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)

Bepridil is an antianginal agent with multiple therapeutic actions. It decreases calcium influx through potential-dependent and receptor-operated sarcolemmic calcium channels and acts intracellularly as a calmodulin antagonist and calcium sensitizer. Thus, in cardiac muscle it enhances the sensitivity of troponin C to calcium, stimulates myofibrillar adenosine triphosphatase activity, removes calmodulin's inhibitory effect on sarcoplasmic reticulum calcium release, and inhibits sodium-calcium exchange--actions that tend to offset the effects of calcium influx blockade on cardiac contractile force. However, in vascular smooth muscle where the calcium-calmodulin complex promotes muscle contraction by activating myosin light-chain kinase phosphorylation of contractile proteins, calmodulin antagonism, coupled with bepridil's blockade of calcium influx, leads to vasorelaxation. In animal models of ischemia, bepridil and other calmodulin inhibitors show antiarrhythmic efficacy following reperfusion. Additionally, interfering with calmodulin's role in sympathetic nerve terminal function may help to limit the ischemia-induced catecholamine release that contributes to arrhythmogenesis. Bepridil shows a lidocaine-like fast kinetic block of inward sodium current (as distinct from the slow or intermediate kinetic inhibition expressed by encainide or quinidine, respectively). This inhibition is pH-dependent; activity is expressed to a greater degree at lower pH levels. This, this potentially antiarrhythmic mechanism is activated by conditions of ischemia. Bepridil's blockade of outward potassium currents and its inhibition of sodium-calcium exchange increase action potential duration and ventricular refractoriness, prolong the QT interval, and form the basis for a class III antiarrhythmic mechanism. Because hypokalemia also prolongs the QT interval, the addition of bepridil in the presence of hypokalemia can lead to excessive prolongation. Bepridil both increases myocardial oxygen supply through coronary vasodilation and decreases myocardial oxygen demand through mild heart rate and afterload reduction, and shows potential antiarrhythmic activity through class IB, III, and IV mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacology of bepridil. 137 85

In this review the pharmacologic properties of the calcium antagonist bepridil have been reexamined, particularly the evidence for an intracellular locus of action for the drug. Physicochemical properties of bepridil show it to be highly lipophylic, rapidly and extensively taken up, and accumulated in certain tissues. Combined electrophysiologic and mechanical studies have provided convincing, but indirect, evidence for an intracellular action of bepridil in cardiac muscle. Bepridil also fulfills, to a greater or lesser extent, certain important pharmacologic criteria necessary for evoking an intracellular action of a drug in cardiac and vascular smooth muscle: 1. Responses to agonists known to utilize intracellular calcium in the response are inhibited to a similar extent to depolarization-induced K+ responses. 2. Phasic and tonic responses to noradrenaline in vascular tissues are not, or are only to a minor extent, differentially antagonized. 3. Responses to the calcium ionophore A 23187 are antagonized. 4. Activity is retained following removal of the cell membrane by surfactants. 5. Isolated enzyme systems (e.g., calmodulin, myosin light-chain kinase) are affected by the drug at similar concentrations to those that are effective in whole cells or tissues. Finally results obtained with bepridil in ischemic myocardium have been reviewed to ascertain whether its broader pharmacologic spectrum over the calcium-entry blockers is associated with enhanced tissue protective properties. Positive results with bepridil in hypoxic myocytes and ischemic myocardium distinguishes this drug from the classical antianginal agents verapamil, nifedipine, and diltiazem. It is suggested that bepridil, because of its paucity of hemodynamic effects, may be of special therapeutic interest in the management of silent ischemia where cellular mechanisms leading to cytoprotection are more desirable than strong hemodynamic activity.
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PMID:Bepridil: a pharmacological reappraisal of its potential beneficial effects in angina and tissue protection following ischemia. 248 9

It is generally accepted that microvascular permeability is controlled by intercellular endothelial cell gap size. This process is controlled in endothelial cell monolayers and peripheral blood vessels by calmodulin (CaM)-dependent myosin light-chain kinase (MLCK), which phosphorylates MLC20 with subsequent actin-myosin interaction. In the present study both CaM and MLCK blockers were studied during ischemia-reperfusion (I/R)-induced injury in isolated buffer-perfused rat lungs. The effects of a calcium ionophore (CaI) were tested in isolated intact rat lungs to compare the effects of increasing intracellular Ca2+ to I/R-induced damage. Because protein kinase C (PKC) could also be a mediator of I/R injury, a PKC inhibitor was studied in lungs subjected to either I/R or CaI. In lungs subjected to I/R alone, a fivefold increase in microvascular permeability occurred after 30 min of reperfusion (P < 0.001), and a tenfold increase was present after an additional 60 min of reperfusion (P < 0.01). Pretreatment of the I/R lungs with a CaM inhibitor (trifluoperazine, 100 microM) or with a MLCK inhibitor (ML-7,500 nM) blocked the microvascular damage at both 30 and 90 min of reperfusion. When the CaM inhibitor was introduced into the venous reservoir after 46 min of reperfusion, after the microvascular damage was present, no further increase in microvascular permeability occurred. Pretreatment of the lungs with a PKC inhibitor (staurosporine, 100 nM) did not alter the magnitude of the increased microvascular permeability produced by I/R or the time course of the damage. The calcium ionophore A23187 (7.5 microM) caused increases in Kfc values similar to those produced by I/R. Pretreatment of A23187-treated lungs with a CaM inhibitor produced no protective effect on the microvascular injury at 30 min after administration. Pretreatment of the CaI-challenged lungs with staurosporine significantly increased the microvascular barrier injury at 30 min compared with that occurring with I/R. When a beta-adrenergic receptor agonist (isoproterenol, 10 microM) was introduced to the lung after CaI-induced damage had occurred, no further increase in microvascular permeability was observed, and a trend toward reversal of injury occurred. We conclude from these studies that CaM/MLCK/MLC20 system is involved in our model of I/R-induced rat lung injury but is not involved in lung injury associated with Ca2+ entering the cell.
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PMID:Role of calmodulin and myosin light-chain kinase in lung ischemia-reperfusion injury. 876 Jan 41

Not all possible mediators of lung I/R injury that have been studied, such as cyclooxygenase and lipoxygenase products, have been presented in this review, but it is very clear that oxygen free radicals are the primary mediators of the damage, regardless of their origin. Oxygen radicals are generated by neutrophils, which are sequestered and activated in the ischemic-reperfused pulmonary tissue, and by xanthine oxidase, which is upregulated by ischemia and/or activated neutrophils. The contributions to lung injury by different species of oxygen radicals may very depending upon the lung model used to study I/R. Also, nitric oxide may be injurious or protective in lung I/R injury, depending upon some critical alveolar PO2 level present either during ischemia or at reperfusion. I/R-induced lung microvascular injury ultimately depends upon some balance between lung metabolic stress, the extent of the I/R-induced inflammatory response, endogenous antioxidant levels, and the timing, magnitude, and duration of oxygen free radical generation during both periods of ischemia and reperfusion. The final common pathway causing microvascular permeability to increase after lung I/R is the activation of the endothelial cell's contractile machinery. Particularly, endothelial contraction may occur in a MLCK-dependent fashion. Endothelial contraction may also be related to an intracellular Ca++ increase and subsequent calmodulin activation. The initiating event causing increased intracellular Ca++ is not known, but may be due to endothelial cell/leukocyte interactions, oxygen radical-mediated Ca++ transients, mobilization of intracellular Ca++ pools by various second messengers, or stimulation of Ca++ influx secondarily to changes in the activity of membrane ion pumps such as the Na+/H+ antiport. Increasing cAMP levels in the postischemic lung can prevent and actually reverse I/R-induced microvascular injury, by affecting MLCK, the endothelial cell cytoskeleton, and/or the function of sequestered leukocytes. Also, cAMP elevation aids the resolution of pulmonary edema by facilitating capillary fluid reabsorption. Whatever the mechanism, elevation of cAMP in the setting of lung I/R injury represents a potentially useful therapy for improving early lung function following lung transplantation. Finally, additional studies are necessary to elucidate the complete mechanisms responsible for producing microvascular injury during lung I/R. Specifically, a better understanding of the relationships between the many factors required to produce lung damage is needed. Many interventions into the lung I/R process provide protection against microvascular injury, suggesting that regulation of the endothelial barrier permeability to fluid, protein, and leukocytes is accomplished by several redundant systems. This situation may be similar to mechanisms reported to regulate the immune response mediated by T cells (62a), where T cell activation depends upon multiple signal inputs for the full immune response to occur. Thus, multiple signals in a correct sequence delivered to the endothelium may be necessary to produce the microvascular injury associated with lung ischemia and reperfusion.
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PMID:Endothelial damage caused by ischemia and reperfusion and different ventilatory strategies in the lung. 890 6

Myosin from cardiac muscle consists of two heavy chains and two pairs of light chain. Regulatory myosin light chain (RMLC) is phosphorylated by a Ca2+ and calmodulin dependent myosin light chain kinase. The impact of experimental myocardial infarction on cardiac RMLC was studied. The left anterior descending coronary artery of rabbits was ligated. Three, 7 and 14 days later the animals were euthanized, sections of the heart were frozen in liquid nitrogen and later subjected to 2-dimensional electrophoresis. Isoelectric focusing was carried out at a pH range of 4.5-5.4. Reproducible patterns of protein separation showed four spots with proteins of phosphorylatable regulatory light chains shifted to a more negative pH as compared to essential light chain. We investigated changes in phosphorylation of RMLC in infarcted heart muscle. As compared to sham operated animals, a decline in phosphorylation of RMLC was present in both infarcted and non-infarcted portions of the left ventricle; the latter was significant 7 days following the onset of ischemia. In contrast, the decline in percent phosphorylation in the infarcted area was not significant. The amount of RMLC decreased significantly in the infarcted portion. A highly significant reduction in the percent of viable cardiomyocytes accompanied the decline in phosphorylation. There was a significant correlation of RMLC following administration of isoproterenol, 7 and 14 days following onset of ischemia. Only faint traces of essential atrial myosin light chain (ALC-1) were present in the non-infarcted portion of the left ventricle. No correlation was found between percent phosphorylation and the amount of RMLC (density) following infusion of saline or isoproterenol. Isoproterenol significantly increased percent phosphorylation without altering the amount of RMLC protein. We conclude that myocardial infarction profoundly affects regulatory myosin light chain phosphorylation in the infarcted and non-infarcted areas of the myocardium and that RMLC plays a significant part in myocardial contractility.
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PMID:Myocardial infarction and regulatory myosin light chain. 934 59

We studied N-methyl-D-aspartate (NMDA) receptor-mediated synaptic potentials in CA1 pyramidal neurons using hippocampal slices of gerbils after transient forebrain ischemia. In the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and bicuculline, stimulation of Schaffer collateral/commissural fibers induced field excitatory postsynaptic potentials (fEPSP) activated by NMDA receptors. We found that in many slices after ischemia, prolonged low-frequency stimulation (0.1-10 Hz) caused repeated depression and potentiation of the NMDA-mediated fEPSP. Changes in fEPSP amplitude were dependent on stimulus frequency and the cycle frequency ranged from 0.08 to 2.5 cycles/min. These cyclic changes were blocked by application of BAPTA-AM, a membrane-permeable Ca2+ chelator, but were little affected by application of verapamil or by lowering the Ca2+ in bathing solution. Intracellular recordings from CA1 neurons revealed that low-frequency stimulation caused periodic depolarizations of membrane potential accompanied by depression of the excitatory postsynaptic potentials. The cyclic changes of fEPSPs were blocked by inhibitors of protein kinase C (PKC) but were unaffected by inhibitors of Ca2+/calmodulin-dependent protein kinase II (CaMKII) or myosin light-chain kinase (MLCK). These results suggest that stimulus-dependent NMDA-receptor activation, mediated by PKC, takes place in the postischemic CA1 neurons and that the cyclic change may reflect abnormal intracellular Ca2+ signaling processes leading to neuronal degeneration.
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PMID:Cyclic changes in NMDA receptor activation in hippocampal CA1 neurons after ischemia. 952 18

To profile gene expression patterns involved in ischemic preconditioning, we monitored global gene expression changes by DNA microarray analysis of 3200 rat-specific genes and by real-time quantitative polymerase chain reaction in rat hearts. Forty-nine genes with altered expression were found after ischemia/reperfusion as compared to control non-ischemic hearts and 31 genes were characteristic for classic preconditioning followed by ischemia/reperfusion as compared to ischemia/reperfusion without preconditioning. Genes with altered expression due to ischemia and/or preconditioning included those controlling protein degradation, stress responses, apoptosis, metabolic enzymes, regulatory proteins, and several unknown cellular functions. Metallothionein, natriuretic peptides, coagulation factor VII, cysteine proteinase inhibitor, peroxisome proliferator activator receptor gamma and myosin light chain kinase genes were previously suspected to be related to several cardiovascular diseases, however, most of these genes have not previously been shown to be related to myocardial ischemia/reperfusion. Some genes were observed to change specifically in response to preconditioning: oligoadenylate synthase, chaperonin subunit epsilon, a cGMP phosphodiesterase (PDE9A1), a secretory carrier membrane protein, an amino acid transporter, and protease 28 subunit. None of these genes has previously been shown to be involved in the mechanism of preconditioning.
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PMID:Effect of classic preconditioning on the gene expression pattern of rat hearts: a DNA microarray study. 1258 34

Excessive excitatory amino acid (EAA) release in cerebral ischemia is a major mechanism responsible for neuronal damage and death. A substantial fraction of ischemic EAA release occurs via volume-regulated anion channels (VRACs). Hydrogen peroxide (H2O2), which is abundantly produced during ischemia and reperfusion, activates a number of protein kinases critical for VRAC functioning and has recently been reported to activate VRACs. In the present study, we explored the effects of H2O2 on volume-dependent EAA release in cultured astrocytes, measured as the release of preloaded D-[3H]aspartate. 100-1,000 microm H2O2 enhanced swelling-induced EAA release by approximately 2.5-3-fold (EC50 approximately 10 microM). The VRAC blockers ATP, phloretin, and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) potently inhibited both control swelling-induced and the H2O2-potentiated release, suggesting a role for VRACs. The H2O2-induced component of EAA release was attenuated by the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM) and completely eliminated by the calmodulin antagonists trifluoperazine and W-7 and the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93. Inhibitors of tyrosine kinases, protein kinase C, and the myosin light chain kinase were ineffective in blocking the H2O2 response. H2O2 treatment of swollen astrocytes, but not swelling alone, resulted in CaMKII activation that was inhibited by KN-93, as determined by a phospho-Thr286 CaMKII antibody. These data demonstrate that H2O2 strongly up-regulates astrocytic volume-sensitive EAA release via a CaMKII-dependent mechanism and in this way may potently promote pathological EAA release and brain damage in ischemia.
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PMID:Hydrogen peroxide potentiates volume-sensitive excitatory amino acid release via a mechanism involving Ca2+/calmodulin-dependent protein kinase II. 1556 71

The aim of this study was to explore the effect of bone morphogenetic protein-2 (BMP-2) and fibroblast growth factor-2 (FGF-2)- paracrine factors implicated in both cardiac embryogenesis and cardiac repair following myocardial infarction (MI)-on murine bone marrow stem cell (mBMSC) differentiation in an ex vivo cardiac microenvironment. For this purpose, green fluorescent protein (GFP) expressing hematopoietic lineage negative (lin-) c-kit ligand (c-kit) and stem cell antigen-1 (Sca-1) positive (GFP-lin-/c-kit+/sca+) mBMSC were co-cultured with neonatal rat ventricular cardiomyocytes (NVCMs). GFP+ mBMSC significantly induced the expression of BMP-2 and FGF-2 in NVCMs, and approximately 4% GFP+ mBMSCs could be recovered from the co-culture at day 10. The addition of BMP-2 in concert with FGF-2 significantly enhanced the amount of integrated GFP+ mBMSCs by 5-fold ( approximately 20%), whereas the addition of anti-BMP-2 and/or anti-FGF-2 antibodies completely abolished this effect. An analysis of calcium cycling revealed robust calcium transients in GFP+ mBMSCs treated with BMP-2/FGF-2 compared to untreated co-cultures. BMP-2 and FGF-2 addition led to a significant induction of early (NK2 transcription factor related, locus 5; Nkx2.5, GATA binding protein 4; GATA-4) and late (myosin light chain kinase [MLC-2v], connexin 43 [Cx43]) cardiac marker mRNA expression in mBMSCs following co-culture. In addition, re-cultured fluorescence-activated cell sorting (FACS)-purified BMP-2/FGF-2-treated mBMSCs revealed robust calcium transients in response to electrical field stimulation which were inhibited by the L-type calcium channel (LTCC) inhibitor, nifedipine, and displayed caffeine-sensitive intracellular calcium stores. In summary, our results show that mBMSCs can adopt a functional cardiac phenotype through treatment with factors essential to embryonic cardiogenesis that are induced after cardiac ischemia. This study provides the first evidence that mBMSCs with long-term self-renewal potential possess the capability to serve as a functional cardiomyocyte precursor through the appropriate paracrine input and cross-talk within an appropriate cardiac microenvironment.
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PMID:BMP-2 and FGF-2 synergistically facilitate adoption of a cardiac phenotype in somatic bone marrow c-kit+/Sca-1+ stem cells. 2044 32

We have previously shown an important role of the chloride channel ClC-2 in orchestrating repair of tight junctions in ischemia-injured mucosa. In this study, we examined the role of ClC-2 in regulating barrier function of normal murine intestinal mucosa. Ex vivo, ClC-2-/- ileal mucosa mounted in Ussing chambers had significantly higher transepithelial electrical resistance (TER) and reduced [(3)H]mannitol mucosal-to-serosal flux compared with wild-type (WT) mouse mucosa. We also noted that ileum from ClC-2-/- mice had a significantly reduced in vivo [(3)H]mannitol blood-to-lumen clearance compared with WT animals. By scanning electron microscopy, flat leaflike villi were found to have tapering, rounded apical tips in ClC-2-/- mucosa. By transmission electron microscopy, the apical intercellular tight junctions in ClC-2-/- intestine revealed lateral membranes that were less well defined but closely aligned compared with electron-dense and closely apposed tight junctions in WT mucosa. The width of apical tight junctions was significantly reduced in ClC-2-/- intestine. Such an alteration in tight junction ultrastructure was also noted in the testicular tissue from ClC-2-/- mice. The ClC-2-/- intestinal mucosa had reduced expression of phospho-myosin light chain (MLC), and inhibition of myosin light chain kinase (MLCK) in WT mucosa partially increased TER toward the TER in ClC-2-/- intestine. Contrary to our prior work on the reparative role of ClC-2 in injured mucosa, this study indicates that ClC-2 reduces barrier function in normal mucosa. The mechanisms underlying these differing roles are not entirely clear, although ultrastructural morphology of tight junctions and MLCK appear to be important to the function of ClC-2 in normal mucosa.
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PMID:ClC-2 regulates mucosal barrier function associated with structural changes to the villus and epithelial tight junction. 2048 43


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