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PubMed1983

Inosine : a naturally occurring cardiotonic agent.

For many years, Inosine was considered to be a simple metabolite of adenosine which was devoid of any cardiovascular effects. This theoretical ineffectiveness can be explained in the light of recent studies by the use of inadequate doses. In fact, higher doses of inosine, a non-toxic nucleoside, have demonstrated, experimentally, a cardiovascular activity and the pharmacological profile of this naturally occurring substance has been defined. Like adenosine, inosine is a potent coronary vasodilator. The vasodilatation induced by inosine is only partly due to increased metabolic demands. Inosine has a direct action on coronary artery relaxation independent of the inotropic effect. It alters the balance between oxygen supply and demand which is reflected by an intramyocardial redistribution of oxygen in favour of the sub-endocardial zones. Inosine acts on the coronary circulation like a "regulator of myocardial nutrition", unlike adenosine, which can be thought of as a "coronary vasoregulator". This dissociation between the two nucleosides is apparently due to different vascular sites of action. The positive inotropic action of inosine, which has been demonstrated in both healthy and pathological myocardium in all of the experimental animal species studied, is not due to stimulation of the cardiac beta-adrenergic receptors, as beta-blockers do not antagonize the positive inotropic effect of inosine. This increase in myocardial contractile dynamics is evident in infarcted as well as healthy areas of myocardium. The inotropic and coronary vasodilator effects of inosine are not associated with any modification of the chronotropic function. Inosine is not arrhythmogenic, even at high doses. Furthermore, it does not affect atrioventricular conduction. It has been demonstrated that inosine is capable of antagonizing ouabain induced arrhythmias. Various clinical studies confirm the positive inotropic action of inosine, without any alteration in the post-load, the pre-load or the heart rate. The positive inotropic action of inosine can therefore be considered to be selective. Together with these haemodynamic effects, it has been shown that the addition of inosine to cardioplegic solutions improves the functional recovery of the myocardium, by increasing the quantity of energy-rich phosphates. Similar beneficial results have been obtained in renal transplantation, both experimentally and in clinical studies. The mechanism of action of inosine remains unknown. Are the haemodynamic effects of this compound due to its metabolic effects? Are there specific myocardial purinergic receptors? (ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗
PubMed2005

Inosine released after hypoxia activates hepatic glucose liberation through A3 adenosine receptors.

Inosine, an endogenous nucleoside, has recently been shown to exert potent effects on the immune, neural, and cardiovascular systems. This work addresses modulation of intermediary metabolism by inosine through adenosine receptors (ARs) in isolated rat hepatocytes. We conducted an in silico search in the GenBank and complete genomic sequence databases for additional adenosine/inosine receptors and for a feasible physiological role of inosine in homeostasis. Inosine stimulated glycogenolysis (approximately 40%, EC50 4.2 x 10(-9) M), gluconeogenesis (approximately 40%, EC50 7.8 x 10(-9) M), and ureagenesis (approximately 130%, EC50 7.0 x 10(-8) M) compared with basal values; these effects were blunted by the selective A3 AR antagonist 9-chloro-2-(2-furanyl)-5-[(phenylacetyl)amino][1,2,4]-triazolo[1,5-c]quinazoline (MRS 1220) but not by selective A1, A2A, and A2B AR antagonists. In addition, MRS 1220 antagonized inosine-induced transient increase (40%) in cytosolic Ca2+ and enhanced (90%) glycogen phosphorylase activity. Inosine-induced Ca2+ mobilization was desensitized by adenosine; in a reciprocal manner, inosine desensitized adenosine action. Inosine decreased the cAMP pool in hepatocytes when A1, A2A, and A2B AR were blocked by a mixture of selective antagonists. Inosine-promoted metabolic changes were unrelated to cAMP decrease but were Ca2+ dependent because they were absent in hepatocytes incubated in EGTA- or BAPTA-AM-supplemented Ca2+-free medium. After in silico analysis, no additional cognate adenosine/inosine receptors were found in human, mouse, and rat. In both perfused rat liver and isolated hepatocytes, hypoxia/reoxygenation produced an increase in inosine, adenosine, and glucose release; these actions were quantitatively greater in perfused rat liver than in isolated cells. Moreover, all of these effects were impaired by the antagonist MRS 1220. On the basis of results obtained, known higher extracellular inosine levels under ischemic conditions, and inosine's higher sensitivity for stimulating hepatic gluconeogenesis, it is suggested that, after tissular ischemia, inosine contributes to the maintenance of homeostasis by releasing glucose from the liver through stimulation of A3 ARs.

Adenosine↗
PubMed2005

Protective mechanisms of inosine in platelet activation and cerebral ischemic damage.

OBJECTIVE: Inosine is a naturally occurring nucleoside degraded from adenosine. Recent studies have demonstrated that inosine has potent immunomodulatory and neuroprotective effects. In the present study, we further investigated the inhibitory effects of inosine on platelet activation in vitro and in vivo, as well as in attenuating middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia in rats. METHODS AND RESULTS: Inosine concentration-dependently (0.5 to 6.0 mmol/L) inhibited platelet aggregation stimulated by agonists. Inosine (1.5 and 3.0 mmol/L) inhibited phosphoinositide breakdown, [Ca+2]i, and TxA2 formation in human platelets stimulated by collagen (1 microg/mL). In addition, inosine (1.5 and 3.0 mmol/L) markedly increased levels of cyclic guanylate monophosphate (GMP) and cyclic GMP-induced vasodilator-stimulated phosphoprotein Ser157 phosphorylation. Rapid phosphorylation of a platelet protein of molecular weight 47,000 (P47), a marker of protein kinase C activation, was triggered by collagen (1 microg/mL). This phosphorylation was markedly inhibited by inosine (3.0 mmol/L). Inosine (1.5 and 3.0 mmol/L) markedly reduced hydroxyl radical in collagen (1 microg/mL)-activated platelets. In in vivo studies, inosine (400 mg/kg) significantly prolonged the latency period of inducing platelet plug formation in mesenteric venules of mice, and administration of 2 doses (100 mg/kg) or a single dose (150 mg/kg) of inosine significantly attenuated MCAO-induced focal cerebral ischemia in rats. CONCLUSIONS: Platelet aggregation contributes significantly to MCAO-induced focal cerebral ischemia. The most important findings of this study suggest that inosine markedly inhibited platelet activation in vitro and in vivo, as well as cerebral ischemia. Thus, inosine treatment may represent a novel approach to lowering the risk of or improving function in thromboembolic-related disorders and ischemia-reperfusion brain injury.

Animals↗
PubMed2006

Effects of inosine on neuronal apoptosis and the expression of cytochrome C mRNA following hypoxic-ischemic brain damage in neonatal rats.

OBJECTIVE: It has been reported that neuronal apoptosis plays a critical role in pathology of hypoxic-ischemic encephalopathy (HIE). Cytochrome C (CytC) is an important apoptotic protease activating factor. Inosine might have a neuroprotective effect against cerebral ischemia reperfusion injury by inhibiting the neuronal apoptosis and the expression of CytC mRNA in adult rats. This study examined the effects of inosine on neuronal apoptosis and CytC mRNA expression following hypoxic-ischemic brain damage (HIBD) in order to investigate the neuroprotectivity of inosine against cerebral ischemia injury in neonatal rats and the possible mechanism. METHODS: A total of 140 healthy 7-day-old Sprague-Dawley rat pups were randomly assigned into Control (n=40), HIBD (n=50) and Inosine treatment groups (n=50). HIBD rat models were established by ligating the left common carotid artery, followed by 8% O2 hypoxia exposure for 2 hrs in the HIBD and Inosine treatment groups. The Control group was not subjected to hypoxia-ischemia (HI). The Inosine treatment and the HIBD groups were randomly divided into 5 sub-groups sacrificed at 6 and 12 hrs, and 1, 3 and 7 days post- HI (n=10 each). The Control group rats were sacrificed at the corresponding time points (n=8 each). Inosine was administered to the Inosine treatment group by intraperitoneal injection immediately after HIBD at the dosage of 100 mg/kg twice daily for 7 days. TUNEL staining and in situ hybridization method was used to detect neuronal apoptosis and CytC mRNA expression respectively. RESULTS: Few apoptotic cells and CytC mRNA positive cells were found in brain tissues of the Control group. In the HIBD group, the number of apoptotic cells and the CytC mRNA expression in the cortical and hippocampal gyrum CA1 areas increased 6 hrs after HI, peaking at 1 day after HI and then decreased gradually. Until the 7th day, the number of apoptotic cells and the CytC mRNA expression in the cortical and hippocampal gyrum CA1 areas in the HIBD group remained significantly higher than in the Control group. Inosine treatment decreased the apoptotic cells and the CytC mRNA expression in both areas from 6 hrs to 7 days after HI compared with the HIBD group. The linear correlation analysis demonstrated that the number of apoptotic cells was positively correlated to the CytC mRNA expression in neonatal rats with HIBD (r=0.88, P < 0.01) . CONCLUSIONS: Inosine can reduce the number of apoptotic cells and down-regulate the expression of CytC mRNA following HIBD in neonatal rats. The decreased number of apoptotic cells was positively correlated to the decreased CytC mRNA expression after inosine treatment, suggesting that inosine offered neuroprotectivity against HIBD possibly through inhibiting the CytC mRNA expression and resulting in a decrease of cell apoptosis.

Animals↗
PubMed1985

Alterations of inosinate branchpoint enzymes in cultured human lymphoblasts.

The specific activities of the three enzymes of the inosinate branchpoint are independently regulated when lymphoblasts are grown under various tissue culture conditions. In comparison to rapidly dividing cells, lymphoblasts at high cell density with no cellular division have decreased activity of the enzymes which commit inosinate to adenylate or guanylate, while cytoplasmic 5'-nucleotidase is relatively preserved. A linear relationship between inosinate dehydrogenase activity and growth rate (r = 0.92) exists in lymphoblasts with slowed growth rates. In contrast, in dividing cells adenylosuccinate synthetase and 5'-nucleotidase do not vary with growth rate. Adenylosuccinate synthetase and inosinate dehydrogenase activities appear to be related to the presence or rate of cellular division, as opposed to the presence or degree of neoplastic transformation. Lymphoblast lines with alterations of specific purine metabolic enzymes have characteristic alteration of the inosinate utilizing enzymes. Deficiencies of purine nucleoside phosphorylase or hypoxanthine phosphoribosyltransferase, abnormalities which render the cell unable to salvage purine effectively, are associated with depressed inosinate dehydrogenase activity. Insertion of the hypoxanthine phosphoribosyltransferase gene into hypoxanthine phosphoribosyltransferase-deficient cells normalizes inosinate dehydrogenase activity, while a hypoxanthine phosphoribosyltransferase-deficient mutant selected from a hypoxanthine phosphoribosyltransferase-containing line has depressed inosinate dehydrogenase activity. In contrast, overactivity of phosphoribosylpyrophosphate synthetase, with enhanced excretion of purines due to excessive production, is associated with elevated inosinate dehydrogenase activity. Inosinate dehydrogenase appears to be regulated according to the availability of purine nucleotides. Patients who overproduce uric acid and potentially have undescribed purine metabolic defects are now being screened for abnormalities in the inosinate branchpoint enzymes.

5'-Nucleotidase↗
PubMed1985

The liver is an organ site for the release of inosine metabolized by non-glycolytic pig red cells.

The metabolic energy source used by the pig red cell, which is unable to metabolize blood-borne glucose, was examined. Potential physiological substrates include adenosine, inosine, ribose, deoxyribose, dihydroxyacetone and glyceraldehyde, of which inosine was previously implicated. A net ATP synthesis by red cells occurs during in situ perfusion through the adult miniature pig liver. HPLC analysis of the perfusate revealed the presence primarily of inosine and hypoxanthine. Inosine production by the liver was 0.015 mumol/g per min. Moreover, red cells maintain ATP when suspended in a balanced salt medium during a 6 h incubation at 38 degrees C, in which inosine is continuously infused to give an external concentration of no more than 3 mumol/l, mimicking its plasma level. Inosine consumption under these infusion conditions was 56 nmol/ml cell per h, which is two orders of magnitude lower than when inosine is present in millimolar concentration. The total red cell inosine consumption of 9.63 mumol/h is much less than the total liver inosine production of 212 mumol/h. These findings suggest that the liver is an organ site elaborating inosine, and that maintenance of a 3 mumol/l inosine in plasma is sufficient to meet the energy requirements of the pig red cells.

Adenosine Triphosphate↗
PubMed1994

Addition of e-aq and H atoms to hypoxanthine and inosine and the reactions of alpha-hydroxyalkyl radicals with purines. A pulse radiolysis and product analysis study.

The reactions of hydrated electrons e-aq with hypoxanthine and inosine were followed using pulse radiolysis methods. In a neutral solution the electron adduct of inosine is immediately protonated at the heteroatoms of the purine ring by water (k >> 2.5 x 10(6)s-1) to give In(N,O-H).. These N,O-protonated intermediates have a single absorption maximum at 300 nm. In basic solution the protonation of the electron adduct of inosine by water leads to other intermediate products with an absorption maximum at 350 nm. These intermediates are believed to be the C-protonated electron adducts of inosine (In(N,O-H).). In (N,O-H). and In(C-H). differ strongly in their ability to reduce p-nitroacetophenone (PNAP). In(N,O-H). are strong reductants and reduce PNAP quantitatively to PNAP.-. Based on the pH dependence of PNAP.- yields, two types of tautomers of In(C-H). could be distinguished. One of the tautomers can reduce PNAP, albeit with slower rate than In(N,O-H)., the other tautomer has no reducing properties. The latter is the one with the higher pKa and therefore thermodynamically more stable. The absorption spectrum of the intermediates produced in the reaction of e-aq with hypoxanthine at neutral pH is very similar to that of In(N,O-H). with a maximum at 300 nm. However, no build-up at 350 nm was observed in basic solution as in the case of the electron adduct of inosine. The reaction of H atoms with inosine produces in basic solution intermediate radicals with the same absorption spectrum as the C-protonated electron adducts of inosine. It is suggested that both the reactions of e-aq and H. with inosine in basic solution produce the same radical, namely the H-adduct of inosine (In(C-H)) with the highest pKa. alpha-Hydroxyalkyl radicals were found to react very slowly with purine bases and nucleosides in neutral to basic solutions. In acidic solution their reactivity increases and a number of rate constants were determined by pulse radiolysis measurements at pH 0.4. The intermediates from the reaction of 2-hydroxy-2-propyl radicals with inosine could be observed pulse spectrometrically in neutral and in basic solutions. In basic solution this reaction leads to intermediates with the same absorption maximum at 350 nm as that of the H-adduct of inosine. Furthermore, the yield of acetone was found to increase strongly in basic pH.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetophenones↗
PubMed2001

Inosine improves gut permeability and vascular reactivity in endotoxic shock.

OBJECTIVE: To investigate the effects of inosine administration on vascular reactivity, gut permeability, neutrophil accumulation and lipid peroxidation in tissues in murine endotoxin shock. DESIGN: Randomized, prospective laboratory study. SETTING: Research laboratory. SUBJECTS: BALB/c mice 6-8 wks age. INTERVENTIONS: BALB/c mice were randomly assigned to one of five groups: a) vehicle controls, which received saline intraperitoneally; b) inosine controls, which received inosine alone (100 mg/kg, ip); c) lipopolysaccharide (LPS)-treated animals, which received LPS (40 and 100 mg/kg, ip, depending on the experimental protocol); d) inosine pretreatment group, which received inosine (100 mg/kg, ip) 30 mins before LPS; and finally, e) inosine posttreatment group, which received inosine (100 mg/kg, ip) 60 mins after LPS. MEASUREMENTS AND MAIN RESULTS: The passage of fluorescein isothiocyanate-conjugated dextran (4 kDa, FD4) was analyzed in everted gut ileal sacs incubated ex vivo as an index of gut permeability. LPS induced a significant intestinal hyperpermeability, and inosine exerted protective effects both in pre- and posttreatment regimens. Myeloperoxidase and malondialdehyde were also measured to study neutrophil accumulation and lipid peroxidation in selected tissues. Inosine, both in pre- and posttreatment regimens ameliorated the increases in myeloperoxidase and malondialdehyde in the lung and gut. LPS-treated animals showed decreased contractile and relaxant responses, and inosine pretreatment (but not posttreatment) partially improved these responses. CONCLUSIONS: Taken together, inosine has organ protective effects during shock. A significant portion of its protective action is maintained even in the posttreatment scenario.

Animals↗
PubMedDate not supplied

Inosine protects against the development of diabetes in multiple-low-dose streptozotocin and nonobese diabetic mouse models of type 1 diabetes.

Inosine, a naturally occurring purine, was long considered to be an inactive metabolite of adenosine. However, recently inosine has been shown to be an immunomodulator and anti-inflammatory agent. The aim of this study was to determine whether inosine influences anti-inflammatory effects and affects the development of type 1 diabetes in murine models. Type 1 diabetes was induced either chemically by streptozotocin or genetically using the nonobese diabetic mouse (NOD) model. Mice were treated with inosine (100 or 200 mg kg(-1)d(-1)d) and diabetes incidence was monitored. The effect of inosine on pancreas immune cell infiltration, oxidative stress, and cytokine profile also was determined. For the transplantation model islets were placed under the renal capsule of NOD mice and inosine (200 mg kg(-1)d d(-1)d) treatment started the day of islet transplantation. Graft rejection was diagnosed by return of hyperglycemia accompanied by glucosuria and ketonuria. Inosine reduced the incidence of diabetes in both streptozotocin-induced diabetes and spontaneous diabetes in NOD mice. Inosine decreased pancreatic leukocyte infiltration and oxidative stress in addition to switching the cytokine profile from a Th1 to a Th2 profile. Inosine prolonged pancreatic islet graft survival, increased the number of surviving beta cells, and reduced the number of infiltrating leukocytes. Inosine protects against both the development of diabetes and against the rejection of transplanted islets. The purine exerts anti-inflammatory effects in the pancreas, which is its likely mode of action. The use of inosine should be considered as a potential preventative therapy in humans susceptible to developing Type 1 diabetes and as a possible antirejection therapy for islet transplant recipients.

Animals↗
PubMed2001

Anti-inflammatory effects of inosine in human monocytes, neutrophils and epithelial cells in vitro.

Inosine is an endogenous purine, which has been recently shown to exert immunomodulatory, anti-inflammatory and anti-shock effects in rodent experimental systems. Some of these actions may be related to partial adenosine receptor agonistic effects. It has not been investigated previously whether inosine exerts similar immunomodulatory or anti-inflammatory effects in human cells or enzymes. Here we investigated the effects of inosine on the activation of human monocytes, neutrophils and epithelial cells in vitro. Furthermore, using a human inosine-5'-monophosphate dehydrogenase (IMPDH) enzyme, we examined the potential effects of inosine on the activity of IMPDH, an enzyme involved in the regulation of certain inflammatory/immune processes. Tumor necrosis factor alpha (TNF-alpha) production of bacterial lipopolysaccharide (LPS) stimulated whole blood was used as an indicator of human monocyte activation. The response was dose-dependently, partially suppressed in the presence of inosine. Inosine exerted a dose-dependent and, at the highest dose (3 mM), complete inhibition of the ability of human neutrophils activated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) to induce cytochrome C reduction in vitro. In the human colon cancer cell line HT-29, inosine dose-dependently attenuated the production of IL-8. Inosine failed to affect the activity of IMPDH. Taken together, we conclude that inosine exerts anti-inflammatory effects in many human cell types. Further studies need to establish whether inosine supplementation exerts anti-inflammatory effects in human beings.

Anti-Inflammatory Agents↗
PubMed1983

Role of Inosine Monophosphate Oxidoreductase in the Formation of Ureides in Nitrogen-Fixing Nodules of Cowpea (Vigna unguiculata L. Walp.).

Cell-free extracts from nodules of cowpea (Vigna unguiculata L. (Walp.) cv Caloona:Rhizobium strain CB756) prepared in the presence of 15% (v/v) glycerol showed high rates (30 to 60 nanomoles NAD reduced per minute per gram fresh weight nodule) of inosine monophosphate oxidoreductase (EC 1.2.1.14) activity. The enzyme was labile (half-life of activity less than 3 hours) but could be stabilized for up to 18 hours by inclusion of the substrates NAD and inosine monophosphate in the breaking media. Activity showed a broad pH optimum between 8.5 and 9.5, had an apparent K(m) (inosine monophosphate) of 4 and 12 micromolar at pH 7.5 and 9.0, respectively, and was largely (96%) associated with the plant cell cytosol fraction of the nodule.Metabolism of [8-(14)C]inosine monophosphate and [1-(14)C]glycine by the cell-free system showed two pathways for purine base production from inosine monophosphate, one via xanthosine monophosphate, xanthosine, and xanthine, the other via inosine and hypoxanthine. The proportion of inosine monophosphate utilized by inosine monophosphate oxidoreductase and the xanthine-based pathway was increased from 30% at 0.5 millimolar to 80% at 0.01 millimolar inosine monophosphate. The data are interpreted to indicate that in vivo inosine monophosphate oxidation rather than dephosphorylation is the predominant metabolic route leading to ureide synthesis and that inosine monophosphate provides the link between de novo purine nucleotide synthesis in the plastid and ureide production in the plant cell cytosol.

Journal Article↗