Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During induced ischemia for cardiac surgery, 5'-nucleotidase (5NT) catalyzes nucleotide breakdown by dephosphorylating AMP and IMP to diffusible precursors--adenosine and inosine. These precursors become unavailable upon reperfusion washout limiting nucleotide resynthesis, resulting in poor postischemic function. Neonatal hearts, which are more resistant to ischemia than adults, have low 5NT activity, trapping available precursors. Adult rabbit hearts given cardioplegia with a 5NT inhibitor, pentoxifylline, demonstrated improved postischemic contractility, compliance, and myocardial oxygen consumption after 120 min of 34 degrees C ischemia. To determine if this improved function was a result of enhanced nucleotide precursor availability during or following ischemia, total nondiffusible nucleotides, ATP, ADP, AMP, and IMP, and total diffusible nucleotides, adenosine, inosine, hypoxanthine, and xanthine, were measured by HPLC at end ischemia, 1 and 15 min after reperfusion. While all preischemic values were equivalent, pentoxifylline-treated hearts had significantly greater total non-diffusible nucleotides at end ischemia, 1 and 15 min after reperfusion. Additionally, pentoxifylline-treated hearts had significantly greater total diffusible nucleosides at end ischemia and 1 min after reperfusion, but were equal to control at 15 min after reperfusion. Furthermore, coronary sinus effluent had a significantly higher release of total diffusible nucleosides in control vs pentoxifylline-treated hearts. The data indicate that precursor trapping with pentoxifylline prevented nucleotide catabolism to diffusible precursors and enhanced postischemic nucleotide availability. We postulate the increased precursor availability augmented myocardial nucleotide resynthesis and correlated with the improved functional recovery noted. This strategy may have application in adult cardiac surgery.
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PMID:Precursor trapping: a "neonatal" mechanism of myocardial protection. 841 63

To determine the capacity for purine nucleotide degradation among skeletal muscle fiber types, we established energy-depleted conditions in muscles of the rat hindlimb by inducing muscle contraction during ischemia. After 5, 10, 15, or 20 min of ischemic contractions, representative muscle sections were freeze-clamped and analyzed for purine nucleotides, nucleosides, and bases. Fast-twitch muscle sections accumulated about fourfold more IMP than the slow-twitch red soleus muscle. Inosine begins to accumulate at < 0.5 mumol/g IMP in slow-twitch muscle and at approximately 2 mumol/g IMP in fast-twitch muscle. This suggests that inosine is formed intracellularly by 5'-nucleotidase acting on IMP and that the activity and/or substrate affinity of the 5'-nucleotidase present in slow-twitch muscle may be higher than in fast-twitch muscle. At similar concentrations of precursor IMP, slow-twitch muscle has a greater capacity for purine nucleoside formation and should be more dependent on salvage and de novo synthesis of purine for the maintenance of muscle adenine nucleotides. Fast-twitch muscles are better able to retain IMP for subsequent reamination due to their lower capacity to degrade IMP to inosine.
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PMID:Purine nucleoside formation in rat skeletal muscle fiber types. 849 84

The major enzyme responsible for adenosine production during myocardial hypoxia or ischemia is 5'-nucleotidase. We purified an AMP-specific 5'-nucleotidase to homogeneity from the 150,000-g supernatant of dog heart homogenate using phosphocellulose, DEAE-cellulose, and ADP-agarose affinity chromatography. Sodium dodecyl sulfate-poly-acrylamide gel electrophoresis of the purified enzyme yielded a single protein band of 43 kDa. The molecular mass of the holoenzyme, determined by gel filtration and sucrose density-gradient centrifugation, was approximately 166 kDa, suggesting a tetrameric structure. Dog heart cytosolic 5'-nucleotidase was active at physiological pH (6.8-7.8) and demonstrated a preference for AMP over IMP as substrate. The enzyme exhibited sigmoidal saturation kinetics, with half-maximal activity at 2.6 mM AMP in the absence of ADP. ADP (0-250 microM) activated cytosolic 5'-nucleotidase by increasing maximal velocity and affinity for AMP. The enzyme was inhibited by 4 mM ATP, but 5'-nucleotidase activity increased as [ATP] was reduced. Mg2+ was required for activity, with maximal activation at approximately 3.5 mM free Mg2+. These data suggest that the regulation of AMP-specific cytosolic 5'-nucleotidase by adenine nucleotides and free Mg2+ may be important in the production of adenosine during conditions promoting ATP hydrolysis, such as myocardial hypoxia or ischemia.
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PMID:Purification and regulation of an AMP-specific cytosolic 5'-nucleotidase from dog heart. 849 66

Clinical evaluation of 123I-iomazenil, a new imaging agent for central-type benzodiazepine receptors with SPECT, was performed in patients with ischemic cerebrovascular disease. We investigated 15 patients with angiographically-proven severe occlusive lesions (occlusion or > 70% stenosis) in the unilateral carotid system. 123I-iomazenil SPECT images were compared with cerebral blood flow (CBF) images and the cerebral perfusion reserve, which were measured using the "split dose 123I-IMP SPECT method" before and after the intravenous injection of 1 g of acetazolamide. For the detection of ischemic lesions, CBF images were superior to 123I-iomazenil images based on visual analysis. Regarding the count ratio of the affected MCA territory to the non-affected (L/N), 123I-IMP was lower than 123I-iomazenil in most of the cases. In five patients showing "crossed cerebellar diaschisis" by 123I-IMP, asymmetry of the cerebellar accumulation was observed in only one patient with 123I-iomazenil, which was less prominent than with 123I-IMP. There was no significant correlation between the L/N ratio with 123I-iomazenil and the cerebral perfusion reserve in the affected MCA territory. However, in some cases showing a decreased L/N ratio (< 90%) with 123I-iomazenil, a decreased CBF with normal perfusion reserve and cerebral hemi-atrophy were observed with 123I-IMP and MRI, which suggested the influence of neuronal loss due to chronic ischemia. These results indicate that 123I-iomazenil SPECT, which provides new information regarding neuronal loss due to ischemic damage to the brain, is useful for the evaluation of ischemic cerebrovascular disease.
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PMID:[Evaluation of 123I-iomazenil SPECT in patients with ischemic cerebrovascular disease: comparative study with 123I-IMP SPECT]. 874 3

Intracellular AMP hydrolysis probably produces sufficient adenosine in ischemic heart to exert physiological activity. Because data on adenosine-producing systems in human heart are scarce, we measured 1) formation of adenosine (catabolites) in ischemic human heart slices and 2) cytoplasmic 5'-nucleotidase activity in human left ventricle. We also measured the latter in rat ventricle and cardiomyocytes. During the first 5 min of incubation, adenosine production in slices (n = 5) equaled 26 +/- 10 (SD) nmol.min-1.g wet wt-1, and total AMP content was 0.81 +/- 0.46 mM. Cytoplasmic IMP-preferring 5'-nucleotidase activity in homogenates of human heart (N-II, 167 +/- 78 mU/g, n = 23) was significantly higher than that of the AMP-preferring one (N-I, 107 +/- 61 mU/g, n = 24). Both isozymes were two to three times more active in rat heart than in human heart. Rat cardiomyocytes contained comparable amounts of the two 5'-nucleotidases. Kinetics of N-I isolated from explanted human heart displayed features similar to the enzyme from animal heart, with a Michaelis constant of 1.5 mM under maximally stimulated conditions. This form can provide the amount of adenosine found in ischemic slices. In conclusion, human heart shows lower cytosolic 5'-nucleotidase activities than rat heart. Nevertheless, cytosolic 5'-nucleotidase activity in human heart can easily account for adenosine formation during ischemia.
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PMID:Soluble forms of 5'-nucleotidase in rat and human heart. 896 93

The effect of intravenously administered ascorbate on the ischemic and reperfused rat skeletal muscle was investigated. Purine nucleotides and phospholipids in skeletal muscle from rats subjected to 4 h of ischemia followed by 1-h reperfusion were analyzed by high-performance liquid chromatography. In addition, ATP, phosphocreatine (PCr), Pi, and phosphomonoesters (PME) were analyzed by 31P-nuclear magnetic resonance at 202.4 MHz, and individual PME such as glucose-6-phosphate and IMP were quantified. PCr and ATP were exhausted after 4 h of ischemia and recovered poorly upon reperfusion in the soleus and tibialis muscle of untreated rats. Postischemic reperfusion resulted in significant loss of cardiolipin. Treatment with 55 mM ascorbate resulted in total restoration of PCr during reperfusion, and ATP recovered to 42% of control in the soleus. Recovery was improved in the tibialis as well, and the cardiolipin decrease was limited. A lower ascorbate concentration (5 mM) did not enhance postischemic recovery. Our findings show that a high dose of ascorbate improves the energetic state of rat skeletal muscle during postischemic reperfusion, probably due to its antioxidant function.
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PMID:Purine nucleotides and phospholipids in ischemic and reperfused rat skeletal muscle: effect of ascorbate. 903 25

A variety of recent studies suggest a role for both inflammatory cytokines such as interleukin-1 beta (IL-1 beta), and apoptosis in ischemic brain injury. Because IL-1 beta converting enzyme (ICE) is required for the conversion of proIL-1 beta to its biologically active form, and has homology with proteins that regulate apoptosis in invertebrates, we studied the effect of cerebral ischemia on brain injury in mutant mice deficient in the ICE gene (ICE knockout [KO] mice). Focal cerebral ischemia, produced by occlusion of the middle cerebral artery, resulted in brain edema (increased water and sodium content) at 4 hours and a histologically defined brain lesion at 24 hours. Both of these markers of brain injury were significantly reduced in the ICE KO mice as compared to wild-type C57BL/6 mice. Regional cerebral blood flow, determined using the flow tracer, N-isopropyl [methyl 1,3-(14)C] p-iodoamphetamine (14C-IMP), was similar in the two strains of mice, indicating that the reduced brain injury in the KO mice was not a result of a lesser degree of ischemia. These data show that ICE contributes to the development of ischemic brain damage, and that it plays a role at an early time in the pathologic process. Although the mechanism of this effect is uncertain, our results suggest that pharmacologic inhibition of ICE may be a useful treatment for stroke.
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PMID:Reduced ischemic brain injury in interleukin-1 beta converting enzyme-deficient mice. 946 61

The purpose of this study was to examine in situ regulation of AMP deaminase in newborn piglet cardiac myocytes and to determine its role in nucleotide metabolism during ischemia. When a rapid deenergization paradigm was used to assay AMP deaminase, enzyme activity depended on the hormonal and metabolic status of cells just before deenergization. Inosine 5'-monophosphate (IMP) formation was increased 150% in deenergized myocytes pretreated with phorbol 12-myristate 13-acetate (PMA; EC50 = 4.7 x 10(-8) M). This effect was 90% blocked with the protein kinase C (PKC) inhibitor staurosporine. In addition, the beta-adrenergic agonist isoproterenol stimulated AMP deaminase activity (EC50 = 1.5 x 10(-8) M), and IMP formation was directly correlated to intracellular cAMP levels (r2 = 0.9). Furthermore, adenosine increased IMP formation, whereas nonrespiring, glycolyzing piglet myocytes had reduced AMP deaminase activity. Pretreatment of perfused piglet hearts with adenosine, but not PMA, before exposure to global ischemia resulted in enhanced conversion of AMP to IMP during the ischemic period. Similar results were obtained in piglet myocytes preincubated with adenosine or PMA before exposure to simulated ischemia. These results may be relevant to the preconditioning phenomenon.
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PMID:AMP deaminase in piglet cardiac myocytes: effect on nucleotide metabolism during ischemia. 1033 Feb 32

Adenosine increases blood flow and decreases excitatory nerve firing. In the heart, it reduces rate and force of contraction and preconditions the heart against injury by prolonged ischemia. Based on indirect kinetic arguments, an AMP-selective cytosolic 5'-nucleotidase designated cN-I has been implicated in adenosine formation during ATP breakdown. The molecular identity of cN-I is unknown, although an IMP/GMP-selective cytosolic 5'-nucleotidase (cN-II) and an ecto-5'-nucleotidase (e-N) have been cloned. We utilized the high abundance of cN-I in pigeon heart to purify a 40-kDa subunit for partial protein sequencing and subsequent cDNA cloning. We obtained a full-length clone encoding a novel 40-kDa peptide, unrelated to cN-II or e-N, that was most abundant in heart, brain, and breast muscle. Immunolocalization in heart showed a striated cytoplasmic location, suggesting association with contractile elements. Transient expression in COS-7 cells, generated a 5'-nucleotidase that catalyzed adenosine formation from AMP, which was increased during ATP catabolism. In conclusion, the cloning and expression of cN-I provides definitive evidence of its ability to produce adenosine during ATP breakdown.
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PMID:The mechanism of adenosine formation in cells. Cloning of cytosolic 5'-nucleotidase-I. 1036 22

It is important for dural arteriovenous fistula (DAVF) to evaluate venous ischemia in the brain related to venous hypertension, but only a few such studies have been performed. In this study, regional cerebral blood flow(rCBF) in DAVF was examined for venous ischemia by 123I-IMP SPECT. The subjects were eighteen patients with DAVF. Of the eighteen patients, nine had DAVF with low perfusion areas and venous ischemia. The factors affecting rCBF in DAVF are: 1) the presence of retrograde leptomeningeal venous drainage, 2) sinus occlusion, and 3) DAVF with high flow. The presence of retrograde leptomeningeal venous drainage was observed in nine patients, sinus occlusion in four patients, high flow in three patients. In two patients, pure leptomeningeal venous drainage was formed by patent sinus, and blood regurgitated from DAVF on the sinus wall to cortical vein. When DAVF was associated with LMVD, most patients had venous hypertension and concomitant venous congestion in the same areas due to reduced venous circulation, resulting in a decrease in rCBF and an increase in regional cerebral blood volume. These hemodynamics suggest venous ischemia in the brain. 123I-IMP SPECT was useful for evaluating rCBF and as a parameter of the treatment.
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PMID:[rCBF study with 123I-IMP SPECT of dural arteriovenous fistula]. 1121 74


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