Hypoxanthine, xanthine and uridine in body fluids, indicators of ATP depletion

Harkness, R. A.

doi:10.1016/s0378-4347(00)83873-6

Cited by 134 publications

(71 citation statements)

References 64 publications

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“…There is a high renal clearance of hypoxanthine (20), and acute changes in plasma hypoxanthine concentrations may therefore be reflected in the urine. The renal clearance of xanthine, however, can exceed creatinine clearance, suggesting a tubular origin for at least some of the excreted xanthine (10). Urinary xanthine will therefore not reflect plasma xanthine as sensitively …”

Section: Resultsmentioning

confidence: 98%

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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Section: Resultsmentioning

confidence: 98%

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

et al. 1990

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“…hypoxanthine, xanthine, inosine) are able to move freely between the inside and the outside of cells, whereas nucleotides (e-g. ATP, ADP, AMP) are larger and mainly confined in the cell interior. 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).…”

Section: --30mentioning

confidence: 99%

“…Adenosine is of great interest because it possesses strong biologic activity dependent on the 6-amino group (11). Adenosine causes coronary vasodilation and protects the myocardium after hypoxia-ischemia (9,16).…”

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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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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“…It is known that measurements of purine and pyrimidine catabolites in the CSF can be used as an indicator for cerebral energy failure, or even as an early marker for brain cell damage (8). An early marker for brain cell damage due to hypoxemia might facilitate recognition of the neonate at risk for cerebral injury (9).…”

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confidence: 99%

Purine and Pyrimidine Metabolism and Electrocortical Brain Activity during Hypoxemia in Near-Term Lambs

Os¹,

Abreu²,

Hopman³

et al. 2004

Pediatr Res

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Insufficient cerebral O 2 supply leads to brain cell damage and loss of brain cell function. The relationship between the severity of hypoxemic brain cell damage and the loss of electrocortical brain activity (ECBA), as measure of brain cell function, is not yet fully elucidated in near-term newborns. We hypothesized that there is a strong relationship between cerebral purine and pyrimidine metabolism, as measures of brain cell damage, and brain cell function during hypoxemia. Nine near-term lambs (term, 147 d) were delivered at 131 (range, 120-141) d of gestation. After a stabilization period, prolonged hypoxemia (fraction of inspired oxygen, 0.10; duration, 2.5 h) was induced. Mean values of carotid artery blood flow, as a measure of cerebral blood flow, and ECBA were calculated over the last 3 min of hypoxemia. At the end of the hypoxemic period, cerebral arterial and venous blood gases were determined and CSF was obtained. CSF from 11 normoxemic siblings was used for baseline values. HPLC was used to determine purine and pyrimidine metabolites in CSF, as measures of brain cell damage. Concentrations of purine and pyrimidine metabolites were significantly higher in hypoxemic lambs than in their siblings, whereas ECBA was lower in hypoxemic lambs. Significant negative linear relationships were found between purine and pyrimidine metabolite concentrations and, respectively, cerebral O 2 supply, cerebral O 2 consumption, and ECBA. We conclude that brain cell function is related to concentrations of purine and pyrimidine metabolites in the CSF. Reduction of ECBA indeed reflects the measure of brain damage due to hypoxemia in near-term newborn lambs. Despite the increase in survival of preterm infants, long-term morbidity has not changed (1). Hypoxia-ischemia-related brain damage is an important contributor to perinatal mortality and long-term morbidity in survivors (2).The immature brain is very vulnerable to disturbances in cerebral oxygenation and hemodynamics. Cerebral O 2 supply depends on both CaO 2 and CBF. Cerebral hypoxia is defined as an insufficient O 2 supply to the brain, resulting from either hypoxemia (decreased CaO 2 ) or hypoperfusion (decreased CBF). During hypoxemia, the brain is considered to be protected adequately from injury by an increase in CBF to preserve cerebral O 2 supply and to stabilize brain metabolism, unless cerebral ischemia occurs from supervening systemic hypotension. With the neuronal oxygen and glucose debts arising from severe hypoxemia, oxidative metabolism shifts to anaerobic glycolysis, with its inefficient generation of highenergy phosphate reserves, necessary to maintain cellular ionic gradients and other metabolic processes. However, when hypoxemia progresses, cellular energy failure ultimately occurs, which, if not promptly reversed, results in decreased neuronal viability and death of the cell (3).During insufficient cerebral O 2 supply, an accumulation of purine metabolites, which are the degradation products from high-energy phosphate compounds (ATP, ADP, and AMP),...

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Hypoxanthine, xanthine and uridine in body fluids, indicators of ATP depletion

Cited by 134 publications

References 64 publications

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

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

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

Purine and Pyrimidine Metabolism and Electrocortical Brain Activity during Hypoxemia in Near-Term Lambs

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