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)

Flunarizine, a class IV Ca++ antagonist non-selective for slow Ca++ channels, has been shown to be beneficial in the prophylactic treatment of migraine, the treatment of vertigo, and as add-on treatment in therapy-resistant forms of epilepsy. Flunarizine protects the brain against functional and/or structural neuronal damage in various animal models of cerebral ischemia. In addition to its cerebrovascular effect, flunarizine has also direct neuroprotective actions. New data have emerged on flunarizine with regard to Ca++ and Na+ channels in neuronal cells. There are several possible mechanisms involved in the mode of action of flunarizine. Flunarizine may block Ca++ and Na+ channels, both of which may flux Ca++ as well as Na+. A decrease in Ca++ influx may prevent further release of glutamate, and activation of NMDA receptor gated Ca++ channels at physiological pH. A decrease in Na+ influx may prevent cytotoxicity secondary to a large gain in intracellular Ca++, by reverse operation of the Na+/Ca++ exchanger. This mechanism may be important when the glycolytic rate is increased with concomitant acidosis, and phospholipids are broken down as occurs typically during ischemia. Given the complexity of biochemical events leading to cell death, blocking exclusively one channel subtype is not likely to yield sufficient protection. Hence, it may be useful to develop anti-ischemic compounds which act on a series of pathways involved in Ca++ overload, rather than selectively block one such channel.
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PMID:Ca++ and Na+ channels involved in neuronal cell death. Protection by flunarizine. 185 Aug 15

The role of voltage-sensitive Ca2+ channels in mediating Ca2+ influx during ischemia was investigated in NG108-15 cells, a neuronal cell line that does not express glutamate-sensitive receptor-mediated Ca2+ channels. Concurrent 31P/19F and 23Na double-quantum filtered (DQF) NMR spectra were used to monitor cellular energy status, intracellular [Ca2+] ([Ca2+]i), and intracellular Na+ content in cells loaded with the calcium indicator 1,2-bis-(2-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic acid (5FBAPTA) during ischemia and reperfusion. Cells loaded with 5FBAPTA were indistinguishable from unloaded cells except for small immediate decreases in levels of phosphocreatine (PCr) and ATP. Ischemia induced a steady decrease in intracellular pH and PCr and ATP levels, and a steady increase in intracellular Na+ content; however, a substantial increase in [Ca2+]i (about threefold) was seen only following marked impairment of cellular energy status, when PCr was undetectable and ATP content was reduced to 55% of control levels. A depolarization-induced increase in [Ca2+]i could be completely blocked by 1 microM nifedipine, whereas up to 20 microM nifedipine had no effect on the increase in [Ca2+]i seen during ischemia. These data demonstrate that voltage-gated Ca2+ channels do not mediate significant Ca2+ flux during ischemia in this cell line and suggest an important role for Ca2+i stores, the Na+/Ca2+ antiporter, or other processes linked to cellular energy status in the increase in cytosolic Ca2+ level during ischemia.
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PMID:Intracellular calcium dynamics and cellular energetics in ischemic NG108-15 cells studied by concurrent 31P/19F and 23Na double-quantum filtered NMR spectroscopy. 852 64

Myocardial hypoxia and ischemia are characterized by the depletion of ATP and the development of intracellular acidosis, which alter cellular ionic homeostasis. Specifically, elevated cytosolic free Ca++ concentrations cause cellular injury during hypoxia/ischemia and lead to irreversible myocardial damage during reoxygenation/reperfusion. An increase in the intracellular Na+ concentration has been shown to correlate with Ca++ overload. Although inhibition of Na+/K+ exchange because of decreased ATP production may be involved, it is more likely that intracellular acidosis drives Na+ into the cells via Na+/H+ exchange. Experimental evidence supports the notion that Na+/H+ exchange is primarily responsible for Na+ influx during hypoxia/ischemia. The accumulation of intracellular Na+ may then activate the Na+/Ca++ exchanger causing Ca++ overload. Therefore, the Na+/Ca++ exchanger plays a crucial role in cellular injury during hypoxia/ischemia and in cell death during reoxygenation/reperfusion. In the past few years, the Na+/Ca++ exchanger has been cloned and the structure/function relationship studied intensively. Agents which inhibit the Na+/Ca++ exchanger may have therapeutic potential for the treatment of ischemic heart disease. These advances will greatly accelerate the understanding of the cellular and molecular mechanisms underlying the role of the Na+/Ca++ exchanger in the development of myocardial damage during hypoxia/ischemia and reoxygenation/reperfusion.
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PMID:Na+/Ca++ exchanger and myocardial ischemia/reperfusion. 1008 32

Ca(2+), which enters cardiac myocytes through voltage-dependent Ca(2+) channels during excitation, is extruded from myocytes primarily by the Na(+)/Ca(2+) exchanger (NCX1) during relaxation. The increase in intracellular Ca(2+) concentration in myocytes by digitalis treatment and after ischemia/reperfusion is also thought to result from the reverse mode of the Na(+)/Ca(2+) exchange mechanism. However, the precise roles of the NCX1 are still unclear because of the lack of its specific inhibitors. We generated Ncx1-deficient mice by gene targeting to determine the in vivo function of the exchanger. Homozygous Ncx1-deficient mice died between embryonic days 9 and 10. Their hearts did not beat, and cardiac myocytes showed apoptosis. No forward mode or reverse mode of the Na(+)/Ca(2+) exchange activity was detected in null mutant hearts. The Na(+)-dependent Ca(2+) exchange activity as well as protein content of NCX1 were decreased by approximately 50% in the heart, kidney, aorta, and smooth muscle cells of the heterozygous mice, and tension development of the aortic ring in Na(+)-free solution was markedly impaired in heterozygous mice. These findings suggest that NCX1 is required for heartbeats and survival of cardiac myocytes in embryos and plays critical roles in Na(+)-dependent Ca(2+) handling in the heart and aorta.
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PMID:Targeted disruption of Na+/Ca2+ exchanger gene leads to cardiomyocyte apoptosis and defects in heartbeat. 1096 99

Normal cardiac function requires adequate oxygen and substrate (fatty acids, glucose lactate) supply for the energetic requirements of the myocardium. Ischaemia induces abnormalities in the production and excretion of products of myocardial metabolism. During ischaemia, the equilibrium which exists during aerobic respiration between the beta-oxidation of fatty acids and carbohydrates and which generates ATP is disturbed. Pyruvate oxidation and beta-oxidation of fatty acids decrease, and ATP is mainly produced by anaerobic glycolysis. Under these conditions, intracellular glycogen is mobilised, the lactate and protons accumulate in the cardiomyocyte. If reperfusion occurs before irreversible lesions are produced, then functional recovery is possible and is mostly dependant on the type of energetic substrate available. Circulating fatty acids are produced in large quantities after ischaemia: their beta-oxidation, which is then the principal source of ATP, may contribute to the aggravation of contractile dysfunction during reperfusion and accentuate or generate arrhythmias. The decoupling between acceleration of anaerobic glycolysis and the defect of pyruvirate oxidation (inhibition of pyruvirate dehydrogenase) participate in a significant fashion to the accumulation of protons. Rapid correction of intracellular acidosis during reperfusion by activation of the Na+/H+ exchanger, coupled with the accumulation of intracellular Na+ induces a deleterious calcium overload via the Na+/Ca++ exchanger. These different aspects of intracellular metabolism constitute pharmacological targets for the development of future cardio-protective agents.
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PMID:[Myocardial metabolism abnormalities during ischemia and reperfusion]. 1122 23

The Na+/Ca2+ exchanger plays a prominent role in regulating intracellular Ca2+ levels in cardiac myocytes and can serve as both a Ca2+ influx and efflux pathway. A novel inhibitor, KB-R7943, has been reported to selectively inhibit the reverse mode (i.e., Ca2+ entry) of Na+/Ca2+ exchange transport, although many aspects of its inhibitory properties remain controversial. We evaluated the inhibitory effects of KB-R7943 on Na+/Ca2+ exchange currents using the giant excised patch-clamp technique. Membrane patches were obtained from Xenopus laevis oocytes expressing the cloned cardiac Na+/Ca2+ exchanger NCX1.1, and outward, inward, and combined inward-outward currents were studied. KB-R7943 preferentially inhibited outward (i.e., reverse) Na+/Ca2+ exchange currents. The inhibitory mechanism consists of direct effects on the transport machinery of the exchanger, with additional influences on ionic regulatory properties. Competitive interactions between KB-R7943 and the transported ions were not observed. The antiarrhythmic effects of KB-R7943 were then evaluated in an ischemia-reperfusion model of cardiac injury in Langendorff-perfused whole rabbit hearts using electrocardiography and measurements of left ventricular pressure. When 3 microM KB-R7943 was applied for 10 min before a 30-min global ischemic period, ventricular arrhythmias (tachycardia and fibrillation) associated with both ischemia and reperfusion were almost completely suppressed. The observed electrophysiological profile of KB-R7943 and its protective effects on ischemia-reperfusion-induced ventricular arrhythmias support the notion of a prominent role of Ca2+ entry via reverse Na+/Ca2+ exchange in this process.
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PMID:Inhibition of Na+/Ca2+ exchange by KB-R7943: transport mode selectivity and antiarrhythmic consequences. 1151 5

Kanebo is investigating KB-R7943, a Na+/Ca2+ ion exchange inhibitor, for the potential treatment of ischemia and reperfusion injury. It inhibited the outward Na+/Ca2+ exchange current (iNCX) more potently than the inward current under unidirectional flow conditions; however, inward and outward current were inhibited equally under bidirectional conditions. The drug was a competitive inhibitor to external calcium, and the inhibition was reversible with a recovery t1/2 of about 30 s. The mammalian Na+/Ca2+ exchanger forms a multigene family of homologous proteins comprising three isoforms, NCX1, NCX2 and NCX3. By examining chimeric constructs between NCX1 and NCX3 expressed in CCL39 cells, it has been demonstrated that it is the conserved internal repeat regions (alpha-1 and alpha-2) of the exchanger that are critical for the drug's action.
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PMID:KB-R7943. Kanebo. 1189 38

To investigate the effect of chronic global cerebral ischemia on gene expression of Na(+)/Ca(2+) exchanger isoforms NCX1, NCX2 and NCX3 in rat brain. Chronic global cerebral ischemia was induced by bilateral common carotid artery ligation (BCAL) in rats for 1 week, 2 weeks and 4 weeks, respectively. Morris water maze was applied to demonstrate the credibility of BCAL models. After BCAL for 4 weeks, there was learning and memory deficiency that the latency and distance of BCAL group were longer than those of sham group from the second trial to tenth trial in hidden platform trials. Reverse transcription-polymerase chain reaction was used to assess the gene expression of Na(+)/Ca(2+) exchanger isoforms at mRNA level in cerebral cortex and hippocampus. For NCX1, its expression was decreased by 35%, 54% and 27% of rats with BCAL for 1 week, 2 weeks and 4 weeks, respectively; For NCX2, its expression was decreased by 41%, 29% and 12% of rats with BCAL for 1 week, 2 weeks and 4 weeks, respectively; For NCX3, its expression was decreased by 29%, 27% and 12% of rats with BCAL for 1 week, 2 weeks and 4 weeks, respectively. However, in hippocampus, the expressions of NCX1 and NCX3 did not change significantly in different BCAL groups. NCX2 was increased by 60% in BCAL for 1 week only, but did not change significantly in BCAL for 2 weeks or 4 weeks. The study indicated that brain ischemia regulated gene expression levels of Na(+)/Ca(2+) exchanger isoforms especially in cerebral cortex.
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PMID:Altered gene expression of Na+/Ca2+ exchanger isoforms NCX1, NCX2 and NCX3 in chronic ischemic rat brain. 1237 75

Using Na+/Ca2+ exchanger (NCX1)-deficient mice, the pathophysiological role of Ca2+ overload via the reverse mode of NCX1 in ischemia/reperfusion-induced renal injury was investigated. Because NCX1(-/-) homozygous mice die of heart failure before birth, we used NCX1(+/-) heterozygous mice. NCX1 protein in the kidney of heterozygous mice decreased to about half of that of wild-type mice. Expression of NCX1 protein in the tubular epithelial cells and Ca2+ influx via NCX1 in renal tubules were markedly attenuated in the heterozygous mice. Ischemia/reperfusion-induced renal dysfunction in heterozygous mice was significantly attenuated compared with cases in wild-type mice. Histological renal damage such as tubular necrosis and proteinaceous casts in tubuli in heterozygous mice were much less than that in wild-type mice. Ca2+ deposition in necrotic tubular epithelium was observed more markedly in wild-type than in heterozygous mice. Increases in renal endothelin-1 content were greater in wild-type than in heterozygous mice, and this reflected the difference in immunohistochemical endothelin-1 localization in necrotic tubular epithelium. When the preischemic treatment with KB-R7943 was performed, the renal functional parameters of both NCX1(+/+) and NCX1(+/-) acute renal failure mice were improved to the same level. These findings strongly support the view that Ca2+ overload via the reverse mode of Na+/Ca2+ exchange, followed by renal endothelin-1 overproduction, plays an important role in the pathogenesis of ischemia/reperfusion-induced renal injury.
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PMID:Attenuation of ischemia/reperfusion-induced renal injury in mice deficient in Na+/Ca2+ exchanger. 1249 Jun 3

The Na(+)/Ca(2+) exchanger (NCX1) is regulated at the transcriptional level in cardiac hypertrophy, ischemia, and failure. Following pressure overload, activation of MAPKs coincides with the kinetics of NCX1 gene upregulation in adult cardiocytes. Using adenoviral gene delivery, we begin to identify the molecular pathways responsible for upregulation of the exchanger gene. Inhibition of ERK with the MEK inhibitor UO126, the ERK protein phosphatase MKP-3, inhibited ERK activation, but only inhibited alpha-adrenergic-induced NCX1 upregulation by 30%. Overexpression of DN-JNK lowered basal NCX1 expression. Overexpression of activated MKK-3 was sufficient for alpha-adrenergic-stimulated upregulation of the reporter gene. Together, this data indicates that (1) JNK mediates basal cardiac expression of the NCX1 gene, (2) ERK and p38 play a role in alpha-adrenergic-stimulated NCX1 upregulation, and (3) p38 activation alone is sufficient for NCX1 upregulation.
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PMID:Pathways regulating Na+/Ca2+ exchanger expression in the heart. 1250 66


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