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)

KATP channels play an important role in physiology and pathophysiology of many tissues. As in the pancreatic beta cells, they couple the change of blood glucose with insulin release. The data coming from Baukrowitz et al. and Shyng and Nichols gave the possible answers to the two old enigmas of KATP channels, i.e., different ATP sensitivity reported in the same tissue and how the channel opened under intracellular millimolar ATP concentration, in which they showed the lipids and lipid metabolites are essential for KATP channel regulation by altering ATP sensitivity. This new information rises several further considerations. How does PIP2 reduce the sensitivity of the channel to ATP? In order to clarify the possibility of direct competing or allosteric effect on the ATP binding site, competitive binding assay should be performed. Since the PIP2 theory seems to be the key event to determine the ATP sensitivity and thus control the channel open probability, then what is the resting concentration of PIP2 in the cell membrane? Is it sufficient to account for the difference in the ATP sensitivity of the intact cell and excised patch from different tissues? Quantitative studies either immunoblotting by PIP2 antibody or fluorescence-labeled lipid assay-may obtain some basic but useful data for further studies to answer these questions. Furthermore, the ATPi mediated restoration of activity was inhibited by antibodies against PIP2. The dualistic behavior of KATP channels to intracellular NDPs should be reexamined with respect to PIP2. The vast majority of preconditioning studies has been performed in intact animals in which myocardial infarct size was used as the end point to define the cardio-protective effect of ischemic PC. These results suggest a key role for the KATP channel as both a trigger and as an end effector of both acute and delayed ischemic PC. The persistent activation of KATP channels during the early reperfusion phase is essential for a smooth and full recovery of contractile function, as well as for maintenance of electrical stability in heart that has been exposed to ischemia. Though activate adenosine A1 receptor coupled with Gi protein can open the KATP channels, adenosine is quickly released during ischemia and exerts potent coronary vasodilatation to maintain coronary blood flow through A2 receptors. This adenosine-induced coronary vasodilatation could be coupled with KATP channels based on the evidence of the augmentation effect of KCOs. Nitric oxide may also play some role in both first and second window of myocardial protection. It is possible that rapid and reversible phosphorylation and activation of constitutive expressed myocardial NOS or by direct KATP channel phosphorylation and activation leads to the first window of myocardial protection. This hypothesis can be further investigated either by using site direct mutagenesis of iNOS or KATP channel, or by applying the dominant negative iNOS in the cell ischemic model, or by building the adenosine or iNOS knock-out mice to study the relationship of these possible mechanisms. Recently, Kontos further showed that KCOs need L-lysine or L-arginine to dilate cerebral arterioles. This suggests that there may be an amino acid binding site inside the KATP channel and nitric oxide can open the KATP channel either by direct acting on the channel protein or by modulating the affinity of the amino acid binding site for L-lysine or L-arginine. Other KATP channel openers in need of additional characterization are the Type III KCOs (nicorandiol). They open the KATP channel only in the presence of elevated intracellular NDPs, which may make them specifically target to the ischemic region, because the intracellular NDP increases mostly in ischemic region. It is possible that type III KCOs can selectively improve blood flow to ischemic areas without diverting blood away to non-ischemic region, and prevents the "steal phenomenon". (ABSTRACT TRUNCATED)
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PMID:ATP sensitive potassium channel and myocardial preconditioning. 1060 45

LY341122 (2-(3, 5-di-t-butyl-4-hydroxyphenyl)-4-(2-(4-methylethylaminomethyl-ph enylox y)ethyl)oxazole) is a potent inhibitor of lipid peroxidation which has been shown to protect against global ischemia and traumatic brain injury in rats. The purpose of this study was to examine the effect of LY341122 on ischemic injury in a highly reproducible model of focal cerebral ischemia in rats. Male Sprague-Dawley rats were anesthetized with halothane and subjected to 120 min of temporary middle cerebral artery occlusion by retrograde insertion of an intraluminal nylon suture coated with poly-L-lysine. The drug (LY341122, n=19) or vehicle (phosphate-buffered saline (PBS), n=10) was administered i.v. (as a 5 or 10 mg/kg bolus followed by a 5 or 10 mg/kg/h infusion for 20 h, respectively, starting 1 or 2 h after the onset of middle cerebral artery occlusion). Neurological status was evaluated during middle cerebral artery occlusion (60 min) and daily for 3 days thereafter. Three days after ischemia, brains were perfusion-fixed and infarct volumes and brain edema were determined. LY341122 significantly improved the neurological score compared to vehicle at 24, 48 and 72 h after middle cerebral artery occlusion. Treatment with LY341122 significantly reduced total infarct volume in all treated groups compared to vehicle rats. Cortical infarct volume was significantly reduced by LY341122 treatment in the 10 mg/kg (1 h) and LY341122 10 mg/kg (2 h) groups compared to vehicle rats (14.7+/-9.5 vs. 106.8+/-20.9 mm(3), and 36.9+/-20.1 vs. 106. 8+/-20.9 mm(3), respectively (mean+/-S.E.M.)). Striatal infarct volume was also significantly reduced by treatment with LY341122 in the 10 mg/kg (1 h) group compared to vehicle (23.7+/-3.4 vs. 68. 2+/-6.7 mm(3)). These results demonstrate the neuroprotective efficacy of LY341122 in focal cerebral ischemia.
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PMID:Neuroprotection by LY341122, a novel inhibitor of lipid peroxidation, against focal ischemic brain damage in rats. 1068 99

Tissue damage resulting from ischemia due to myocardial infarction is thought to be intensified by the proteolytic action of endogenous enzymes. Calpain (calcium dependent cysteine protease) is considered to be a highly likely candidate, since it is activated by calcium ion which increases in concentration under conditions of ischemia. We prepared a mono-specific antibody against the active site histidine stretch, Lys-Leu-Val-Lys-Gly-His-Ala-Tyr-Ser-Val, in the calpain 80 kDa large subunit. The specificity of the antibody was verified by its inhibitory effect on the caseinolytic activity of both mu- and m-calpains, western blotting analysis, and by absorption with the antigen peptide. The antibody was used to localize the intracellular distribution of activated calpains in infarcted regions of the human heart. The results showed that myocardial cells affected by ischemia were stained by the antibody, allowing damaged cells to be distinguished from cells of unaffected regions and that the immunostained regions were essentially the same regions as those identified by dense eosinophilic staining with hematoxylin and eosin. However, the staining pattern obtained with the antibody, was characteristic in denser staining at the cell periphery, whereas the damaged cells were stained homogeneously by hematoxylin and eosin. By the former method, results of staining indicated that the activation site of the calpain proenzyme was in the peri-plasma membrane, whereas by the latter method, diffusely distributed plasma proteins such as albumin and immunoglobulins were visualized as demonstrated in earlier reports.
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PMID:Activation of calpain in myocardial infarction: an immunohistochemical study using a calpain antibody raised against active site histidine-containing peptide. 1072 43

Basic fibroblast growth factor (FGF-2) may protect the heart from ischemia-reperfusion injury (stunning) by stimulating nitric oxide (NO) production. To test this hypothesis, we pretreated coronary-perfused mouse hearts with 1 microg/ml FGF-2 or vehicle control before the onset of ischemia. Intracellular calcium (Ca(i)(2+)) was estimated by aequorin, and NO release was measured with an NO-selective electrode. Hearts perfused with FGF-2 maintained significantly better left ventricular (LV) function during ischemia than hearts perfused with vehicle. FGF-2 significantly delayed the onset of ischemic contracture and improved LV recovery during reperfusion. Ca(i)(2+) was similar in both groups at baseline during ischemia and reperfusion. L-N(6)-(1-iminoethyl)lysine, a selective inhibitor of inducible NO synthase (NOS2), obliterated the protective effects of FGF-2. In transgenic hearts deficient in the expression of NOS2 (NOS2-/-), FGF-2 did not attenuate ischemia-induced LV dysfunction. Measurements of NO release demonstrated that FGF-2 perfusion significantly increased NO in wild-type but not in NOS2-/- hearts. We conclude that basic FGF attenuates myocardial stunning independent of alterations in Ca(i)(2+) by stimulating NO production via an NOS2-dependent pathway.
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PMID:Basic FGF reduces stunning via a NOS2-dependent pathway in coronary-perfused mouse hearts. 1089 65

Recent studies of transient focal ischemia have focused interest on apoptotic mechanisms of neuronal cell death involving constitutive pro-apoptotic proteins. The finding of specific patterns of novel gene expression might indicate the activation of pro-apoptotic genes in previously ischemic areas. Thus, we investigated gene expression for the pro-apoptotic regulators, Bax and caspase-3, after transient focal brain ischemia, together with the p53-regulated cell cycle inhibitor, p21/WAF1/CIP1. Reversible occlusion of the middle cerebral artery for 2 h was carried out in halothane-anesthetized rats using the poly-L-lysine coated filament method. In situ hybridization was performed at 0, 1, 3, 6 h and 1, 3 and 7 d of recirculation and in sham controls. Radioactive antisense probes served for detection of bax, p21 and caspase-3 mRNAs on brain sections, and quantitative film autoradiography was combined with image-averaging techniques. Bax mRNA tended to decline after focal brain ischemia within 1 d. p21 mRNA was upregulated with a perifocal pattern at 3 h and 1 d after ischemia whereas the ischemic regions themselves failed to show significant upregulation. Caspase-3 mRNA was elevated in the resistant dorsomedial cortex at 1 d. A pro-apoptotic pattern of novel gene expression, involving Bax and caspase-3, was not observed after transient focal brain ischemia. Rather, the perifocal expression of p21 and caspase-3 mRNAs observed at 1 d after ischemia points to reactive changes in resistant brain areas.
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PMID:Differential changes of bax, caspase-3 and p21 mRNA expression after transient focal brain ischemia in the rat. 1092 46

Reactive oxygen species are suggested to participate in ischemia-reperfusion (I-R) injury. However, induction of inducible nitric oxide synthase (iNOS) and production of high levels of nitric oxide (NO) also contribute to this injury. NO can combine with superoxide to form the potent oxidant peroxynitrite (ONOO(-)). NO and ONOO(-) were investigated in a rat model of renal I-R injury using the selective iNOS inhibitor L-N(6)-(1-iminoethyl)lysine (L-NIL). Sprague-Dawley rats were subjected to 40 min of bilateral renal ischemia followed by 6 h of reperfusion with or without L-NIL administration. Control animals received a sham surgery and had plasma creatinine values of 0.4 +/- 0.1 mg/dl. I-R surgery significantly increased plasma creatinine levels to 1.9 +/- 0.3 mg/dl (P <.05) and caused renal cortical necrosis. L-NIL administration (3 mg/kg) in animals subjected to I-R significantly decreased plasma creatinine levels to 1.2 +/- 0.10 mg/dl (P <.05 compared with I-R) and reduced tubular damage. ONOO(-) formation was evaluated by detecting 3-nitrotyrosine-protein adducts, a stable biomarker of ONOO(-) formation. Immunohistochemistry and HPLC revealed that the kidneys from I-R animals had increased levels of 3-nitrotyrosine-protein adducts compared with control animals. L-NIL-treated rats (3 mg/kg) subjected to I-R showed decreased levels of 3-nitrotyrosine-protein adducts. These results support the hypothesis that iNOS-generated NO mediates damage in I-R injury possibly through ONOO(-) formation.
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PMID:Evidence for peroxynitrite formation in renal ischemia-reperfusion injury: studies with the inducible nitric oxide synthase inhibitor L-N(6)-(1-Iminoethyl)lysine. 1099 9

Patients suffering from myocardial ischemia reportedly exhibit reduced in vitro binding of exogenous Co(2+) to the N-terminal of human serum albumin (HSA). The purpose of our investigation was to simulate changes in the N-terminus of HSA that may account for these ischemia-induced modifications to the cobalt binding site. HPLC, LC-MS and (1)H NMR analyses have shown that the N-terminal region of HSA Asp-Ala-His-Lys binds the transition metals Co(2+) and Ni(2+). Synthetic peptides with the first 2-12 amino acids of the HSA sequence demonstrated that the first three amino acids, Asp-Ala-His, are essential for strong binding of cobalt. Modification of the N-terminus peptide of HSA by way of N-acetylation or the deletion of one or more amino acid resulted in no binding of cobalt. Because the degradation of the susceptible, specific transition metal binding site of HSA may account for the decreased cobalt binding observed during ischemic events, an assay that detects this reduced binding could be useful in the diagnosis of ischemia.
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PMID:Characterization of the Co(2+) and Ni(2+) binding amino-acid residues of the N-terminus of human albumin. An insight into the mechanism of a new assay for myocardial ischemia. 1112 Nov

Dietary polyunsaturated fatty acids (PUFAs) prevent ischemia-induced fatal cardiac arrhythmias in animals and probably in humans. This action results from inhibition of ion currents for Na+, Ca2+, and possibly other ions. To extend understanding of this protection we are seeking a possible binding site for the PUFAs on the alpha-subunit of the human cardiac Na+ channel, hH1alpha, transiently expressed in HEK293t cells. Three mutated single amino acid substitutions with lysine were made in the alpha-subunit at Domain 4-Segment 6 (D4-S6) for F1760, Y1767 and at D1-S6 for N406. These are in the putative sites of binding of local anesthetics and batrachotoxin, respectively. The mutants F1760K, Y1767K, and N406K, separately and to different extents, affected the current density, the steady-state inactivation potential, accelerated inactivation, delayed recovery from inactivation, and affected voltage-dependent block, but did not affect activation of the hH1alpha. It is essential to learn that single point mutations in D1-S6 and D4-S6 alone significantly modify the kinetics of human cardiac hH1alpha Na+ currents. The effects of PUFAs on these mutant channels will be the subject of subsequent reports.
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PMID:Point mutations in alpha-subunit of human cardiac Na+ channels alter Na+ current kinetics. 1117 58

The involvement of nitric oxide synthase (NOS) in ischemia was evaluated by detecting the expression of neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS) by the immunohistochemical method in the rat model of middle cerebral artery (MCA) occlusion. Transient MCA occlusion (2 hours) was induced in 32 male Wistar rats by extracranial insertion of a 3-0 nylon thread through the internal carotid artery into the MCA. Animals were killed at 0, 6, 24, 72, and 168 hours after MCA occlusion (n = 6, 6, 8, 6, and 6, respectively). The brains were fixed with periodate-lysine-paraformaldehyde, frozen, and sectioned. Sections were stained with polyclonal antibody against nNOS, eNOS, and iNOS. Each section was evaluated by microscopic observation (x100). The number of nNOS-positive neurons was 41.6 +/- 5.8 (mean +/- SD) in the control hemisphere. nNOS was upregulated in the ischemic hemisphere (88.3 +/- 18.9), especially in the border zone at 6 hours after MCA occlusion. However, the number decreased to 36.4 +/- 3.6 and 26.3 +/- 7.3 in the ischemic hemisphere after 72 and 168 hours, respectively. eNOS immunoreactivity was present in the endothelium of major vessels at each time point. eNOS was not detected in the microvessels before ischemia, but faint staining was found in the endothelium at 6 hours after MCA occlusion. Immunostaining became more intense thereafter. Faint iNOS immunoreactivity was seen in the microvessels at 6 hours after MCA occlusion. Macrophages in the ischemic core and astrocytes in the border zone showed immunoreactivity to iNOS at 72 and 168 hours after MCA occlusion. Three types of NOS must be related to different stages of ischemic brain damage. nNOS may be neurotoxic in ischemia in the early phase, like iNOS in the late phase. On the other hand, eNOS seemed to be neuroprotective in all stages. These observations suggest the necessity for tailored therapeutic intervention against NOS isoforms at each stage in patients with ischemic stroke.
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PMID:Time course of expression of three nitric oxide synthase isoforms after transient middle cerebral artery occlusion in rats. 1125 30

Inducible nitric oxide synthase (NOS 2) is thought to play a role in gut motility disorders that occur under proinflammatory conditions. Clinically, ileus occurs after sepsis and shock-induced gut ischemia/reperfusion (I/R). The purpose of this study was to determine if NOS 2 mediates impaired intestinal transit in well-established models of both moderate and severe gut ischemia/reperfusion. At laparotomy, Sprague-Dawley rats had duodenal catheters placed. Small intestinal transit was determined by quantitating the percentage tracer (FITC-dextran) in 10 equal segments of intestine 30 min after catheter injection [expressed as the mean geometric center (MGC) of distribution]. Transit was assessed at 6 and 24 h after gut ischemia [45 or 75 min of superior mesenteric artery occlusion (SMAO) with sham laparotomy as control]. In a separate set of experiments, N(6)-(iminoethyl)-L-lysine (L-NIL), a selective NOS 2 antagonist, was administered 1 h prior to laparotomy and transit was determined after 6 h as described above. Ileal NOS 2 expression was assessed by Western immunoblot and quantitative "real-time" RT-PCR. We observed that both 45 and 75 min of SMAO decreased intestinal transit at 6 h of reperfusion compared to sham. Ileal NOS 2 mRNA and protein were increased after 75, but not 45, min of SMAO. In addition, L-NIL improved transit after 75, but not 45, min of SMAO. We conclude that (1) NOS 2 is upregulated in the gut only after more severe ischemic insults, and (2) ileus is mediated, at least in part, by NOS 2 under these conditions.
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PMID:Inducible nitric oxide synthase mediates gut ischemia/reperfusion-induced ileus only after severe insults. 1134 91


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