenously occurring purines such as inosine exhibit diazepam like effects when administered intracerebroventricularly, and these effects may be related to the interaction of inosine and related compounds with benzodiazepine receptors in the central nervous system.

Animals↗
PubMed1998

Interstitial adenosine, inosine, and hypoxanthine are increased after experimental traumatic brain injury in the rat.

Adenosine is a putative neuroprotectant in ischemia, but its role after traumatic brain injury (TBI) is not clear. Metabolites of adenosine, particularly inosine and hypoxanthine, are markers of ischemia and energy failure. Adenosine triphosphate (ATP) breakdown early after injury and metabolism of cyclic adenosine monophosphate (cAMP) are potential sources of adenosine. Further delineation of the magnitude, location, time course, and source of production of adenosine after TBI is needed. We measured adenosine, inosine, and hypoxanthine in brain interstitial fluid after controlled cortical impact (CCI) in the rat. Rats (n = 15) were prepared for TBI induced by CCI. A microdialysis probe was placed in the cortex, and samples were collected every 10 min. After 3 h of equilibration, the catheter was removed, CCI was performed (4 m/sec, depth 2.5 mm), and the catheter was replaced. In the shams, the catheter was removed and replaced without CCI. The injury group included rats (n = 10) subjected to CCI. Within the injury group, the microdialysis probe was placed in the center of the eventual contusion (center, n = 5) or in the penumbral region (penumbra, n = 5). Purine metabolites were measured using ultraviolet-based high-pressure liquid chromatography. Adenosine, inosine, and hypoxanthine were dramatically increased after injury (61-fold, 37-fold, and 16-fold, respectively sham, all p < 0.05, two-way analysis of variance for repeated measures). No changes in cAMP were observed (p = 0.62 vs. sham). Adenosine peaked in the first 20 min and returned to near baseline 40 min, whereas inosine and hypoxanthine peaked at 30 min and remained increased for 40 min after CCI. Interstitial brain adenosine, inosine, and hypoxanthine were increased early after CCI in rats in the contusion and penumbra. ATP breakdown is a potential source of adenosine in this early period while metabolism of cAMP does not appear to play a role. Confirmation of these data in humans may suggest new strategies targeting this important metabolic pathway.

Adenosine↗
PubMed1978

Preservation of erythrocytes using metabolic regulators and mutrients. V. Inosine and methylene blue.

Methylene blue and inosine have been shown to stimulate glycolytic metabolism in the erythrocytes, increasing the concentration of 2.3-diphosphoglycerate (2,3-DPG), which is necessary for hemoglobin function, by regulating oxidative metabolism and providing a five-carbon nutrient for glycolysis, respectively. However, a recent study suggested that the methylene blue effect was dependent on the presence of inosine. This study was designed to establish, if possible, the existence of a methylene blue effect and to confirm the usefulness of inosine. The optimal concentration of inosine for increasing 2,3-DPG synthesis in a CPD-adenine preservative is confirmed to be 10--15 mM. Concentrations of 2,3-DPG were maintained in the erythrocytes at normal or higher levels for 21 days of storage with 10 or 15 mM inosine, whether the methylene blue was present or not. However, when methylene blue was present, 2,3-DPG concentrations were significantly better maintained.

Adenine↗
PubMed2002

Direct protection of inosine on PC12 cells against zinc-induced injury.

It has been reported that inosine has no direct neuroprotection against respiratory inhibitors due to the absence of purine nucleoside phosphorylase in neurons. Recent evidence, however, has shown that inosine has direct neurotrophic effects. Thus, lack of direct neuroprotection, as reported before, may not be a general conclusion, but is related to special types of injury. We used PC12 cells to explore direct neuroprotection of inosine against high concentration of zinc sulfate, an injury different from the previous one and found that inosine reduced the mortality of PC12 cells significantly in a dose dependent manner. The results indicate that inosine can directly protect neurons from zinc-induced injury, and such effect might be mediated via mechanism(s) other than purine nucleoside phosphorylase.

Animals↗
PubMed1987

Extracellular adenosine, inosine, hypoxanthine, and xanthine in relation to tissue nucleotides and purines in rat striatum during transient ischemia.

Extracellular (EC) adenosine, hypoxanthine, xanthine, and inosine concentrations were monitored in vivo in the striatum during steady state, 15 min of complete brain ischemia, and 4 h of reflow and compared with purine and nucleotide levels in the tissue. Ischemia was induced by three-vessel occlusion combined with hypotension (50 mm Hg) in male Sprague-Dawley rats. EC purines were sampled by microdialysis, and tissue adenine nucleotides and purine catabolites were extracted from the in situ frozen brain at the end of the experiment. ATP, ADP, and AMP were analyzed with enzymatic fluorometric techniques, and adenosine, hypoxanthine, xanthine, and inosine with a modified HPLC system. Ischemia depleted tissue ATP, whereas AMP, adenosine, hypoxanthine, and inosine accumulated. In parallel, adenosine, hypoxanthine, and inosine levels increased in the EC compartment. Adenosine reached an EC concentration of 40 microM after 15 min of ischemia. Levels of tissue nucleotides and purines normalized on reflow. However, xanthine levels increased transiently (sevenfold). In the EC compartment, adenosine, inosine, and hypoxanthine contents normalized slowly on reflow, whereas the xanthine content increased. The high EC levels of adenosine during ischemia may turn off spontaneous neuronal firing, counteract excitotoxicity, and inhibit ischemic calcium uptake, thereby exerting neuroprotective effects.

Adenosine↗