Allopurinol
Pharmacological interventions in the newborn piglet in the first 24 h after hypoxia-ischemia. A hemodynamic and electrophysiological perspective.

Peeters-Scholte C, van den Tweel E, Ioroi T, Post I, Braun K, Veldhuis W, Nicolay K, Groenendaal F, van Bel F.

Department of Neonatology, Wilhelmina Children's Hospital, PO Box 85090, 3508 AB Utrecht, The Netherlands.

The purpose of this study was to investigate whether combined inhibition of neuronal and inducible nitric oxide synthase (NOS) by 2-iminobiotin, free radical scavenging by allopurinol, and non-protein-bound iron chelation with deferoxamine improved cerebral oxygenation, electrocortical brain activity, and brain energy status during the first 24 h after hypoxia-ischemia (HI) in the newborn piglet. Forty-three newborn piglets were subjected to 1 h of severe HI by occluding both carotid arteries and phosphorous magnetic resonance spectroscopy ((31)P-MRS)-guided hypoxia, whereas five served as sham-operated controls. Upon reperfusion, piglets received vehicle (n=12), 2-iminobiotin (n=11), allopurinol (n=10), or deferoxamine (n=10). Cerebral oxygenation was recorded with near-infrared spectrophotometry (NIRS), electrocortical brain activity was assessed with amplitude-integrated EEG (aEEG), and cerebral energy status with (31)P-MRS. The oxygenated hemoglobin (HbO(2)) and total hemoglobin (tHb) were significantly increased in vehicle-treated piglets compared with 2-iminobiotin-treated and deferoxamine-treated piglets. No change in deoxygenated Hb (HHb) was demonstrated over time. The aEEG was significantly preserved in 2-iminobiotin- and deferoxamine-treated piglets compared with vehicle-treated piglets. Allopurinol treatment was not as effective as 2-iminobiotin treatment after HI. Phosphocreatine/inorganic phosphate ratios (PCr/P(i)) were significantly decreased for vehicle-treated piglets at 24 h post-HI, whereas 2-iminobiotin, allopurinol, and deferoxamine prevented the development of secondary energy failure. We speculate that the beneficial effects, especially of 2-iminobiotin, but also of deferoxamine, are due to reduced peroxynitrite-mediated oxidation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12410335&dopt=Abstract allopurinol Zyloprim



Allopurinol
Respective roles of free radicals and energy supply in hypoxic rat liver injury after reoxygenation.

Videla LA.

Departamento de Ciencias Biologicas, Facultad de Medicina, Universidad de Chile, Santiago.

Livers from fasted rats subjected to 60 min of hypoxia followed by 25 min of reflow exhibited a significant release of lactate dehydrogenase (LDH) and protein into the perfusate together with high rates of oxygen consumption, depletion of hepatic glutathione (GSH) and accumulation of thiobarbituric acid reactants (TBAR) in the liver. These changes were observed in the presence and absence of added xanthine (25 microM) and were significantly diminished when experiments were carried out in the presence of either 1 mM allopurinol or 100 microM Trolox. Allopurinol inhibited by 79% the production of uric acid by the liver, which was not altered by Trolox. Hypoxia-reflow studies performed in the presence of 25 microM 2,4-dinitrophenol (DNP) showed a drastic enhancement in LDH (244%) and protein (104%) efflux from the liver, compared with the effects found in its absence, with a moderate increase (35%) in tissue TBAR levels. Liver perfusion in the presence of both allopurinol and DNP exhibited a normalization of the tissue content of GSH and TBAR, while the net increase in LDH and protein release elicited by DNP alone was inhibited by only 20 and 25%, respectively. Similar results were obtained in experiments in which allopurinol was replaced by Trolox. These studies indicate that production of oxygen free-radicals are involved in hypoxic liver injury upon reflow, but its relative importance is significantly diminished when energy stores are severely diminished.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2060865&dopt=Abstract allopurinol Zyloprim



Allopurinol
Effects of diltiazem and allopurinol in postischemic microcirculatory changes in the rat kidney.

Petho-Schramm A, Mielke W, Vetterlein F, Schmidt G.

Institut fur Pharmakologie und Toxikologie, Universitat Gottingen, Germany.

The influence of diltiazem and/or allopurinol on kidney microcirculation was studied in anaesthetized rats, which were subjected to 60 min unilateral renal ischemia followed by 60 min reflow. In histological sections capillary plasma flow patterns were determined based on the distribution of two different fluorochrome-labelled globulins administered i.v.. In the outer medulla (OM) of untreated postischemic kidneys labelling of the capillary network was greatly diminished. Tissue areas occupied by red blood cells increased 4-6 fold. During reperfusion massive penetration of red cells in the urine was demonstrated by the occurrence of hemoglobin in the urine. Maintenance of the rats on allopurinol-saturated drinking water for six days prior to the experiment (daily intake approximately 50 mg allopurinol/kg body wt) combined with the i.v. administration of diltiazem during the pre- and postischemic period (16 mg/kg body wt) resulted in an almost complete normalization of capillary plasma flow patterns in the OM. In this region tissue areas occupied by red blood cells were much lesser in extent than in the untreated controls. Furthermore, urine hemoglobin content after the combined drug regimen was largely decreased when compared to the untreated ischemic group. Effects of the treatment with either of the drugs alone were qualitatively similar, but significantly less pronounced. In conclusion, a synergistic effect of diltiazem and allopurinol in improving postischemic renal microcirculation is clearly evident, whereas no improvement in kidney function was demonstrable. This supports the hypothesis that disturbed microcirculation is not a prerequisite for the generation of the renal functional deterioration in the clamp-induced ischemia model in the rat.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2060998&dopt=Abstract allopurinol Zyloprim



Allopurinol
A useful canine model of ischemic myocardium with coronary retrograde flow diversion, and its application for the study of allopurinol on myocardial infarct size.

Motoe M, Yoshida S.

Second Department of Internal Medicine, Sapporo Medical College, Japan.

This study was undertaken to evaluate the usefulness of a canine ischemic heart model achieved by coronary retrograde flow (RF) diversion, and to examine the effect of allopurinol on the myocardial infarction. The left anterior descending coronary artery (LAD) was occluded for 90 min followed by 4h reperfusion. Group 1 (n = 9) was a simple LAD occlusion group. In group 2 (n = 8), retrograde flowing blood from the distal of the occluded LAD was simultaneously diverted during LAD occlusion. In group 3 (n = 8), allopurinol was administered 60 min before ischemia with RF diversion followed by its continuous infusion. Infarcted myocardium was determined by triphenyl tetrazolium chloride staining and myocardium at risk by the dye double perfusion technique. RF diversion significantly reduced not only regional myocardial blood flow (RBF) (0.21 +/- 0.05 ml/min/g in group 1 vs 0.05 +/- 0.01 ml/min/g in group 2; p less than 0.05) but also its variance (p less than 0.01). Furthermore, the infarct size (infarct/risk ratio) in the allopurinol treated group was significantly reduced without any significant difference in rate pressure product, risk size or RBF (89.4 +/- 4.0% in group 2 vs 48.9 +/- 4.5% in group 3; p less than 0.01). We conclude that the canine RF diversion model is useful for myocardial infarct study because of the minimizing of the difference of collateral flow, and that canine myocardial xanthine oxidase may produce free radicals which take part in myocardial injury after reperfusion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2062000&dopt=Abstract allopurinol Zyloprim



Allopurinol
Failure of allopurinol to protect against cerebral injury when given after the start of hypoxia.

Hegstad E, Berg-Johnsen J, Langmoen IA.

Institute of Surgical Research, National Hospital, Rikshospitalet, Oslo, Norway.

One cause of ischemic brain injury is free radical formation during recirculation. Allopurinol inhibits xanthine oxidase, an important source of free oxygen radicals. It is known that allopurinol pre-treatment has a protective action during cerebral ischemia. In the present study we exposed slices from the rat hippocampus to 9 minutes of hypoxia to test whether it is sufficient that allopurinol is present in the tissue at the time of reoxygenation. Forty-six slices loaded with allopurinol (10(-5) M) prior to reoxygenation (during hypoxia) were compared to 34 control slices. The response of the pyramidal cell population to orthodromic stimulation was reduced in both groups and there was not a significant difference between the two groups.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2063650&dopt=Abstract allopurinol Zyloprim



Allopurinol
Behaviour of energy metabolites and effect of allopurinol in the "stunned" isovolumic rat heart.

Headrick JP, Armiger LC, Willis RJ.

Division of Science and Technology, Griffith University, Brisbane, Australia.

The pathogenesis of post-ischaemic depression of contractility in myocardium was examined in isovolumic rat heart. 31P-NMR was used to monitor changes in ATP, creatine phosphate (CrP), inorganic phosphate (Pi), and [H+] during brief periods of ischaemia and reperfusion with and without allopurinol treatment. During 5, 10, or 15 min of total global ischaemia, the decline in function (rate-pressure product) correlated inversely with [Pi] (r = 0.92, P less than 0.01). Cardiac function exhibited a slow progressive recovery during 20 min of reperfusion, ultimately reaching only 85%, 78%, and 69% of its pre-ischaemic value following 5, 10, and 15 min of global ischaemia respectively. Following each ischaemic period [ATP], [CrP], [Pi], and [H+] all recovered to control levels within 5-10 min of initiating reperfusion. Allopurinol (2 mM) treatment of hearts made ischaemic for 15 min significantly improved contractile recovery to 89 +/- 7%. Allopurinol also exhibited significant anti-arrhythmic activity during the reperfusion period, decreasing the incidence of premature contractions and the duration of tachy-arrhythmias. Allopurinol had no effect on the final repletion of [ATP] and [CrP], or the recovery of [Pi] and [H+], although the rate of ATP repletion was elevated in the initial 5 min of reperfusion. These results show that neither depletion of the cytosolic high-energy phosphate pool, nor sustained elevations in [Pi] or [H+] are important in the production of post-ischaemic contractile impairment. The beneficial action of allopurinol suggests that xanthine oxidase derived oxygen free-radicals may be involved in the sustained contractile dysfunction following brief ischaemic episodes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2095434&dopt=Abstract allopurinol Zyloprim