Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Reperfusion of ischemic liver results in the generation of oxygen radicals, nitric oxide (NO) and their reaction product peroxynitrite, all of which may cause strand breaks in DNA, which activate the nuclear enzyme poly(ADP ribose)synthase (PARS). This results in rapid depletion of intracellular nicotinamide adenine dinucleotide and adenosine 5'-triphosphate (ATP) and eventually induces irreversible cytotoxicity. In this study, we demonstrated that niacinamide, a PARS inhibitor, attenuated ischemia/reperfusion (I/R)-induced liver injury. Ischemia was induced by clamping the common hepatic artery and portal vein of rats for 40 min. Thereafter, flow was restored and the liver was reperfused for 90 min. Blood samples collected prior to I and after R were analyzed for methyl guanidine (MG), NO, tumor necrosis factor (TNF-alpha) and ATP. Blood levels of aspartate transferase (AST), alanine transferase (ALT) and lactate dehydrogenase (LDH) which served as indexes of liver injury were measured. This protocol resulted in elevation of the blood NO level (p < 0.01). Inflammation was apparent, as TNF-alpha and MG levels were significantly increased (p < 0.05 and p < 0.001). AST, ALT and LDH were elevated 4- to 5-fold (p < 0.001), while ATP was significantly diminished (p < 0.01). After administration of niacinamide (10 mM), liver injury was significantly attenuated, while blood ATP content was reversed. In addition, MG, TNF-alpha and NO release was attenuated. These results indicate that niacinamide, presumably by acting with multiple functions, exerts potent anti-inflammatory effects in I/R-induced liver injury.
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PMID:The protective effect of niacinamide on ischemia-reperfusion-induced liver injury. 1170 7

Biochemical cascades initiated by oxidative stress and excitotoxic intracellular calcium rises are thought to converge on mitochondrial dysfunction. We investigated the contribution of mitochondrial dysfunction to free radical (FR) overproduction in rat CA1 pyramidal neurons of organotypic slices subjected to a hypoxic-hypoglycemic insult. Ischemia-induced FR generation was decreased by the mitochondrial complex I blocker, rotenone, indicating that mitochondria are the principal source of ischemic FR production. Measurements of mitochondrial calcium with the mitochondrial calcium probe dihydroRhod-2, revealed that FR production during and after the anoxic episode correlates with the accumulation of mitochondrial calcium. However, the mitochondrial calcium uptake inhibitor Ru360 did not prevent FR generation during ischemia and attenuated it to some degree during reoxygenation. On the other hand, the mitochondrial permeability transition blocker cyclosporinA (CsA) completely arrested both ischemic FR generation and mitochondrial calcium overload, and prevented deterioration of neuronal intrinsic membrane properties. CsA had no effect on the accumulation of intracellular calcium during ischemia-reperfusion. Nicotinamide, a blocker of NAD+ hydrolysis, reproduced the CsA effects on FR generation, mitochondrial calcium accumulation and cytoplasmic calcium increases. These observations suggest that a major determinant of ischemic FR generation in pyramidal neurons is the uncoupling of the mitochondrial respiratory chain, which may be associated with the mitochondrial permeability transition.
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PMID:Dynamics of intracellular calcium and free radical production during ischemia in pyramidal neurons. 1170

Forty rats were subjected to 3 hours of focal ischemia by occluding the left middle cerebral and left common carotid arteries. The propagation of recurrent depolarization around the ischemic core was analyzed using direct-current potential and NADH (reduced nicotinamide adenine dinucleotide) fluorescence images by irradiating the parietal-temporal cortex with ultraviolet light. Based on histological evaluation at direct-current recording sites, the total time of depolarization causing 50% neuronal injury was estimated to be 18.2 minutes. The sites showing recurrent depolarizations resulted in 23 +/- 29% neuronal injury due to the short depolarization time, whereas the sites showing recurrent depolarizations and eventually persistent depolarization resulted in infarction. The NADH fluorescence images showed that recurrent depolarizations propagated along the margin of the ischemic core. In 85.9% of the recurrent depolarizations, the fluorescence disappeared without leaving any traces and did not affect the area of the ischemic core. However, in 47.5% of the animals, 14.1% of recurrent depolarizations merged with the ischemic core and increased the area by 6 +/- 4 mm(2). These findings suggest that recurrent depolarization increases the severity of neuronal injury but does not cause infarction by itself if persistent depolarization does not follow, and that the area of persistent depolarization is enlarged with 14.1% of recurrent depolarizations.
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PMID:Dynamic changes in cortical NADH fluorescence and direct current potential in rat focal ischemia: relationship between propagation of recurrent depolarization and growth of the ischemic core. 1180 96

Poly(adenosine 5'-diphosphate) ribose polymerase is a nuclear enzyme activated in response to genotoxic stress induced by a variety of DNA damaging agents. Several oxygen and nitrogen-centered free radicals, notably peroxynitrite, are strong inducers of DNA damage and poly(adenosine 5'-diphosphate) ribose polymerase activation in vitro and in vivo. Activation of this nuclear enzyme depletes the intracellular stores of its substrate nicotinamide adenine dinucleotide, slowing the rate of glycolysis, mitochondrial electron transport and adenosine triphosphate formation. This process triggers a severe energetic crisis within the cell, leading to acute cell dysfunction and cell necrosis. Poly(adenosine 5'-diphosphate) ribose polymerase also plays an important role in the regulation of inflammatory cascades, through a functional association with various transcription factors and transcription co-activators. Recent works identified this enzyme as a critical mediator of cellular metabolic dysfunction, inflammatory injury, and organ damage in conditions associated with overwhelming oxidative stress, including systemic inflammation, circulatory shock, and ischemia-reperfusion. Accordingly, pharmacological inhibitors of poly(adenosine 5'-diphosphate) ribose polymerase protect against cell death and tissue injury in such conditions, and may therefore represent novel therapeutic tools to limit multiple organ damage and dysfunction in critically ill patients.
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PMID:Poly(adenosine 5'-diphosphate) ribose polymerase activation as a cause of metabolic dysfunction in critical illness. 1184 85

The possible ability of nicotinamide and ketamine to decrease infarction volume and DNA fragmentation was investigated in a middle cerebral artery occlusion rat model. DNA fragmentation was measured with an enzyme linked immunoassay. Control infarct volume was 223.8 +/- 10.6 mm(3). Ketamine alone did not alter infarct volume, 233.2 +/- 61.8 mm(3). Nicotinamide alone did not alter infarct volume, 235.2 +/- 62.8 mm(3). The combination of ketamine and nicotinamide decreased infarct volume to 83.8 +/- 35.2 mm(3). Ketamine produced hypothermia. Nicotinamide and ketamine decreased brain swelling and DNA fragmentation in the cerebral cortex, striatum and hippocampus in rats perfused for 6 or 24 h. Ketamine may synergize the actions of nicotinamide and partially prevent brain damage from ischemia and reperfusion.
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PMID:Nicotinamide and ketamine reduce infarct volume and DNA fragmentation in rats after brain ischemia and reperfusion. 1189 57

A moderate reduction in coronary blood flow results in decreased myocardial oxygen consumption, accelerated glycolysis, decreased pyruvate oxidation, and lactate accumulation. To quantitatively understand cardiac metabolism during ischemia, we have developed a mechanistic, mathematical model based on biochemical mass balances and reaction kinetics in cardiac cells. By numerical solution of model equations, computer simulations showed the dynamic responses in glucose, fatty acid, glucose-6-phosphate, glycogen, triglyceride, pyruvate, lactate, acetyl-CoA, and free-CoA as well as CO2, O2, phosphocreatine/creatine, nicotinamide adenine dinucleotide (reduced form)/nicotinamide adenine dinucleotide (oxidized form) (NADH/NAD+), and adenosine diphosphate/adenosine triphosphate (ADP/ATP). When myocardial ischemia was simulated by a 60% reduction in coronary blood flow, the model generated myocardial concentrations, uptakes, and fluxes that were consistent with experimental data from in vivo pig studies. After 60 min of ischemia the concentrations of glycogen, phosphocreatine, and ATP were decreased by 60%, 75%, and 50%, respectively. With the onset of ischemia, myocardial lactate concentration increased and the myocardium switched from net consumer to net producer of lactate. Our model predicted a rapid 13-fold increase in NADH/NAD+, but only a twofold increase in the ratio of acetyl-CoA to free-CoA. These findings are consistent with the concept that pyruvate oxidation is inhibited during ischemia partially by the rise in NADH/NAD+.
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PMID:Mechanistic model of myocardial energy metabolism under normal and ischemic conditions. 1196 72

Cyclic ADP-ribose (cADPR) is a novel Ca(2+)-mobilizing second messenger in mammalian cells including cardiomyocytes. It is unknown whether myocardial ischemia and reperfusion affect the metabolism of cADPR in the myocardium. The present study therefore examined the effects of myocardial ischemia and reperfusion on the concentrations of myocardial cADPR using high-performance liquid chromatography. Basal levels of cADPR in rat myocardium were 5.3 +/- 1.8 nmol x mg(-1) protein. Myocardial ischemia for 30 min significantly decreased cADPR concentrations to 2.1 +/- 0.4 nmol x mg(-1) protein. During reperfusion, cADPR was maintained at ischemic levels. The activity of ADP-ribosyl cyclase was expressed as the conversion rate of nicotinamide guanine dinucleotide (NGD(+)) to cyclic GDP-ribose. Myocardial ischemia and reperfusion did not alter the activity of ADP-ribosyl cyclase. However, cADPR hydrolase activity, as measured by the conversion rate of cADPR to ADP-ribose, was significantly elevated by ischemia and reperfusion. To determine the mechanism resulting in the enhancement of cADPR hydrolase activity, we examined the effects of changes in ADP, ATP, pH, and PO(2) on the conversion rate of cADPR to ADPR. Alterations of ADP, ATP, or pH in myocardial tissue had no effect on the degradation of cADPR, whereas a decrease in tissue PO(2) markedly increased the hydrolysis of cADPR. These results suggest that myocardial ischemia and reperfusion decrease cADPR in the myocardium by increasing its hydrolysis. Tissue hypoxia may be one of the important mechanisms to activate cADPR hydrolase.
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PMID:Myocardial ischemia and reperfusion reduce the levels of cyclic ADP-ribose in rat myocardium. 1211 Oct 41

Excessive nitric oxide (NO) production has been implicated in the pathophysiology of cardiomyocyte (CMC) apoptosis and necrosis induced by ischemia/reperfusion, inflammation and NO-donating chemicals. Although caspases are known to be involved in apoptosis, the present study examined whether caspases also play a role in NO-induced CMC necrosis. Neonatal rat CMCs were labeled with Annexin-V and propidium iodide, and apoptosis and necrosis were analyzed by confocal images and fluorescence activated cell sorter analysis. CMC apoptosis and necrosis were also evaluated by determining DNA fragmentation in the cell and the supernatant fractions. Treatment of CMCs with the NO donor, diethylenetriamine NO (DETA/NO) or S-nitroso-N-acetyl-penicillamine (SNAP) at concentrations of 10 and 100 microM for 24h induced predominantly apoptosis over necrosis, but a higher concentration (1mM) of DETA/NO or SNAP provoked both apoptosis and necrosis. The lower doses of DETA/NO-induced apoptosis was associated with a gradual increase in caspase-3 activity over 24h without appreciable activation of poly ADP-ribose polymerase (PARP), while the higher dose of DETA/NO induced a marked increase in caspase-3 activity and CMC apoptosis until 2h after the treatment, and increased necrotic CMCs thereafter associated with robust activation of PARP. The caspase inhibitor Z-DEVD-FMK but not the poly ADP-ribose polymerase (PARP) inhibitor 3-aminobenzamide (3-AB) abolished caspase-3 activation and CMC apoptosis induced by 100 microM DETA/NO. However, both Z-DEVD-FMK and 3-AB abolished PARP activation and CMC necrosis induced by 1mM DETA/NO. The amount of nicotinamide adenine dinucleotide (NAD) and adenine nucleotides in CMCs was not significantly affected by treatment with 10 and 100 microM DETA/NO, but was significantly reduced by treatment with 1mM DETA/NO without a decline of adenylate energy charge. The depletion of NAD and adenine nucleotides was abrogated by Z-DEVD-FMK and 3-AB. These results suggest that caspase activation play a crucial role in CMC apoptosis induced by lower concentrations of NO as well as in CMC necrosis induced by a higher concentration of and a longer exposure to NO. NO-induced CMC necrosis is likely mediated by PARP activation which occurs as a consequence of caspase activation.
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PMID:Nitric oxide induces caspase-dependent apoptosis and necrosis in neonatal rat cardiomyocytes. 1223 74

Enhanced oxidative stress, particularly an excess production of superoxide, has been implicated in the altered vasomotor responsiveness observed in diabetes mellitus (DM). Recent evidence suggests that an altered regulation of K+ channel activity by enhanced oxidative stress may participate in the abnormal vascular responses. This review examines the mechanism of hyperglycemia-induced superoxide production and describes the consequences on hyperpolarization-mediated vasodilation. Several pathways have been proposed as mechanisms for hyperglycemia-induced superoxide overproduction, including increased flux through the polyol pathway, depletion of nicotinamide adenine dinucleotide phosphate (NADPH), altered endogenous antioxidant enzymes, and reduced availability of tetrahydrobiopterin, an essential cofactor for nitric oxide synthase (NOS). The resulting excess production of superoxide has been implicated in the impaired dilator responses to ATP-sensitive K+ (KATP) channel openers in aorta and in mesenteric and cerebral arteries of streptozotocin-induced diabetic rats. This may have important implications for ischemia-mediated vasodilation. Potential alterations in voltage-sensitive K+ (KV) channel regulation also have been implicated in the vascular pathogenesis of DM. For example, incubation of small rat coronary arteries in high glucose for 24 h greatly reduces KV channel activity and functional responses, both of which can be partially restored by antioxidant treatment. However, not all K+ channels are adversely affected by reactive oxygen species (ROS). For example, high-conductance Ca(2+)-activated K+ (BKCa) channels may compensate for the loss of other vasodilator mechanisms in disease states such as atherosclerosis where ROS generation is increased. Therefore, BKCa channels may be refractory to superoxide, providing a compensatory mechanism for partially reversing the reduced dilator responses attributed to the dysfunction of other K+ channel types. In summary, determining the effect of ROS on K+ channel-mediated dilation will be important for understanding the pathophysiology of diabetic vascular dysfunction and for developing therapies to improve tissue perfusion in this disease.
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PMID:The coronary circulation in diabetes: influence of reactive oxygen species on K+ channel-mediated vasodilation. 1237 22

This study examined the effects of nicotinamide on adenosine triphosphate (ATP) and nicotinamide adenine (NAD) levels and poly(adenosine diphosphate-ribose) (poly(ADP-ribose)) polymerase activity following ischemia and reperfusion in ketamine pretreated rats. Nicotinamide was administered at the end of the ischemic period. Nicotinamide protected against the depletion of ATP and NAD at 6 and 24 h of reperfusion. Nicotinamide is known to inhibit poly(ADP-ribose) polymerase at early time points, but was found to increase poly(ADP-ribose) polymerase activity at 24 h of reperfusion. It appears that nicotinamide can help maintain cellular energetics during reperfusion, thereby protecting cells from necrotic and apoptotic mechanisms.
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PMID:The effects of nicotinamide on energy metabolism following transient focal cerebral ischemia in Wistar rats. 1241 88


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