Cerebrospinal fluid concentrations of hypoxanthine, xanthine, uridine and inosine: high concentrations of the ATP metabolite, hypoxanthine, after hypoxia.

Harkness, R. A.; Lund, Richard

doi:10.1136/jcp.36.1.1

Cited by 97 publications

(66 citation statements)

References 24 publications

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“…Values of hypoxanthine, xanthine, and inosine obtained in the current study are comparable with human data from newborns after hypoxia (14). A microdialysis technique showed similar hypoxanthine and xanthine levels in the extracellular compartment of the brain of severely asphyxiated exteriorized fetal lambs.…”

Section: --30supporting

confidence: 75%

“…It is evident that extracellular levels of nucleosides and bases reflect the breakdown of intracellular nucleotides and are therefore indicative for cellular energy shortage or even for cellular damage (11). Because serum hypoxanthine levels during asphyxia mainly orig- inate from fetal heart and liver (13), we decided to determine nucleoside concentrations in CSF, especially because high levels of CSF hypoxanthine and xanthine after hypoxia have been associated with evidence of brain damage or subsequent death (14). Table 1 stresses the importance of recovery after instrumentation.…”

Section: --30mentioning

confidence: 99%

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Effects of Surgery and Asphyxia on Levels of Nucleosides, Purine Bases, and Lactate in Cerebrospinal Fluid of Fetal Lambs

et al. 1994

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During severe oxygen shortage, the fetal brain resorts to anaerobic metabolism and ATP becomes catabolized. High levels of nucleosides, hypoxanthine, and xanthine (ATP catabolites) in cerebrospinal fluid (CSF) may therefore be associated with increased neonatal neurologic morbidity. In 22 fetal lambs (3 to 5 d after surgery, gestational age 123.5 r 3.5 d), arterial oxygen content was progressively reduced to 35% of the baseline value with a balloon occluder around the maternal common internal iliac artery. This resulted in a 1-h period of asphyxia, leading to a pH of 7.02 ? 0.03 and a base excess of -17.0 ? 1.0 mM. Mortality was 50%. CSF was sampled from the spinal cistern and analyzed using HPLC. During reoxygenation, hypoxanthine and xanthine may serve as substrate for xanthine oxidase with concomitant production of oxygen-derived free radicals, which may aggravate cerebral damage. The main difference between surviving and nonsurviving animals was the speed of increment of ATP catabolites in CSF: in the surviving group levels increased steadily, recovery values being significantly elevated compared with asphyxia values, whereas in the nonsurviving group the rise was rapid and levels during asphyxia did not differ significantly from levels during recovery. We conclude that I ) catheterization of the spinal cistern leads to increased levels of CSF hypoxanthine, xanthine, and inosine, and 2) during fetal asphyxia, levels of these ATP catabolites and lactate in CSF increase. 3 ) Maximum levels are reached during the recovery period and are similar for surviving and nonsurviving animals, but during asphyxia CSF levels of hypoxanthine and lactate were higher in the nonsurviving fetuses. 4) The rate of increase of ATP catabolites in CSF is higher in the nonsurviving animals and may therefore be predictive for fetal death. (1) and preferential streaming of well-oxygenated blood in the heart (2), the fetal cerebrum is provided with as much oxygen as possible. During severe or sustained oxygen shortage, however, the brain too resorts to anaerobic metabolism. Lack of oxygen impairs mitochondria1 functioning, leading to energy shortage (3); ATP becomes degraded to AMP and, after dephosphorylation, further to adenosine, inosine, and hypoxanthine. Serum levels of hypoxanthine are considered a sensitive indicator of the hypoxic insult (4). Moreover, formation of hypoxanthine and xanthine may aggravate outcome after such an insult, because during reoxygenation hypoxanthine and xan-

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Section: --30supporting

confidence: 75%

Section: --30mentioning

confidence: 99%

Effects of Surgery and Asphyxia on Levels of Nucleosides, Purine Bases, and Lactate in Cerebrospinal Fluid of Fetal Lambs

et al. 1994

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“…In the control group, neither hypoxanthine nor xanthine excretion changed. DISCUSSION We found a higher basal concentration of hypoxanthine in CSF of pigs (15.8 flmol/L) than has been reported in normal human newborns, children, and adults (3.5 flmol/L) (14). During hypoxemia in both groups I and 2, the hypoxanthine concentrations increased about 2.5-fold in the CSF.…”

Section: Resultsmentioning

confidence: 37%

Hypoxanthine, Xanthine, and Uric Acid Concentrations in the Cerebrospinal Fluid, Plasma, and Urine of Hypoxemic Pigs

et al. 1990

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MATER IALS AND METHODSuate hypoxia , but to correlate a biochemi cally measured value with th e outco me of hypoxia is difficult . Measure me nts of th e pu rine metabol ite hypoxanthine can be used as an ind icator of hypoxia (I). Du rin g tissue hypo xia, elevated hypoxanthine levels have been found in plasm a (2-5), CSF (6, 7), and urine (8).H owever, no clear definition of clinical hypoxia is available, and ma ny autho rs do not distinguish between the terms hypoxemia an d hypoxia, whic h adds to the confusio n. Our meanin g of hypoxia has previou sly been described ( I). In our study th e pigs were subjected to hypoxemia. We define hypoxe mia as deficient oxygenation of th e blood. Hypoxem ia may, however, not necessarily lead to tissue hypoxia.To further assess the usefuln ess of hypoxanthine as a biochemical marker of hypoxia, we repo rt how three degrees of hypoxemi a in young pigs in fluence the level of hypoxanthine, xanthine, and uric acid in the CSF and plasma , as well as th e pigs' urin ary excretion of hypoxan thine an d xanthine.Approval. The local hosp ital' s ethi cal com m ittee for an im al studies approved these experim ents.Animal model. T he anima l model was similar to th at previously described (9). T went y-two young pigs of eit her sex (the males had been castrated shortly after birth ) weighing 17-22 kg (mea n 18.1 kg) were used. Th ey were anes thetized with an intraperitoneal injection of sodium pentobar bital (30 mg/kg). An i.v. line was estab lished through an ear vein, an d a contin uo us infusion of Ringer acetate ( 10 mL/kg/h) was given during the experime nt. A further 100 mg of sodium pentobar bital was given i.v, if necessary every 30 min. A cuffed tu be was placed in the trachea via a tracheostom y. Art ificial ventilation was given by a ventilato r (Servo-ventilator 900B, Elema-Schenander, Stoc kholm, Sweden). Ventilation rate and tidal volume were adjusted unt il Paco, ranged between 4 and 5.3 kPa (30-40 mm Hg). No further adjustme nts of the ventilato r .were done du ring th e hypoxemic period.A midlin e supr apubic laparotomy was performed and a urinary catheter was placed in the bladder for measuring diuresis and urinary hypoxanthin e and xanthine.Polyeth ylene catheters were inserted into a fem oral artery and a fem oral vein. T he arterial cathe ter was used for taking blood samples and for measuring blood pressure continuously with a strai n gauge tra nsdu cer, Go uld recorde r 2600S (Gould In c. Recording System s, Cleveland, OH). Th e venous cath eter was used for giving Ringer acetate plu s additional sodium pentobarbital.Th e pigs were divided int o three hypoxemi c and one contro l group. Seven animals were made hypoxem ic by art ificial ventilation with 8% oxygen in nitrogen (FiO z = 0.08) (group 1). Seven

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“…Animal blood may also be used while recognizing the potential for uricase-generated allantoin. Purine metabolites were linked to hypoxia as early as 1963 and the reliability of hypoxanthine, xanthine, and uric acid as biochemical indicators of neonatal hypoxia was validated by several investigators [10][11][12][13] . The HPLC method used for the quantification of purine compounds is fast, reliable, and reproducible.…”

Section: Most Mammals Humans Exempted Possess the Enzyme Uricasementioning

confidence: 99%

Biochemical Measurement of Neonatal Hypoxia

Plank

Calderon

Asmerom

et al. 2011

JoVE

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Neonatal hypoxia ischemia is characterized by inadequate blood perfusion of a tissue or a systemic lack of oxygen. This condition is thought to cause/exacerbate well documented neonatal disorders including neurological impairment 1-3 . Decreased adenosine triphosphate production occurs due to a lack of oxidative phosphorylation. To compensate for this energy deprived state molecules containing high energy phosphate bonds are degraded 2 . This leads to increased levels of adenosine which is subsequently degraded to inosine, hypoxanthine, xanthine, and finally to uric acid. The final two steps in this degradation process are performed by xanthine oxidoreductase. This enzyme exists in the form of xanthine dehydrogenase under normoxic conditions but is converted to xanthine oxidase (XO) under hypoxia-reperfusion circumstances 4, 5 . Unlike xanthine dehydrogenase, XO generates hydrogen peroxide as a byproduct of purine degradation 4, 6 . This hydrogen peroxide in combination with other reactive oxygen species (ROS) produced during hypoxia, oxidizes uric acid to form allantoin and reacts with lipid membranes to generate malondialdehyde (MDA) [7][8][9] . Most mammals, humans exempted, possess the enzyme uricase, which converts uric acid to allantoin. In humans, however, allantoin can only be formed by ROS-mediated oxidation of uric acid. Because of this, allantoin is considered to be a marker of oxidative stress in humans, but not in the mammals that have uricase.We describe methods employing high pressure liquid chromatography (HPLC) and gas chromatography mass spectrometry (GCMS) to measure biochemical markers of neonatal hypoxia ischemia. Human blood is used for most tests. Animal blood may also be used while recognizing the potential for uricase-generated allantoin. Purine metabolites were linked to hypoxia as early as 1963 and the reliability of hypoxanthine, xanthine, and uric acid as biochemical indicators of neonatal hypoxia was validated by several investigators [10][11][12][13] . The HPLC method used for the quantification of purine compounds is fast, reliable, and reproducible. The GC/MS method used for the quantification of allantoin, a relatively new marker of oxidative stress, was adapted from Gruber et al 7 . This method avoids certain artifacts and requires low volumes of sample. Methods used for synthesis of MMDA were described elsewhere 14,15 . GC/MS based quantification of MDA was adapted from Paroni et al. and Cighetti et al. 16,17 . Xanthine oxidase activity was measured by HPLC by quantifying the conversion of pterin to isoxanthopterin 18 . This approach proved to be sufficiently sensitive and reproducible.

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Cerebrospinal fluid concentrations of hypoxanthine, xanthine, uridine and inosine: high concentrations of the ATP metabolite, hypoxanthine, after hypoxia.

Cited by 97 publications

References 24 publications

Effects of Surgery and Asphyxia on Levels of Nucleosides, Purine Bases, and Lactate in Cerebrospinal Fluid of Fetal Lambs

Effects of Surgery and Asphyxia on Levels of Nucleosides, Purine Bases, and Lactate in Cerebrospinal Fluid of Fetal Lambs

Hypoxanthine, Xanthine, and Uric Acid Concentrations in the Cerebrospinal Fluid, Plasma, and Urine of Hypoxemic Pigs

Biochemical Measurement of Neonatal Hypoxia

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