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)

The mitochondrial permeability transition pore (PTP) may operate as a physiological Ca2+ release mechanism and also contribute to mitochondrial deenergization and release of proapoptotic proteins after pathological stress, e.g. ischemia/reperfusion. Brain mitochondria exhibit unique PTP characteristics, including relative resistance to inhibition by cyclosporin A. In this study, we report that 2-aminoethoxydiphenyl borate blocks Ca2+-induced Ca2+ release in isolated, non-synaptosomal rat brain mitochondria in the presence of physiological concentrations of ATP and Mg2+. Ca2+ release was not mediated by the mitochondrial Na+/Ca2+ exchanger or by reversal of the uniporter responsible for energy-dependent Ca2+ uptake. Loss of mitochondrial Ca2+ was accompanied by release of cytochrome c and pyridine nucleotides, indicating an increase in permeability of both the inner and outer mitochondrial membranes. Under these conditions, Ca2+-induced opening of the PTP was not blocked by cyclosporin A, antioxidants, or inhibitors of phospholipase A2 or nitric-oxide synthase but was abolished by pretreatment with bongkrekic acid. These findings indicate that in the presence of adenine nucleotides and Mg2+,Ca2+-induced PTP in non-synaptosomal brain mitochondria exhibits a unique pattern of sensitivity to inhibitors and is particularly responsive to 2-aminoethoxydiphenyl borate.
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PMID:Cyclosporin A-insensitive permeability transition in brain mitochondria: inhibition by 2-aminoethoxydiphenyl borate. 1275 Mar 71

The aim of this study was to determine whether changes in protein content and/or gene expression of Na+-K+-ATPase subunits underlie its decreased enzyme activity during ischemia and reperfusion. We measured protein and mRNA subunit levels in isolated rat hearts subjected to 30 min of ischemia and 30 min of reperfusion (I/R). The effect of ischemic preconditioning (IP), induced by three cycles of ischemia and reperfusion (10 min each), was also assessed on the molecular changes in Na+-K+-ATPase subunit composition due to I/R. I/R reduced the protein levels of the alpha2-, alpha3-, beta1-, and beta2-isoforms by 71%, 85%, 27%, and 65%, respectively, whereas the alpha1-isoform was decreased by <15%. A similar reduction in mRNA levels also occurred for the isoforms of Na+-K+-ATPase. IP attenuated the reduction in protein levels of Na+-K+-ATPase alpha2-, alpha3-, and beta2-isoforms induced by I/R, without affecting the alpha1- and beta1-isoforms. Furthermore, IP prevented the reduction in mRNA levels of Na+-K+-ATPase alpha2-, alpha3-, and beta1-isoforms following I/R. Similar alterations in protein contents and mRNA levels for the Na+/Ca2+ exchanger were seen due to I/R as well as IP. These findings indicate that remodeling of Na+-K+-ATPase may occur because of I/R injury, and this may partly explain the reduction in enzyme activity in ischemic heart disease. Furthermore, IP may produce beneficial effects by attenuating the remodeling of Na+-K+-ATPase and changes in Na+/Ca2+ exchanger in hearts after I/R.
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PMID:Preconditioning attenuates ischemia-reperfusion-induced remodeling of Na+-K+-ATPase in hearts. 1276 51

The status of phospholamban (PLB) phosphorylation in the ischemia-reperfused hearts remains controversial. Although a decrease in the phosphorylation of both PLB residues (Ser16, PKA site, and Thr17, CaMKII site) was previously reported, experiments from our laboratory failed to detect this decrease. In an attempt to elucidate the cause for this discrepancy, experiments were performed in Langendorff-perfused rat hearts with two main goals: (1) To determine whether keeping pacing during ischemia, a protocol followed in other ischemia-reperfusion models, decreases the phosphorylation of PLB residues, below pre-ischemic values; (2) To investigate whether a maximal beta-adrenergic challenge allows to detect a decrease in the ability of PLB to be phosphorylated in ischemia-reperfused hearts. Hearts were submitted to a global ischemia/reperfusion protocol (20/30 min) with (P) or without (NP) pacing during ischemia, and phosphorylation of PLB residues was assessed by immunodetection. The recovery of contractility upon reperfusion was lower in P vs. NP hearts. Ser16 of PLB, was phosphorylated at the end of ischemia in NP hearts. This increase appeared earlier in P hearts and was significantly diminished by catecholamine depletion and beta-blockade. Thr17 site was phosphorylated at the beginning of ischemia and the onset of reperfusion. The ischemia-induced phosphorylation of Thr17 was higher and more sustained in P vs. NP hearts, and inhibited by the calcium channel blocker, nifedipine, whereas the reperfusion-induced increase in Thr17 phosphorylation was similar in P and NP hearts and was significantly diminished by the Na+/Ca2+ exchanger inhibitor KB-R7943. Phosphorylation of PLB residues did not decrease below basal levels at any time during ischemia and reperfusion. However, the phosphorylation, inotropic and lusitropic response to beta-adrenergic stimulation was significantly decreased both in P and NP hearts.
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PMID:Phospholamban phosphorylation in ischemia-reperfused heart. Effect of pacing during ischemia and response to a beta-adrenergic challenge. 1457 98

The Na+/Ca2+ exchanger (NCX) is an ion transporter that exchanges Na+ and Ca2+ in either Ca2+ efflux or Ca2+ influx mode, depending on the ion gradients across the plasma membrane and the membrane potential. In heart, smooth muscle cells, neurons, and nephron cells, the NCX is thought to play an important role in the regulation of intracellular Ca2+ concentration. Recently, a novel selective inhibitor (KB-R7943 and SEA0400) of the Ca2+ influx mode of the NCX has been developed. NCX inhibitor is expected to be a pharmaceutical agent that offers effective protection against ischemia/reperfusion injury in several organs such as heart and kidney. Here, we summarize pharmacological profiles of KB-R7943 and SEA0400, the molecular mechanism of its action, and its future prospect as a novel pharmaceutical agent.
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PMID:Development and application of Na+/Ca2+ exchange inhibitors. 1512 19

The Na+/Ca2+ exchanger (NCX) is the primary Ca2+ extrusion mechanism in cardiomyocytes. To further investigate the role of NCX in excitation-contraction coupling and Ca2+ homeostasis, we created murine models with altered expression levels of NCX. Homozygous overexpression of NCX resulted in mild cardiac hypertrophy. Decline of the Ca2+ transient and relaxation of contraction were increased and the reverse mode of NCX was augmented. Overexpression also led to a higher susceptibility to ischemia-reperfusion injury and to a greater ability of NCX to trigger Ca2+-induced Ca2+ release. Furthermore, an increase in peak L-type Ca2+ current was observed suggesting a direct influence of NCX on L-type Ca2+ current. Whereas global knockout of NCX led to prenatal death, a recently generated cardiac-specific NCX knockout mouse was viable with surprisingly normal contractile properties. Expression levels of other Ca2+-handling proteins were not altered. Ca2+ influx in these animals is limited by a decrease of peak L-type Ca2+ current. An alternative Ca2+ efflux mechanism, presumably the plasma membrane Ca2+-ATPase, is sufficient to maintain Ca2+-homeostasis in the NCX knockout mice.
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PMID:Genetic manipulation of cardiac Na+/Ca2+ exchange expression. 1533 80

We used Na+/Ca2+ exchanger (NCX) knockout mice to evaluate the effects of NCX in cardiac function and the infarct size after ischemia/reperfusion injury. The contractile function in NCX KO mice hearts was significantly better than that in wild type (WT) mouse hearts after ischemia/reperfusion and the infracted size was significantly smaller in NCX KO mice hearts compared with that in WT mice hearts. NCX is critically involved in the development of ischemia/reperfusion-induced myocardial injury, and therefore the inhibition of NCX function may contribute to cardioprotection against ischemia/reperfusion injury.
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PMID:Forefront of Na+/Ca2+ exchanger studies: role of Na+/Ca2+ exchanger--lessons from knockout mice. 1535 83

Calcium (Ca2+) overload is an important pathophysiological factor in myocardial ischemic/reperfusion injury. We investigated the effects of a cardioprotective drug, MCC-135, 5-methyl-2-(1-piperazinyl) benzenesulfonic acid monohydrate, on (1) cardiac contractile dysfunction and Ca2+ overload induced by ischemia and reperfusion, and (2) the Na+/Ca2+ exchanger in Langendorff-perfused rat hearts. Low-flow 45-min ischemia and 30-min reperfusion decreased developed tension and increased ventricular Ca2+ content, effects which were ameliorated by MCC-135 and amiloride given after reperfusion. Combination of intracellular Na+ overload induced by monensin (Na+ ionophore; 5 microM) and zero-flow 15-min ischemia followed by 30-min reperfusion resulted in a decrease in developed tension and in the intracellular Na+-dependent increase in ventricular Ca2+ content. MCC-135 and the highest dose of amiloride given after reperfusion reduced the increase in ventricular Ca2+ content, whereas developed tension was increased only with MCC-135. These results suggest that the cardioprotective effect of MCC-135 in ischemia/reperfusion is associated with suppression of Ca2+ overload and is attributable to inhibition of intracellular Na+-dependent Ca2+ influx via the Na+/Ca2+ exchanger.
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PMID:Cardioprotective effect of MCC-135 is associated with inhibition of Ca2+ overload in ischemic/reperfused hearts. 1536 65

Activation of the Na+/Ca2+ exchanger may contribute to Ca2+ overload during reperfusion after transient ischemia. We examined the effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a selective inhibitor of Na+/Ca2+ exchange, on a canine model of ischemia/reperfusion injury (myocardial stunning). Myocardial stunning was induced by a 15-min occlusion of the left anterior descending coronary artery followed by a 4-h reperfusion in anesthetized open-chest dogs. Reperfusion gradually restored myocardial percent segment shortening but remained depressed during a 4-h reperfusion period. A bolus intravenous injection of SEA0400 (0.3 or 1.0 mg/kg), given 1 min before reperfusion, improved significantly the recovery of percent segment shortening in the ischemic/reperfused myocardium. SEA0400 did not affect the hemodynamics and electrocardiogram parameters. In addition, SEA0400 did not affect reperfusion-induced change in coronary blood flow. These results suggest that the Na+/Ca2+ exchanger is involved in the stunned myocardium of dogs after reperfusion, and that SEA0400 has a protective effect against myocardial stunning in dogs.
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PMID:Effects of SEA0400, a novel inhibitor of the Na+/Ca2+ exchanger, on myocardial stunning in anesthetized dogs. 1555 49

In brain ischemia, gating of postsynaptic glutamate receptors and other membrane channels triggers intracellular Ca2+ overload and cell death. In excitotoxic settings, the initial Ca2+ influx through glutamate receptors is followed by a second uncontrolled Ca2+ increase that leads to neuronal demise. Here we report that the major plasma membrane Ca2+ extruding system, the Na+/Ca2+ exchanger (NCX), is cleaved during brain ischemia and in neurons undergoing excitotoxicity. Inhibition of Ca2+-activated proteases (calpains) by overexpressing their endogenous inhibitor protein, calpastatin or the expression of an NCX isoform not cleaved by calpains, prevented Ca2+ overload and rescued neurons from excitotoxic death. Conversely, down-regulation of NCX by siRNA compromised neuronal Ca2+ handling, transforming the Ca2+ transient elicited by non-excitotoxic glutamate concentrations into a lethal Ca2+overload. Thus, proteolytic inactivation of NCX-driven neuronal Ca2+ extrusion is responsible for the delayed excitotoxic Ca2+ deregulation and neuronal death.
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PMID:Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. 1568 Mar 32

Although hypercholesterolemia is a strong risk factor for cardiovascular disease, it has in some instances paradoxically been associated with reduced infarct size and preserved contractile function in isolated hearts after ischemia and reperfusion. To elucidate potential cellular protective mechanisms, myocytes of hypercholesterolemic apolipoprotein E-deficient (ApoE-/-) and wild-type mice were subjected to hypoxic metabolic inhibition (I) with subsequent reoxygenation (R). Intracellular Ca2+ concentration ([Ca2+]i) and pH (pHi) were monitored as well as cell length and arrhythmic events. Force measurements in papillary muscles were also recorded, and myocardial expression of Na+/H+ exchanger 1 (NHE1) and three Ca2+ handling proteins [sarco(endo)plasmic reticulum Ca2+-ATPase, Na+/Ca2+ exchanger, and plasma membrane Ca2+-ATPase] was quantified. After 30 min of I and 35 min of R, Ca2+ overload was more pronounced in wild-type cells (P < 0.05). In these myocytes, pHi also dropped faster and remained below those values determined in ApoE-/- cells (P < 0.05). Furthermore, more wild-type myocytes remained in a contracted state (P < 0.05). This group also showed a higher incidence of arrhythmic events during R (P < 0.05). No group difference was found in the expression of the Ca2+ handling proteins. However, NHE1 protein was downregulated in hearts of ApoE-/- mice (P < 0.05). Histological results depict hyperplasia in ApoE-/- hearts without atherosclerosis of the coronaries. Contractile dysfunction was not observed in papillary muscles from ApoE-/- hearts. Our results suggest that downregulated myocardial NHE1 expression in hypercholesterolemic ApoE-/- mice could have contributed to increased tolerance to I/R. It remains to be elucidated whether NHE1 downregulation is a unique feature of these genetically altered animals.
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PMID:Increased tolerance to hypoxic metabolic inhibition and reoxygenation of cardiomyocytes from apolipoprotein E-deficient mice. 1573 85


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