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)

Ca(2+) overload in myocardial cells is responsible for arrhythmia. Sodium-calcium exchanger (NCX) inhibitors are more effective than sodium-hydrogen exchanger (NHE) inhibitors with regard to modulation of Ca(2+) overload, because NCX inhibitors can directly inhibit the influx of Ca(2+) into cells. NCX is an attractive target for the treatment of heart failure and ischemia-reperfusion. We have designed and synthesized a series of N-(2-aminopyridin-4-ylmethyl)nicotinamide derivatives, based on compound 5. We have discovered a novel NCX inhibitor (23 h) with an IC(50) value of 0.12 microM against reverse NCX. The inhibitory activities of our NCX inhibitors against cytochrome P450 were also evaluated. The effects on heart failure and the pharmacokinetic profile of compound 23 h are discussed.
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PMID:Discovery of an N-(2-aminopyridin-4-ylmethyl)nicotinamide derivative: a potent and orally bioavailable NCX inhibitor. 1591 15

The effect of ischemia induced acute renal failure (ARF) on the transport of phosphate (Pi) after early (15-30 min) and prolonged (60 min) ischemia in the brush border membrane vesicles (BBMV) from rat renal cortex was studied. Sodium-dependent transport of Pi declined significantly and progressively due to ischemia. Western blot analysis of BBM from ischemic rats showed decreased expression of NaPi-2. A compensatory increase was observed in Pi uptake in BBMV from contralateral kidneys. There was no significant difference in NaPi-2 expression between BBMV from sham and contralateral kidneys. Early blood reperfusion for 15 min after 30 min ischemia caused further decline in Pi uptake. Prolonged reperfusion for 120 min caused partial reversal of transport activities in 30-min ischemic rats. However, no improvement in the transport of Pi was observed in 60-min ischemic rats after 120 min of blood reperfusion. Kinetic studies showed that the effect of ischemia and blood reperfusion was dependent on the Vmax of the Na-Pi transporter. Western blot analysis showed increased expression of NaPi-2 in the BBMs from ischemia-reperfusion animals. Further, a shift in the association of Na ions to transport one molecule of Pi was observed under different extracellular Na concentrations [Na]o. Feeding rats with low Pi diet and/or treatment with thyroid hormone (T3) prior to ischemia resulted in increased basal Pi transport. Ischemia caused similar decline in Pi transport in BBM from LPD and/or T3 animals. However, recovery in these animals was faster than the normal Pi diet fed (NPD) animals. The study suggests a change in the intrinsic properties of the Na-Pi transporter in rat kidneys due to ischemia. The study also indicates that treatment with T3 and feeding LPD prior to ischemia caused faster recovery of phosphate uptake due to ischemia-reperfusion injury.
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PMID:Effect of ischemia reperfusion on sodium-dependent phosphate transport in renal brush border membranes. 1618 35

Besides initiating and propagating action potentials in established neuronal circuits, voltage-dependent sodium channels sculpt and bolster the functional neuronal network from early in embryonic development through adulthood (e.g., differentiation of oligodendrocyte precursor cells into oligodendrocytes, myelinating axon; competition between neighboring equipotential neurites for development into a single axon; enhancing and opposing functional interactions with attractive and repulsive molecules for axon pathfinding; extending and retracting terminal arborization of axon for correct synapse formation; experience-driven cognition; neuronal survival; and remyelination of demyelinated axons). Surprisingly, different patterns of action potentials direct homeostasis-based epigenetic selection for neurotransmitter phenotype, thus excitability by sodium channels specifying expression of inhibitory neurotransmitters. Mechanisms for these pleiotropic effects of sodium channels include reciprocal interactions between neurons and glia via neurotransmitters, growth factors, and cytokines at synapses and axons. Sodium channelopathies causing pain (e.g., allodynia) and neurodegeneration (e.g., multiple sclerosis) derive from 1) electrophysiological disturbances by insults (e.g., ischemia/hypoxia, toxins, and antibodies); 2) loss-of-physiological function or gain-of-pathological function of mutant sodium channel proteins; 3) spatiotemporal inappropriate expression of normal sodium channel proteins; or 4) de-repressed expression of otherwise silent sodium channel genes. Na(v)1.7 proved to account for pain in human erythermalgia and inflammation, being the convincing molecular target of pain treatment.
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PMID:Roles of voltage-dependent sodium channels in neuronal development, pain, and neurodegeneration. 1707 4

Cardiac surgery often generates oxidative stress leading to ischemia reperfusion injury (I-R). Antioxidants have been shown to prevent this injury and have been added to cardioplegic solutions to assist in recovery. In this study, we tested the effectiveness of sodium selenite in protecting against ischemia reperfusion injury and investigated the mechanisms behind this protection. Hearts from male Wistar rats were subjected to ischemia reperfusion using the Langendorf model. Krebs-Henseleit perfusion solutions were supplemented with 0, 0.1, 0.5, 1.0, and 10 microM sodium selenite. Hearts were perfused for 30 min and then subjected to 22.5 min of global ischemia followed by 45 min reperfusion. Heart rate, ischemic contracture, end diastolic pressure, and developed ventricular pressure were monitored. At the completion of the experiment, hearts were homogenized and tissue extracts were assayed for glutathione peroxidase (GSH-Px) and thioredoxin reductase (Thx-Red) activity. Sodium selenite, at a concentration of 0.5 microM, demonstrated a protective effect on the recovery of cardiac function following I-R, as evidenced by a lower end diastolic pressure and enhanced recovery of rate pressure product. There was no beneficial effect observed in hearts perfused with 0.1 microM sodium selenite-supplemented buffer, whereas poorer functional recovery was observed in hearts perfused with 10 microM sodium selenite-supplemented buffer. The beneficial effect of sodium selenite was not mediated through increased activity of GSH-Px or Thx-Red. This study demonstrates that the addition of sodium selenite to reperfusion solutions, at an optimal concentration of 0.5 microM, assists in cardiac recovery following ischemia reperfusion.
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PMID:Effect of sodium selenite-enriched reperfusion solutions on rat cardiac ischemia reperfusion injury. 1720 2

Sodium/calcium exchangers are neuronal plasma membrane transporters, which by coupling Ca2+ and Na+ fluxes, may play a relevant role in brain ischemia. The exchanger gene superfamily comprises two arms: the K+-independent (NCX) and K+-dependent (NCKX) exchangers. In the brain, three different NCX (NCX1, NCX2, NCX3) and three NCKX (NCKX2, NCKX3, NCKX4) family members have been described. Up to now, no sutides about the role played by NCKX proteins in cerebral ischemia have been published. The aim of the present study was to investigate the role of NCKX2 in an in vivo model of permanent middle cerebral artery occlusion (pMCAO). The role of this protein in the development of ischemic damage was assessed by knocking-down its expression with an antisense oligodeoxynucleotide (AS-ODN), intracerebroventricularly infused by an osmotic minipump for 48 h, starting from 24 h before pMCAO. The results showed that NCKX2 knocking-down by using antisense strategy increased the extent of the ischemic lesion. The results of this study suggest that NCKX2 could exert a neuroprotective effect during ischemic injury.
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PMID:Involvement of the potassium-dependent sodium/calcium exchanger gene product NCKX2 in the brain insult induced by permanent focal cerebral ischemia. 1744 91

Sodium-dependent glutamate transporters expressed in astroglial cells and neurons are essential for clearance of extracellular glutamate. In the present study, we found elevation of extracellular glutamate concentration associated with concomitant downregulation of glutamate transporters following rat microsphere embolism (ME). A marked increase in extracellular glutamate in the rat striatum was observed by microdialysis immediately after ME induction, and glutamate remained elevated at least 12h after ischemia. Concomitantly, impairment of high KCl (146 mM)-induced glutamate release was observed in the striatum 12h after ME. Consistent with the persistent increase in extracellular glutamate, expression of the glutamate transporters EAAC1 and GLT-1 significantly decreased 6h after insult without a change in GLAST levels. GLT-1 expression was restored to basal levels within 48 h, whereas EAAC1 expression remained decreased up to at least 72 h after ME. Restoration of GLT-1 was associated with increased expression of the astroglial marker GFAP, whereas markedly reduced EACC1 levels were correlated with reduced levels of the neuronal marker MAP2, likely due to loss of vulnerable neurons. Taken together, downregulation of glutamate transporters after ME is associated with dysregulation of basal glutamate concentrations and KCl-induced glutamate release in the brain.
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PMID:Downregulation of glutamate transporters is associated with elevation in extracellular glutamate concentration following rat microsphere embolism. 1807 58

Ischemia/reperfusion (I/R) injury is a variable yet unavoidable complication in liver surgery and transplantation. Selenium-dependent glutathione-peroxidases (GPx) and selenoproteins function as antioxidant defense systems. One target in preventing I/R injury is enhancing the capacity of endogenous redox defense. It was the aim of this study to analyze the effects of selenium substitution on liver microcirculation, hepatocellular injury and glutathione status in a model of partial warm liver ischemia in the rat. Sodium selenite was administered in three different dosages i.v.: 0.125 microg/g, 0.25 microg/g and 0.375 microg/g body weight and compared to an untreated control group (each n=10). Intravital microscopy was performed after 70 min of partial warm liver ischemia and 90 min of reperfusion. Liver tissue and plasma samples were taken at the end of the experiment for laboratory analysis. Microcirculation improved significantly in all therapy groups in contrast to control animals. ALT levels decreased significantly whereas malondialdehyde levels remained unchanged. In liver tissue, selenium supplementation caused an increase in the amount of total and reduced glutathione without changes in oxidized glutathione. This effect is likely mediated by selenite itself and selenoprotein P rather than by modulating GPx activity. We were able to show that selenite substitution has an immediate protective effect on I/R injury after warm hepatic ischemia by acting as a radical scavenger and preserving the antioxidative capacity of the liver.
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PMID:The influence of selenium substitution on microcirculation and glutathione metabolism after warm liver ischemia/reperfusion in a rat model. 1857 1

Development of intracellular calcium overload is an important pathophysiological factor in myocardial ischemia/reperfusion or anoxia/reoxygenation injury. Recent studies have shown that Sodium Ferulate (SF) stimulates nitric oxide (NO) production and exerts a cardioprotective effect in the ischemia-reperfused heart. However, it has not been determined whether the cardioprotection of SF is associated with suppression of Ca(2+) overload via NO/cyclic GMP (cGMP)/cGMP-dependent protein kinase (PKG) pathway. In this work, after cardiomyocytes were incubated with 100, 200, 400, or 800 microM SF for 3 h, anoxia/reoxygenation injury was induced and intracellular Ca(2+) concentration, NO synthase (NOS) activity, guanylate cyclase activity, NO, and cGMP formation were measured appropriately. The results showed that treatment with SF concentration-dependently inhibited calcium overload induced by anoxia/reoxygenation. We also demonstrated that SF (100-800 microM) concentration dependently enhanced NO and cGMP formation through increasing NOS activity and guanylate cyclase activity in the cardiomyocytes. On the contrary, inhibition of calcium overload by SF was markedly attenuated by addition of an NOS inhibitor, an NO scavenger, an soluble guanylate cyclase inhibitor, and a PKG inhibitor: N(G)-nitro-l-arginine methyl ester (L-NAME, 100 microM), 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl-3-oxide (c-PTIO, 1.0 microM), 1H-[1, 2, 4] oxadiazolo [4, 3-alpha] quinoxalin-1-one (ODQ, 20 microM) and KT5823 (0.2 microM), respectively. Our findings indicate that SF significantly attenuates anoxia/reoxygenation-induced Ca(2+) overload and improves cell survival in cultured cardiomyocytes through NO/cGMP/PKG signal pathway.
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PMID:Sodium ferulate attenuates anoxia/reoxygenation-induced calcium overload in neonatal rat cardiomyocytes by NO/cGMP/PKG pathway. 1908 73

Global ischemia was induced in gerbil by bilateral occlusion of the common carotid arteries for 5 min. Sodium ionophore monensin or sodium channel blocker tetrodotoxin (TTX) was administered at doses of 10 micorg/kg, i.p., 30 min before ischemia induction; the dose was repeated after 22 hr. Subsequently, brain infarct occurred, determined at 24 hr after occlusion. Large, well-demarcated infarcts were observed in both hemispheres, an important observation because it critically influences the interpretation of the data. Because nitric oxide (NO) production is thought to be related to ischemic neuronal damage, we examined increases in Ca(2+) influx, which lead to the activation of nitric oxide synthase (NOS). Then we evaluated the contributions of neuronal NOS, endothelial NOS, and inducible NOS to NO production in brain cryosections. The cytosolic release of apoptogenic molecules like cytochrome c and p53 were confirmed after 24 hr of reflow. TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) labeling detected the apoptotic cells, which were confirmed in neuron-rich cell populations. After 24 hr, all the ischemic changes were amplified by monensin and significantly attenuated by TTX treatment. Additionally, the nesting behavior and histological outcomes were examined after 7 day of reflow. The neuronal damage in the hippocampal area and significant decrease in nesting scores were observed with monensin treatment and reduced by TTX pretreatment after day 7 of reflow. To our knowledge, this report is the first to highlight the involvement of the voltage-sensitive Na(+) channel in possibly regulating in part NO system and apoptosis in a cytochrome c-dependent manner in global ischemia in the gerbil, and thus warrants further investigation.
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PMID:The neuronal apoptotic death in global cerebral ischemia in gerbil: important role for sodium channel modulator. 1911 7

Sodium pyruvate has shown protective effects in various experimental models of brain ischemia. The main holdup of this drug is that most of the benefits are reported with a very narrow time window for intervention. Here we investigated whether pyruvate could protect the brain against ischemic damage using a model of 2-hour middle cerebral artery occlusion in the rat. The time course of blood pyruvate after i.p. administration of sodium pyruvate (400 mg/kg) was studied. Animals were treated with the drug or with vehicle 45 min after reperfusion following 2-hour ischemia. Tissue ATP content was determined 5 and 10 h after ischemia onset, and infarct volume was measured at days 1 and 2. The neurological score was evaluated before and after treatment in the different experimental groups. Pyruvate prevented the drop of cortical ATP induced by ischemia in the ipsilateral cortex and ameliorated the neurological deficit at 5 h after the onset of ischemia, supporting some beneficial effects of the treatment. However, these effects were not sustained at 10 h. Furthermore, pyruvate failed to significantly reduce infarct volume and the neurological deficit at 24 and 48 h, in spite of some trend to smaller infarction after pyruvate administration. Therefore, under the present experimental conditions, systemic administration of sodium pyruvate at 3 h after the beginning of ischemia exerted only a transient benefit but not a persistent protection against brain damage.
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PMID:Transient benefits but lack of protection by sodium pyruvate after 2-hour middle cerebral artery occlusion in the rat. 1934 78


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