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PubMed2003

H2O2, but not menadione, provokes a decrease in the ATP and an increase in the inosine levels in Saccharomyces cerevisiae. An experimental and theoretical approach.

When Saccharomyces cerevisiae cells, grown in galactose, glucose or mannose, were treated with 1.5 mm hydrogen peroxide (H2O2) for 30 min, an important decrease in the ATP, and a less extensive decrease in the GTP, CTP, UTP and ADP-ribose levels was estimated. Concomitantly a net increase in the inosine levels was observed. Treatment with 83 mm menadione promoted the appearance of a compound similar to adenosine but no appreciable changes in the nucleotide content of yeast cells, grown either in glucose or galactose. Changes in the specific activities of the enzymes involved in the pathway from ATP to inosine, in yeast extracts from (un)treated cells, could not explain the effect of H2O2 on the levels of ATP and inosine. Application of a mathematical model of differential equations previously developed in this laboratory pointed to a potential inhibition of glycolysis as the main reason for that effect. This theoretical consideration was reinforced both by the lack of an appreciable effect of 1.5 mm (or even higher concentrations) H2O2 on yeast grown in the presence of ethanol or glycerol, and by the observed inhibition of the synthesis of ethanol promoted by H2O2. Normal values for the adenylic charge, ATP and inosine levels were reached at 5, 30 and 120 min, respectively, after removal of H2O2 from the culture medium. The strong decrease in the ATP level upon H2O2 treatment is an important factor to be considered for understanding the response of yeast, and probably other cell types, to oxidative stress.

Adenosine Triphosphate↗

PubMed1996

Inosine mediates the protective effect of adenosine in rat astrocyte cultures subjected to combined glucose-oxygen deprivation.

Preliminary evidence suggests adenosine, a neuromodulator, has neuroprotective properties during cerebral ischemia. It is unclear, however, if adenosine has glioprotective effects. We studied the effect of adenosine on cellular injury in astroglial cultures subjected to combined glucose-oxygen deprivation. Adenosine (100-1,000 microM)dramatically reduced astroglial injury, whereas the adenosine agonists 2-chloroadenosine (10 nM-100 microM), N6-cyclopentyladenosine (1 nM-10 microM), 5'-N-ethylcarboxamidoadenosine (10 nM-100 microM), and N6-2-(4-aminophenyl)ethyladenosine (10 nM-100 microM) had no effect. Furthermore, the adenosine antagonists 8-cyclopentyl-1,3-dipropylxanthine (1 nM-1 microM), xanthine amine congener (10 nM-10 microM), and 8-(p-sulfophenyl)-theophylline (10-300 microM) failed to reverse the protective effect of 200 microM adenosine. Next, adenosine degradation products were studied. Inosine proved to be glioprotective at concentrations nearly identical to those of adenosine, but hypoxanthine and ribose had no effect. The protective effect of 200 microM inosine was not reversed by 8-(p-sulfophenyl)theophylline (10-300 microM). Adenosine deaminase (1 unit/ml) had no effect on protection produced by adenosine, whereas erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (10 microM) reversed the protective effect of adenosine. Dipyridamole (4 microM) inhibited the protective effect of both adenosine and inosine. We conclude that adenosine dramatically decreases astroglial injury during combined glucose-oxygen deprivation and that this protective effect appears to be mediated by inosine.

2-Chloroadenosine↗

PubMed1988

Purine metabolite inosine is an adrenergic neurotrophic substance for cultured chicken sympathetic neurons.

Purines are ubiquitous endogenous cellular metabolites that have been postulated as neurotransmitters or neuromodulators in the nervous system. Recently, we showed that a low-molecular-mass component present in liver-conditioned medium selectively enhances the adrenergic properties of dissociated chicken sympathetic neurons in culture. We report here that this substance is inosine, a purine metabolite. Indeed, analysis of the low-molecular-mass fraction of liver-conditioned medium by HPLC shows that the neurotrophic activity coelutes with and has the same absorption spectrum as inosine. Inosine increases incorporation of [3H]leucine into neuronal protein and stimulates catecholamine, but not acetylcholine, production by the sympathetic neurons in a dose-dependent fashion (half-maximal stimulation at 10(-6) M). This effect can be blocked by 5 x 10(-6) M dipyridamole, an inhibitor of nucleoside transport. Inosine therefore appears to be capable of modulating adrenergic phenotypic expression in cultured sympathetic neurons by acting via an as-yet-unknown intracellular pathway.

Animals↗

PubMed1999

Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury.

The purine nucleoside inosine has been shown to induce axon outgrowth from primary neurons in culture through a direct intracellular mechanism. For this study, we investigated the effects of inosine in vivo by examining whether it would stimulate axon growth after a unilateral transection of the corticospinal tract. Inosine applied with a minipump to the rat sensorimotor cortex stimulated intact pyramidal cells to undergo extensive sprouting of their axons into the denervated spinal cord white matter and adjacent neuropil. Axon growth was visualized by anterograde tracing with biotinylated dextran amine and by immunohistochemistry with antibodies to GAP-43. Thus, inosine, a naturally occurring metabolite without known side effects, might help to restore essential circuitry after injury to the central nervous system.

Animals↗

PubMedDate not supplied

High-performance liquid chromatography (HPLC) determination of inosine, a potential biomarker for initial cardiac ischaemia, using isolated mouse hearts.

Each year in the USA approximately 7-8 million patients with non-traumatic chest pain come to hospital emergency rooms. It is estimated that approximately 2-5% of these patients are experiencing cardiac ischaemia, but due to the shortcomings of the available testing methods they are incorrectly diagnosed and discharged without appropriate therapy having been provided. Preliminary data with a globally ischaemic mouse heart model has demonstrated that endogenous inosine might be a potential biomarker of initial cardiac ischaemia before cardiac tissue necrosis. A high-performance liquid chromatographic diode array detection (HPLC-DAD) method was utilized for the detection and quantification of inosine in Krebs-Henseleit (Krebs) buffer solution perfusing from surgically removed and isolated mouse hearts undergoing global cardiac ischaemia. A C18 column at a flow rate of 0.6 ml min-1 with an aqueous mobile phase of trifluoroacetic acid (0.05% trifluoroacetic acid in deionized water, pH 2.2, v/v) and methanol gradient was used for component separation. The assay detection limit for inosine in Krebs buffer solution was 500 ng ml-1 using a 100-microl neat injection. The HPLC results were used to determine total cardiac effluxed inosine into the Krebs effluent for each mouse during oxidative stress and compared with the per cent cardiac ventricular functional recovery rate to determine if a relationship exists amongst this cardiovascular parameter during periods of cardiac oxidative stress.

Animals↗

PubMed1983

Mechanism of the inotropic action of inosine on canine myocardium.

The positive inotropic effect of inosine in intact dog hearts was approximately halved by beta-adrenergic blockade with sotalol. The same result was obtained in dogs with chronic denervation of the heart, in which the sympathetic nerve terminals had degenerated. Therefore part of the positive inotropic action of inosine appears to be non-adrenergic. Inosine infusion caused supersensitivity of the positive inotropic effect over a wide range of doses of adrenaline. It is postulated that inosine may act by blocking the desensitising action of cyclic AMP on the reaction between calcium ions and the contractile proteins.

Animals↗

PubMed1997

A ribonuclease specific for inosine-containing RNA: a potential role in antiviral defence?

RNA transcripts in which all guanosine residues are replaced by inosine are degraded at a highly accelerated rate when incubated in extracts from HeLa cells, sheep uterus or pig brain. We report here the partial purification and characterization of a novel ribonuclease, referred to as I-RNase, that is responsible for the degradation of inosine-containing RNA (I-RNA). I-RNase is Mg2+ dependent and specifically degrades single-stranded I-RNA. Comparison of the Km of the enzyme for I-RNA with the Ki for inhibition by normal RNA suggests a approximately 300-fold preferential binding to I-RNA, which can account for the specificity of degradation. The site of cleavage by I-RNase is non-specific; I-RNase acts as a 3'-->5' exonuclease generating 5'-NMPs as products. The presence of alternative unconventional nucleotides in RNA does not result in degradation unless inosine residues are also present. We show that I-RNase is able to degrade RNAs that previously have been modified by the RED-1 double-stranded RNA adenosine deaminase (dsRAD). dsRADs destabilize dsRNA by converting adenosine to inosine, and some of these enzymes are interferon inducible. We therefore speculate that I-RNase in concert with dsRAD may form part of a novel cellular antiviral defence mechanism that acts to degrade dsRNA.

Adenosine Deaminase↗

PubMed2000

Blood glucose and insulin concentrations are reduced in humans administered sucrose with inosine or adenosine.

Recently we found that some nucleosides such as inosine or adenosine inhibited alpha-glucosidase from rat intestine. The aim of this study was to determine whether these nucleosides are sucrase inhibitors in humans as well as rats. Blood glucose and insulin responses were examined in 23 healthy volunteers (18 males and 5 females) administered sucrose with inosine and 8 (males) administered sucrose with adenosine. The initial increase in plasma glucose and serum insulin concentrations at 30 min after loading sucrose (50 g) alone were significantly reduced by co-administration of inosine (2.5 and 1.0 g) or adenosine (2.5 g). The total increases in the areas under the plasma glucose and serum insulin concentration curves for 3 h after administration of the same amount of sucrose with inosine were also significantly less than those when the volunteers were administered sucrose alone. These results in humans agree with the findings obtained in our previous studies in rats. These nucleosides may be used as one of the components of artificial sweeteners when mixed with sucrose and may be useful as food additives to suppress increases in blood glucose and insulin.

Adenosine↗

PubMed1994

Sequence-dependent effects on DNA stability resulting from guanosine replacements by inosine.

The effect of replacing a G.C base-pair with an I.C base-pair on DNA stability was investigated for a related set of 14-mers. DNA melting analysis of the 14-mers was used to determine delta Hzero, delta Szero and delta G(zero)37 of the double to single stranded transition. All 14mers were shown to have B-DNA character by circular dichroism analysis. 14mers substituted with a single inosine in place of guanosine at different positions showed that consequences on DNA stability are sequence-dependent. Large changes in delta Hzero and delta Szero result when inosine is substituted within the trinucleotide sequence d(TCG).d(CGA) while substitution within d(TCC).d(GGA) causes minor changes in enthalpy and entropy. Moreover, some 14-mers with two inosine substitutions five base-pairs apart showed non-additive free energy changes for the double to single stranded transition. These results clearly indicate that the structural consequences of replacing a single guanosine with an inosine are transmitted over a significant distance.

Base Composition↗

PubMed1997

Effects of diaminopurine and inosine substitutions on A-tract induced DNA curvature. Importance of the 3'-A-tract junction.

Gel migration and uranyl photoprobing have been used to study the effects of inosine and 2,6-diaminopurine (2,6-DAP) substitution on adenine-tract (A-tract) induced DNA curvature. Using a 10mer repeated sequence including five inosines we show by uranyl photoprobing that a narrow minor groove varying in phase with the helix repeat is not the cause of DNA curvature. Further, we have systematically studied by gel migration the effects on A-tract induced curvature of either single or full substitution with inosine and/or 2,6-DAP in a 5'-AAAAAGCCGC-3'sequence. DNA curvature is shown to increase when inosines are substituted for the guanosines in the sequence between the A-tracts. By comparing the effects of each monosubstitution it can be seen that when the G closest to the 3'-end of the A-tract is substituted the effect on DNA curvature is much stronger than when substitution is made at any other position. By contrast, curvature is abolished when 2,6-DAP residues are substituted for all adenines, and monosubstitution reveals that the effect of substituting a single adenine is strongest at the 3'-end of the A-tract. These results favor a model in which the curvature induced by an A-tract in DNA molecules is primarily located at the junction with the 3'-end of the A-tract, and this peculiar junction is created because the A-tract has a preference to form a non-B-DNA structure which builds up from the 5'-end.

2-Aminopurine↗

PubMed1987

Intravenous infusion of adenosine but not inosine stimulates respiration in man.

The effects on respiration of intravenous infusions of the endogenous nucleoside adenosine and its deaminated metabolite, inosine, administered in random order, single-blind, were compared in six healthy volunteers. The infusion rate of each nucleoside was initially 3.1 mg min-1 and was increased stepwise every 2 min, as tolerated, up to a possible maximum of 23.4 mg ml-1. The maximum dose rates received by all subjects were 8.5 mg min-1 for adenosine and 16.8 mg min-1 for inosine. Adenosine infusion at rates of 6.1 mg min-1 and above caused a significant increase in minute ventilation, principally due to an increase in tidal volume, with an associated significant fall in end-tidal Pco2. Mean inspiratory flow rate increased and expiratory duration decreased during adenosine infusion, but there was no change in inspiratory duration. Adenosine infusion also caused a significant increase in heart rate and a slight, but significant increase in systolic blood pressure. Infusion of inosine at dose rates up to 16.8 mg min-1 produced no pharmacological effects. This study shows that adenosine by infusion produces sustained respiratory stimulation in man and demonstrates that it does not depend on prior conversion of adenosine to inosine or related metabolites and that it is not secondary to systemic hypotension.

Adenosine↗

PubMed1991

Treatment of alopecia totalis with a combination of inosine pranobex and diphencyprone compared to each treatment alone.

Recent developments in alopecia areata have included the use of oral inosine pranobex and the introduction of diphencyprone as a contact sensitizer. Good results have been claimed for these treatments even in severe forms of the disease. We performed a study to investigate the efficacy of a combination of these treatments in the most severe form of alopecia areata. Thirty-three patients suffering from alopecia totalis were enrolled. Subjects were divided into three groups matched for age and sex. One group received treatment with inosine pranobex (50 mg/kg/day) for 6 months. The second was sensitized to diphencyprone and treated for 6 months by maintenance of contact allergic dermatitis on the scalp. The third received both treatments. There was no evidence of response to inosine pranobex in any of the 22 subjects who received this treatment. Only two of 22 patients responded to diphencyprone. Patients with long-standing alopecia totalis contemplating diphencyprone therapy should be advised that the chances of success are only around 10%. Inosine pranobex does not appear to improve the response rate.

Adolescent↗

PubMed1979

An ultrastructural study on the effects of warm ischaemia on the inosine-protected kidney.

Unperfused, saline-perfused and inosine-perfused rat kidneys were subjected to various times of warm ischaemia with and without resumption of blood flow. Tissues were examined with a transmission electron microscope. Inosine has a protective effect on the epithelial cells of the proximal convoluted tubules, where microvilli are less damaged by ischaemia than those of the proximal convoluted tubular cells of the control animals. Three is also a much higher ratio of autophagic vacuoles to lysosomes present in cells of inosine-treated kidneys, reflecting their ability to sequester and digest organelles damaged during ischaemia and thus protect themselves from degradation products. A major effect of inosine seems to be the preservation of the organelles and rush border of the cells of the proximal tubule during warm ischaemia.

Animals↗

PubMed1981

Inosine in ischaemic renal surgery: long-term follow-up.

Inosine, a purine nucleotide, has been used in 33 patients as a method of preventing ischaemic renal damage. The long-term results have been reviewed with a mean follow-up of 28 months. Inosine was administered either intra-arterially or intravenously. Renal function was assessed by serum creatinine, creatinine clearance and divided function renography. Inosine afforded satisfactory protection in ischaemic periods of up to 60 min, particularly if pre-operative function was normal. It was less reliable if pre-operative function was poor or in ischaemic periods greater than 60 min. Inosine is a helpful aid in ischaemic renal surgery.

Adolescent↗

PubMed1982

The influence of inosine on the size of myocardial ischaemia and myocardial metabolism in the pig.

In acute experiments on open chest pigs 15 min occlusions of the left anterior descending coronary artery were performed, each occlusion followed by 45 min reperfusion. Myocardial ischaemia was defined by epicardial electrogram recorded from the border of the ischaemic area. Myocardial extraction of lactate and glucose as well as the extraction of FFA were measured before and at the 15th min of occlusion. Inosine (5 mg/kg/min) or 0.9% NaCl infusion was administered i.v. throughout the occlusion period. Inosine significantly diminished the number of ischaemic points and reduced an increase in R-wave voltage induced by coronary occlusion. Myocardial extraction of measured substrates was not significantly influenced by inosine administration. In conclusion, inosine decreases the area of ischaemic injury induced by acute coronary occlusion in the pig.

Acute Disease↗

PubMed1994

Separation between ischemic and reperfusion injury by site specific entrapment of endogenous adenosine and inosine using NBMPR and EHNA.

BACKGROUND: Although myocardial ATP is essential for myocardial viability and ventricular function, it is a major source of free radical substrates for endothelial xanthine oxidase. Correlation between myocardial ATP and ventricular function has been hindered by the impact of ATP catabolites on ventricular function during reperfusion. OBJECTIVES: This work results from four separate experiments assessing the role of nucleoside efflux in reperfusion mediated injury to determine the dual role of myocardial ATP in postischemic ventricular dysfunction. An adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), and an adenine nucleoside transport blocker, p-nitrobenzylthioinosine (NBMPR), were used to specifically inhibit adenosine deamination and block nucleoside release, respectively. This pharmacological intervention results in site-specific entrapment of intramyocardial adenosine and inosine, generated during ischemia, and blocks degradation to free radical substrates during reperfusion, thereby limiting the impact of reperfusion mediated injury. METHODS: Forty-three anesthetized dogs were instrumented to monitor left ventricular performance from the slope of the relationship between stroke work and end-diastolic length (SW/EDL). Hearts were subjected to varying periods (30, 60, or 90 min) of global ischemia and 60 or 120 minutes of reperfusion. Two control groups for 30 and 60 minutes of ischemia (16 dogs) received only saline solution. Four treated groups (27 dogs) received saline containing 100 microM EHNA and 25 mM NBMPR prior to ischemia or only during reperfusion (n = 7). Myocardial biopsies were analyzed for ATP catabolites and NAD+. RESULTS: Myocardial ATP and left ventricular function were severely depressed by 50% and 80% in the untreated controls, following 30 and 60 minutes of ischemia (37 degrees C), respectively. Ventricular dysfunction was inversely related to inosine levels in the myocardium at the end of the ischemic period. Administration of EHNA/NBMPR before ischemia or only during reperfusion resulted in significant accumulation of mainly adenosine or inosine, respectively. Entrapment of nucleosides was associated with complete recovery of ventricular function after 30 or 60 minutes of ischemia. Hearts subjected to 90 minutes of ischemia developed contracture. CONCLUSIONS: Despite severely reduced ATP levels, ventricular function significantly recovered to preischemic values only in the EHNA/NBMPR-treated groups. Selective blockade of purine release during reperfusion is cardioprotective against post-ischemic reperfusion mediated injury. It is concluded that nucleoside transport plays an important role in regulation of endogenous adenosine and inosine affecting the degree of myocardial injury or protection from reperfusion mediated injury.

Adenine↗

PubMed1983

Genetic studies on the role of the nucleoside transport function in nucleoside efflux, the inosine cycle, and purine biosynthesis.

A mutant clone (AU-100) which is 90% deficient in adenylosuccinate synthetase activity was characterized from wild-type murine S49 T-lymphoma cells. This AU-100 cell line and its hypoxanthine-guanine phosphoribosyltransferase-deficient derivative, AUTG-50B, overproduce purines severalfold and excrete massive amounts of inosine into the culture medium (Ullman et al., Proc. Natl. Acad. Sci. U.S.A. 79:5127-5131, 1982). We introduced a mutation into both of these cell lines which make them incapable of taking up nucleosides from the culture medium. The genetic deficiency in nucleoside transport prevents the adenylosuccinate synthetase-deficient AU-100 cells from excreting inosine. Because of an extremely efficient intracellular inosine salvage system, the nucleoside transport-deficient AU-100 cells also no longer overproduce purines. AUTG-50B cells which have been made genetically deficient in nucleoside transport still overproduce purines but excrete hypoxanthine rather than inosine. These studies demonstrate genetically that nucleoside transport and nucleoside efflux share a common component and that nucleoside transport has an important regulatory function which profoundly affects the rates of purine biosynthesis and purine salvage.

Adenylosuccinate Synthase↗

PubMed1980

Inosine synthesis and phosphoribosylpyrophosphate availability in rat liver cells in the presence of allopurinol.

In the presence of allopurinol, apparent phosphoribosylpyrophosphate (PP-ribose-P) availability as measured by adenine incorporation into ribonucleotides was decreased in rat liver cells, hypoxanthine incorporation into ribonucleotides was increased, and there was a large synthesis of inosine from hypoxanthine. Inosine was formed directly by the reversal of the purine nucleoside phosphorylase reaction which was very rapid in liver cells. We tested the hypothesis that utilization of ribose 1-phosphate for inosine synthesis could decrease PP-ribose-P availability. Our results indicate that the apparent decrease of PP-ribose-P availability in the presence of allopurinol was due to competition between adenine and hypoxanthine salvage pathways into nucleotides, and not to the synthesis of inosine.

Adenine↗