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PubMed1985

Central effects of nicotinamide and inosine which are not mediated through benzodiazepine receptors.

The actions of nicotinamide and inosine were investigated on rat cerebellar Purkinje cells using ionophoretic and extracellular recording techniques. Ionophoretic application of nicotinamide or inosine showed that they were potent inhibitors of Purkinje cell firing. This inhibition differed from that induced by benzodiazepines in that it was not reversed by the GABA antagonists bicuculline methiodide and picrotoxin. RO 15-1788, the specific benzodiazepine antagonist, did not reverse the effects of nicotinamide. Chlordiazepoxide has been shown to increase significantly social interaction between pairs of male rats and this increase can be reversed by RO 15-1788, 20 mg kg-1 i.p. Nicotinamide also caused a small increase in social interaction but this effect was not reversed by the benzodiazepine antagonist. Inosine did not increase social interaction. [3H]-flunitrazepam binding studies showed that nicotinamide and inosine have only low affinities for the benzodiazepine binding site. These results suggest that while nicotinamide may exert some neuronal depressant and anxiolytic activity, its site of action appears not to be associated with the benzodiazepine receptor site. Similarly, inosine exerts a neuronal depressant effect dissimilar from that of benzodiazepines.

Action Potentials↗
PubMed1991

Interstitial lactate, inosine and hypoxanthine in rat kidney during normothermic ischaemia and recirculation.

The aim of this study was to determine the potential value of extracellular fluid (ECF) lactate, inosine and hypoxanthine for monitoring the disturbance in energy metabolism associated with kidney ischaemia and recirculation, using intrarenal microdialysis as sampling technique. Normothermic ischaemia was produced in rats by clamping of the left renal pedicle. Microdialysis probes were implanted into the renal cortex and the medulla, respectively. Dialysates were collected in 10-minute fractions before, during 20 (Group A) or 40 minutes (Group B) ischaemia and 2 hours of recirculation. Samples were analysed by HPLC for lactate, inosine and hypoxanthine. Ischaemia caused a dramatic increase of extracellular fluid lactate, inosine and hypoxanthine in both groups, reflecting the disturbance of energy metabolism. The basal extracellular fluid level of lactate as well as that during ischaemia was markedly higher in the medulla compared to cortex, whereas the relative change in lactate concentration was similar (i.e. about 4-fold). In group A all three metabolites returned to the pre-ischaemic level within 20 minutes after reperfusion. However, while inosine and hypoxanthine returned promptly to base line in Group B, recovery of lactate varied dramatically between animals suggesting a persistent metabolic disturbance in some rats. Our results indicate that extracellular fluid lactate, inosine and hypoxanthine, measured by intrarenal microdialysis, may be useful for monitoring of the energy state of the kidney during normothermic ischaemia and that extracellular fluid lactate may be a sensitive indicator of post-ischaemic disturbances in energy metabolism.

Animals↗
PubMed1984

Release of adenosine, inosine and hypoxanthine from rabbit non-myelinated nerve fibres at rest and during activity.

The composition of the efflux from desheathed rabbit vagus nerve, loaded with radioactivity by incubation in [3H]adenosine, was studied at rest and during electrical activity and after application of inhibitors of ecto-enzymes and modifications of intermediary metabolism. In addition, the degradation of externally applied ATP and adenosine was examined. [3H]ATP applied to the incubation medium was degraded to ADP, AMP, adenosine and inosine. The hydrolysis to nucleosides was inhibited by alpha, beta-methylene ADP; the appearance of AMP and nucleosides was slowed by beta, gamma-methylene ATP. Deamination of [3H]adenosine was blocked by 2-deoxycoformycin. The effluent from resting and stimulated preparations showed the presence of large amounts of inosine and hypoxanthine, smaller amounts of adenosine and adenine and traces of nucleotides. The composition of the effluent was not significantly altered by addition of alpha, beta-methylene ADP; beta, gamma-methylene ATP or 2-deoxycoformycin. Application of glucose-free solutions caused a large release of adenosine instead of inosine and hypoxanthine and a small increase in resting and stimulated efflux of 3H. Addition of 2-deoxyglucose produced a large increase in resting efflux and increased liberation of adenosine. Cyanide, 2,4-dinitrophenol, arsenate or salicylate increased the resting efflux of adenosine, inosine and hypoxanthine, and the effect of activity. It is concluded that electrical activity leads to release of adenosine, inosine and hypoxanthine, in various proportions depending on metabolic state, and that there is practically no liberation of nucleotides from nerve axons.

Action Potentials↗
PubMed1977

Mutation of an inosine-producing strain of Bacillus subtilis to DL-methionine sulfoxide resistance for guanosine production.

An inosine-producing strain of Bacillus subtilis was mutated to resistance against the antagonist of glutamine, DL-methionine sulfoxide. Among the mutants derived, guanosine producers were observed frequently. The best strain, 14119, produced 9.6 g of guanosine per liter at a weight yield of 12% from consumed sugar. Inosine production decreased concomitantly. When resistance was increased further by exposure to higher doses of DL-methionine sulfoxide, another strain, AG169, was obtained that did not excrete inosine but produced increased amounts of xanthosine. In these strains, the specific activity of 5'-nucleotidase was lower and that of inosine 5'-monophosphate (IMP) dehydrogenase was higher than the parent strain. It is speculated that the metabolic flow from IMP to xanthosine 5'-monophosphate proceeds more smoothly than that from IMP to inosine and yields more xanthosine and guanosine.

Bacillus subtilis↗
PubMed1979

Effect of inosine on ventricular regional perfusion and infarct size after coronary occlusion.

In 16 dogs inosine was infused at 0.5 mmol/min i.v. for 5 min beginning 15 min after coronary occlusion. Tracer microspheres were used to estimate flow in subepicardium and subendocardium of nonischemic, central ischemic, and borderline ischemic muscle. Estimates of flow before occlusion, 5 min after occlusion, during inosine infusion, 30 min after infusion and 60 min after infusion were obtained. Coronary occlusion reduced flow in the central ischemic regions by 75-95%. The reduction in flow was greatest in subendocardium. In the borderline regions subendocardial flow was reduced by 30% while subepicardial flow was unaffected. The major effects of inosine were seen in nonischemic and borderline ischemic regions. Flow in borderline subendocardium returned to its pre-occlusion value, and flow in nonischemic myocardium increased by approximately 60-80%. However, only in the ischemic regions was the increase in flow sustained for the entire 60 min. In 20 dogs infarct size was determined using nitro blue tetrazolium stain. In 10 controls infarct size was 20.1%, while in 10 inosine-treated dogs infarct size was 15.2% of left ventricular weight (p less than 0.01). Thus, following coronary occlusion inosine infusion was associated with an increase in perfusion of ischemic myocardium and a reduction in infarct size.

Animals↗
PubMed1979

Myocardial release of lactate, inosine and hypoxanthine during atrial pacing and exercise-induced angina.

The coronary venous efflux of lactate, inosine and hypoxanthine during pacing-induced angina has been compared with myocardial extraction of the catabolites during exercise-induced angina. Inosine and hypoxanthine were analyzed by enzyme assay after separation by column chromatography. Myocardial lactate extraction at rest (15 +/- 9%, mean +/- SD) was converted to production levels (-34 +/- 26%) during pacing-induced angina (p less than 0.0005) and increased (24 +/- 13%) during exercise (p less than 0.05). The arterial values at rest (850 +/- 330 mumol/1) were unchanged during pacing and increased five-fold during exercise (4380 +/- 1860 mumol/1). The mean myocardial inosine extraction at rest (33 +/- 10%) was transformed to release values (-41 +/- 30%) during pacing (p less than 0.0005) as well as during exercise (-20 +/- 27%) (p less than 0.0005). The hypoxanthine extraction at rest (25 +/- 11%) decreased during pacing (-7.8 +/- 29%) (p less than 0.0025) and exercise (10 +/- 25%) (NS). The slight increase of arterial inosine and hypoxanthine values was not significant. Myocardially produced lactate, a sensitive marker of pacing-induced ischemia, was obscured by elevated arterial concentrations during exercise. However, inosine significantly correlated with lactate during pacing, and was useful in detecting ischemic myocardial energy deficiency during exercise-induced angina.

Angina Pectoris↗
PubMed1989

Transendothelial transport and metabolism of adenosine and inosine in the intact rat aorta.

This study was aimed at defining the role of vascular endothelium in the transport and metabolism of adenosine. For this purpose, endothelium-intact and endothelium-denuded isolated rat aortas, perfused at constant flow (2 ml/min), were prelabeled with 3H-adenosine or 3H-inosine for 10 minutes at concentrations of 0.012-100 microM. Sequestration of adenosine by endothelium was determined from radioactivity recovered during selective endothelial cell removal with deoxycholic acid (0.75% for 15 seconds). In the physiological concentration range of adenosine (0.012-1 microM), fractional sequestration by endothelium was 90-92% of the total adenosine incorporation by the aorta. Endothelial sequestration of inosine at 0.1 microM was 85%. At 100 microM adenosine or inosine, fractional sequestration by aortic endothelium was 33% and 39%, respectively. Analysis of the specific radioactivity of adenine nucleotides extracted from prelabeled aortas indicated that most of the adenosine was incorporated into endothelial adenine nucleotides. Incorporation of inosine into endothelial ATP was approximately 15% that of adenosine. Inhibition of aortic adenosine deaminase with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) did not influence sequestration of 0.1 microM adenosine, but resulted in a 49% reduction of total endothelial incorporation at 100 microM adenosine. Transfer of radioactive purines from the endothelium to underlying smooth muscle after prelabeling was equivalent to only 1%/hr of total endothelial radioactivity. Our findings suggested that 1) macrovascular endothelium of the aorta constitutes a highly effective metabolic barrier for circulating adenosine and inosine; 2) transfer of labeled adenine nucleotides from endothelium to underlying smooth muscle is rather small and most likely proceeds via dephosphorylated purine compounds; and 3) measurement of adenosine trapping in endothelial and smooth muscle compartments overestimates the transendothelial adenosine concentration gradient.

Adenine↗
PubMed1997

Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation.

We investigated the mechanism by which inosine, a metabolite of adenosine that accumulates to > 1 mM levels in ischemic tissues, triggers mast cell degranulation. Inosine was found to do the following: (a) compete for [125I]N6-aminobenzyladenosine binding to recombinant rat A3 adenosine receptors (A3AR) with an IC50 of 25+/-6 microM; (b) not bind to A1 or A2A ARs; (c) bind to newly identified A3ARs in guinea pig lung (IC50 = 15+/-4 microM); (d) lower cyclic AMP in HEK-293 cells expressing rat A3ARs (ED50 = 12+/-5 microM); (e) stimulate RBL-2H3 rat mast-like cell degranulation (ED50 = 2.3+/-0.9 microM); and (f) cause mast cell-dependent constriction of hamster cheek pouch arterioles that is attenuated by A3AR blockade. Inosine differs from adenosine in not activating A2AARs that dilate vascular smooth muscle and inhibit mast cell degranulation. The A3 selectivity of inosine may explain why it elicits a monophasic arteriolar constrictor response distinct from the multiphasic dilator/constrictor response to adenosine. Nucleoside accumulation and an increase in the ratio of inosine to adenosine may provide a physiologic stimulus for mast cell degranulation in ischemic or inflamed tissues.

Adenine↗
PubMed2001

Investigation of various genotype characteristics for inosine accumulation in Escherichia coli W3110.

For the derivation of an inosine-overproducing strain from the wild type microorganism, it is known that the addition of an adenine requirement, removal of purine nucleoside hydrolyzing activity, removal of the feedback inhibition, and repression of key enzymes in the purine nucleotides biosynthetic pathway are essential. Thus, the disruption of purA (adenine requirement), deoD (removal of purine nucleosides phosphorylase activity), purR (derepression of the regulation of purine nucleotides biosynthetic pathway), and the insensitivity of the feedback inhibition of phosphoribosylpyrophosphate (PRPP) amidotransferase by adenosine 5'-monophosphate (AMP) and guanosine 5'-monophosphate (GMP) were done in the Escherichia coli strain W3110, and then the inosine productivity was estimated. In the case of using a plasmid harboring the PRPP amidotransferase gene (purF) that encoded a desensitized PRPP amidotransferase, purF disrupted mutants were used as the host strains. It was found that the innovation of the four genotypes brought about a small amount of inosine accumulation. Furthermore, an adenine auxotrophic mutant of E. coli showed inappropriate adenine use because its growth could not respond efficiently to the concentration of adenine added. As the presence of adenosine deaminase is well known in E. coli and it is thought to be involved in adenine use, a mutant disrupted adenosine deaminase gene (add) was constructed and tested. The mutant, which is deficient in purF, purA, deoD, purR, and add genes, and harboring the desensitized purF as a plasmid, accumulated about 1 g of inosine per liter. Although we investigated the effects of purR disruption and purF gene improvement, unexpectedly an increase in the inosine productivity could not be found with this mutant.

Adenosine Deaminase↗
PubMed1978

Effects of fluorocarbons, chlorinated solvents, and inosine on the cardiopulmonary system.

The effects of fluorocarbons and chlorinated solvents on the cardiopulmonary system are reviewed. The new information, not hitherto reported, relates to the antagonistic action of inosine, a naturally occurring nucleoside formed in the body by deamination of adenosine. The effect of inosine on methylene chloride toxicity was investigated in open chest dogs anesthetized with pentobarbital sodium. Methylene chloride (5% in air or 50,000 ppm) elicited a decrease of ventricular contractility represented by the diminished left ventricular (dp/dt)(max) and myocardial contractile force measured directly with a Walton-Brodie strain gauge arch. Coronary blood flow decreased slightly after exposure to methylene chloride. Arterial blood pressure and heart rate did not change. The negative inotropic effect of methylene chloride was reversed or prevented to a substantial extent by intravenous infusion of inosine (5 mg/kg-min). The effect of the latter compound was also characterized by significant coronary vasodilation. It was shown by the experiments that the cardiostimulatory action of inosine was associated with improved hypoxic adaptability of the coronary blood vessels. In contrast, the effect of catecholamines (epinephrine and isoproterenol) was not accompanied by such a beneficial coronary vascular effect. On the basis of these results, the conclusion has been arrived at that inosine might be recommended as a useful antidote in methylene chloride poisoning in particular, and of poisoning by chlorinated solvents and fluorocarbons in general.

Adenosine↗
PubMed1990

[Therapeutic effect of inosine in Tourette syndrome and its possible mechanism of action].

We found incidentally 3 years ago that inosine relieved the symptoms in a patient with Tourette syndrome. Since then, 36 patients suffered from Tourette syndrome were exclusively treated with inosine, 50-90 mg/kg daily in divided doses. The vocal and non-vocal tic attacks were counted either by the observation of an examiner or with a video-tape record. The clinical status was scored as the sum of the number of various tic attacks recorded during a period of 60 minutes (video-tape record) or 20 minutes (direct observation). According to the scores obtained from double blind cross-over trial (11 cases) and open trial (25 cases), the tic attacks were well controlled in 75% of patients treated. A follow-up study by the end of one year medication the efficacy of inosine was still impressive in 50% of patients. Since we have observed that inosine potentiated the release of dopamine from rat striatal synaptosomes, mimicked the action of some dopamine antagonists, it is suggested that inosine might behave as a dopamine antagonist and exerts its effect on Tourette syndrome as haloperidol does.

Child↗
PubMed1988

Inosine and adenosine formation in ischemic and non-ischemic contracting muscles of rats: difference between fast and slow muscles.

Inosine and adenosine formation was evaluated in different types of rat skeletal muscle during ischemic and non-ischemic contraction. Extensor digitorum longus (EDL, fast) and soleus (slow) muscles were stimulated electrically via the sciatic nerve (5 Hz, 10 min). Under non-ischemic condition, the concentrations of IMP, inosine, adenosine, and hypoxanthine increased in EDL muscles but not in soleus muscles during stimulation. Under ischemic condition, these metabolites increased in both EDL and soleus muscles, although the increases in IMP and inosine were greater in EDL muscles. The increase in inosine had a strong positive correlation with that in IMP in ischemic EDL and soleus muscles, but the ratio, delta inosine/delta IMP was smaller in EDL muscles. The increase in adenosine under ischemic condition was not significantly different between the two muscles. These findings suggest that ischemia enhances degradation of purine nucleotides in contracting fast and slow muscles, and that although the degradation of purine nucleotides to IMP is greater in fast muscles than in slow muscles, the relative degradation rate of IMP to inosine is rather smaller in fast muscles.

Adenosine↗
PubMed1986

Anti-parasite activity of nucleoside analogues: the metabolism of carbocyclic inosine in promastigotes of Leishmania tropica and Leishmania donovani and its activity against amastigotes of Leishmania donovani in vitro.

Carbocyclic inosine is a potent inhibitor for the growth of the promastigote form of Leishmania tropica and Leishmania donovani. In culture, the EC50 values of carbocyclic inosine are 8.3 X 10(-8) and 1.3 X 10(-7) M for the promastigotes of L. tropica and L. donovani, respectively. On the other hand, it is less toxic towards mouse mammary tumor FM3A cells: the EC50 value is 2.7 X 10(-4)M. Carbocyclic inosine is metabolized by Leishmania promastigotes to give carbocyclic adenosine-5'-triphosphate(aristeromycin-5'-triphosphate) and carbocyclic guanosine-5'-triphosphate. This metabolic conversion provides a mechanism for the parasite-selective toxicity of carbocyclic inosine. Carbocyclic inosine was found to be active against L. donovani amastigotes in an in vivo-like cultivation in vitro.

Animals↗
PubMed1977

Further studies of renal preservation: protection of the ischemic kidney with inosine.

Preliminary data are presented on additional means of renal preservation, particularly in the case of warm ischemic insult. We hypothesize that 1 factor responsible for the failure of kidneys to recover after ischemic insult may be depletion of energy sources during the warm ischemic period. Specifically, adenosine triphosphate in the kidney is the principal source of energy for metabolic activity and membrane stability. Inosine, an adenosine triphosphate precursor, was used in a canine model and preliminary work suggested that inosine, when coupled with mannitol, may provide enhanced protection. In vivo assay of kidney slices suggests that inosine may, indeed, tend to maintain adenosine triphosphate levels in the ischemic kidney in contrast to relative adenosine triphosphate depletion in the kidneys not protected with inosine. These data are in concert with the apparently favorable survival data in inosine and mannitol-treated animals.

Adenosine Triphosphate↗
PubMed1984

Synthesis of nucleotides with specific radiolabels in ribose. Primary 14C and secondary 3H kinetic isotope effects on acid-catalyzed glycosidic bond hydrolysis of AMP, dAMP, and inosine.

Adenosine 5'-phosphate was synthesized with 3H or 14C label specifically located as [1'-3H]AMP, [1'-14C] AMP, [5'-3H]AMP, and [5'-14C]AMP. The synthesis was accomplished from adenine and glucose or adenine and ribose using enzymes from the pentose pathway and/or from the purine salvage pathways. Structural analysis of the compounds confirmed the locations of the radiolabels. The methods provide a general scheme for the efficient synthesis of adenine nucleotides of high purity with 3H or 14C at any stable position on the ribose ring. Synthesis of [5'-14C]dAMP and [1'-3H] dAMP from the corresponding ribonucleotides was accomplished with ribonucleotide reductase. Labeled inosine was prepared by enzymatic dephosphorylation and deamination of labeled AMP. These compounds have been used to measure the secondary kinetic isotope effects on the acid-catalyzed hydrolysis of the N-glycosidic bond of AMP, dAMP, and inosine and the corresponding primary kinetic isotope effects with AMP. Acid hydrolysis in 0.1 or 0.2 N HCl at 50 degrees C gave 1H/3H secondary kinetic isotope effects of 1.23 +/- 0.01, 1.26 +/- 0.01, and 1.230 +/- 0.003 for AMP, dAMP, and inosine, respectively. The primary kinetic isotope effect for 12C/14C was 1.049 +/- 0.010 for AMP. The apparent rate constants for hydrolysis under these conditions were similar for inosine and AMP and were in the range 10(-6)-10(-5)s-1. Acid hydrolysis of dAMP is approximately 1000-fold faster than AMP but gives a similar 1H/3H kinetic isotope effect. The results of secondary isotope effects indicate that the transition states for the acid-catalyzed hydrolysis of the N-glycosidic bonds of inosine, AMP, and dAMP have similar bonding to 1'-3H in the transition state and have considerable carboxonium character. Results with [1'-14C]AMP demonstrate that a significant primary isotope effect can be measured in the acid solvolysis of the N-glycosidic bond of AMP.

Adenosine Monophosphate↗
PubMed1978

Tryptaminergic mechanism participating in induction of vasoconstriction by adenine nucleotides, adenosine, IMP and inosine in the isolated and blood-perfused hindlimb preparation of the rat.

The isolated right hindlimb of the recipient rat was perfused at a constant flow rate through the femoral artery with heparinized blood from the carotid artery of a donor. The preparations were under a 99.0 +/- 0.8 mmHg of mean perfusion pressure (N = 63) and 3.3 +/- 0.1 ml/min of blood flow through the right femoral artery. The actions of adenosine, adenosine tri-, die- and monophosphate, inosine monophosphate and inosine on the femoral vascular bed were investigated, respectively. These substances injected into the femoral artery, with the exception of inosine, caused a dose-dependent vasoconstriction always preceded by a temporal vasodilatation. Inosine induced only a prompt vasoconstriction. The vasoconstrictor responses to these substances were diminished or reverted to vasodilator ones after repeated administrations and such were significantly prevented by pretreatment with either reserpine or methysergide. These results indicate that all the purines tested induce a vasoconstriction in the femoral vascular bed of the rat through a common (tryptaminergic) mechanism and that such seem to be potent releasers of 5-hydroxytryptamine from peripheral tryptaminergic storage sites.

Adenine Nucleotides↗
PubMed2000

Development of an improved assay for purine nucleoside kinase activity in cell extracts and detection of inosine kinase activity in Brevibacterium acetylicum ATCC 953, related species, and Corynebacterium flaccumfaciens ATCC 6887.

An improved assay was developed to detect direct purine nucleoside phosphorylating activity in cell-free extracts. Direct inosine phosphorylating activity was detected in 2 of 70 species tested. Both activities, which depended on magnesium ion and ATP, phosphorylated a hydroxyl group at the 5' position of inosine. The new assay was shown to be useful for screening of direct purine nucleoside phosphorylating activity and have the potential to detect inosine kinase in the presence of a background of nucleoside phosphorylase and purine phosphoribosyltransferase activities. Previously, the latter two activities made it difficult to correctly detect direct phosphorylation of inosine by inosine kinase.

Adenosine Triphosphate↗
PubMed1990

Randomised, double blind, placebo controlled trial of inosine pranobex in rheumatoid arthritis.

In a randomised, placebo controlled, double blind study inosine pranobex was assessed as a possible second line drug in rheumatoid arthritis. Twenty four patients received inosine pranobex (3 g/day) and 26 patients received placebo for up to 24 weeks. Morning stiffness, articular index, grip strength, pain score, erythrocyte sedimentation rate, C reactive protein, IgG, IgM, and serum urate were assessed at weeks 0, 12, and 24. Baseline characteristics were similar except for a significantly higher C reactive protein in the placebo group. No significant improvement occurred in any variable: (a) when comparing week 0 with week 12 or week 24 for either group, (b) comparing active drug with placebo at week 12 or 24, or (c) taking all 50 patients as one group. Withdrawal from the study for lack of response or side effects was similar in both groups. Serum urate increased transiently but significantly with inosine pranobex (a recognised side effect). It is concluded that inosine pranobex has no second line activity in rheumatoid arthritis. Further, 50 patients effectively given placebo showed no spontaneous improvement in their disease activity.

Adult↗