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)

During reperfusion with pH 7.2 media after 55 min of ischemia, the recovery of developed tension (DT) and the maximal resting tension (RT) of the isolated right ventricular wall of rats were 58.8 +/- 6.5 and 201 +/- 20%, respectively, of the preischemic values. DT and RT in the ventricular wall perfused with pH 7.9 media for 6 min during reperfusion were 40 +/- 5.9 and 285 +/- 13%, respectively, of the preischemic values (P less than .05 vs. pH 7.2 group). The Na(+)-H+ exchange inhibitor, 5-(N,N-dimethyl)amiloride (DMA), effectively antagonized the detrimental effect of pH 7.9 media. A pH 6.5 media inhibited DT recovery and the rise in RT in the first 6 min of reperfusion. Subsequent reperfusion with pH 7.2 media resulted in cardiac dysfunction similar to that observed when reperfused at pH 7.2 only. Cellular Na+ and Ca++ were significantly elevated after 6 min of reperfusion at pH 7.2. Na+ and Ca++ levels were increased further if reperfusion was carried out at pH 7.9. Inclusion of 20 microM DMA during reperfusion at 7.9 significantly reduced cellular Na+ and Ca++. Creatine phosphokinase activity in the coronary effluent rose significantly during reperfusion at pH 7.2 and this was exacerbated if the reperfusion pH was 7.9. DMA treatment during reperfusion could significantly inhibit this elevation. The data lend further support for an important role of Na(+)-H+ exchange in the development of ischemia-reperfusion injury.
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PMID:Influence of perfusate pH on the postischemic recovery of cardiac contractile function: involvement of sodium-hydrogen exchange. 165 37

During reperfusion in the isolated right ventricular wall of the rat after 60 min of ischemia, developed tension and resting tension were 35 +/- 4 and 221 +/- 12%, respectively, of preischemic values. Including 35 microM ouabain in the perfusate before and after ischemia resulted in more severe cardiac dysfunction during reperfusion than in drug-untreated hearts. Introduction of the Na(+)-H+ exchange inhibitor, 5-(N,N-dimethyl)-amiloride (DMA), could effectively protect the right ventricular wall against ischemia-reperfusion dysfunction in the presence or absence of ouabain. The ion content in the right ventricular wall was measured with atomic absorbance spectrophotometry. Before ischemia, Na+,Ca++ and K+ content were 53.4 +/- 6.4, 2.70 +/- 0.22 and 262 +/- 7.7 mumol/g of dry weight tissue, respectively. After 60 min of ischemia and 6 min of reperfusion, Na+,Ca++ and K+ content were 73.4 +/- 7.2, 3.79 +/- 0.31 and 180 +/- 15 mumol/g of dry weight tissue, respectively (P less than .05). Introduction of 20 microM DMA normalized ion content in the muscles which was consistent with the contractile function recovery during reperfusion. The data suggest that a rise in intracellular Na+ in the early stage of reperfusion represents a crucial or primary step for the development of cardiac contractile dysfunction. DMA, which protects against severe reperfusion-induced cardiac contractile dysfunction, appears to act via a normalization of tissue sodium levels. This action is consistent with its proposed role as a blocker of transsarcolemmal Na(+)-H+ exchange.
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PMID:Involvement of sodium in the protective effect of 5-(N,N-dimethyl)-amiloride on ischemia-reperfusion injury in isolated rat ventricular wall. 200 74

An Na(+)-H+ exchange inhibitor, 5-(N,N-dimethyl)amiloride (DMA), was used to probe the possible role of Na(+)-H+ exchange in ischemia-reperfusion injury in coronary perfused isolated rat right ventricular wall. In DMA-untreated hearts, 60 min of ischemia resulted in a significant rise in testing tension (RT: 174 +/- 8% of preischemic level). Thirty minutes of reperfusion further increased RT (273 +/- 12%) and induced a poor recovery in developed tension (DT: 28 +/- 4%). Both the rate of tension development and relaxation (+dT/dt and -dT/dt) recovered to a similar degree. When 1, 5, or 20 microM DMA was included in the perfusate (3 min before ischemia and in the first 3 min of reperfusion), the maximal postischemic RT of the heart was reduced to 204 +/- 21, 166 +/- 15, and 139 +/- 45% of the preischemic levels (P less than 0.05), respectively, and DT was 39 +/- 3, 63 +/- 10, and 79 +/- 8% of the preischemic levels (P less than 0.05), respectively. Similar qualitative recovery of +/- dT/dt was observed. Recovery was similar if DMA was present only during reperfusion. DMA treatment also significantly protected against creatine phosphokinase release during reperfusion. The results demonstrate that DMA can significantly protect the heart during the initial stages of reperfusion. The data suggest that Na(+)-H+ exchange may play an important role in the development of cardiac dysfunction and damage during the first minutes of reperfusion.
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PMID:Protective effects of 5-(N,N-dimethyl)amiloride on ischemia-reperfusion injury in hearts. 233 91

A lecithin-emulsified "Pluronic F-68"-free perfluorochemical compound, named F-1,3-DMA, was tested as a new agent in the prevention of central nervous tissue ischemia. A permanent ischemia leading to cerebral infarction was induced after microsurgical exposure and occlusion of the internal carotid, anterior, and middle cerebral arteries in the rabbit. Following arterial occlusion, F-1,3-DMA was administered intravenously, in a solution rendered isotonic to plasma, over a 30 minute period. The F-1,3-DMA was well tolerated. Hemodynamic, cardiovascular and metabolic parameters were not affected by the infusion of F-1,3-DMA. Although PO2 remained virtually unchanged, animals treated with F-1,3-DMA (n = 9), had smaller infarct volume by 61 percent as compared to the control (n = 8) group (P < 0.04, Student's t-test). Histopathology did not reveal any F-1,3-DMA related damage in the non-infarcted brain. These results suggest that F-1,3-DMA has nervous tissue ischemia protective properties possibly because of microflow effects although O2 transport to "local" tissue may be enhanced as well. We believe that further research is necessary in order to make clinical trials of F-1,3-DMA possible.
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PMID:Effects of lecithin-emulsified perfluorochemical compounds in ischemic brain injury. 805 99

The purpose of the present study was to compare the protective effects of amiloride and three of its derivatives (which are selective inhibitors of Na(+)-H+ exchange) during postischemic reperfusion. Previously, amiloride has been shown to have a protective effect on ischemia-reperfusion injury. However, because of its nonselective actions, the mechanism of its effect is unclear. 5-(N,N-dimethyl)-amiloride (DMA) is also protective and appears to act via inhibition of the Na(+)-H+ exchanger. However, corroborative effects using other selective Na(+)-H+ exchange blockers are needed. Amiloride, DMA, ethylisopropyl amiloride (EIPA), and 5-(N,N-hexamethylene)-amiloride (HMA) were included for 10 min in the reperfusion period after 60 min of global ischemia in the rat right ventricular wall. Peak developed tension and the rates of tension generation and relaxation were significantly improved during reperfusion in the presence of 100 microM amiloride, 10 microM DMA, 2.5 microM HMA, or 1 microM EIPA compared with those of drug-untreated muscles. Contracture formation was significantly depressed in the presence of these drug concentrations as was release of creatine kinase from the ventricular wall into the coronary effluent. The efficacy of these drugs for protecting the right ventricular wall from postischemic contractile dysfunction correlates well with their potency as blockers of Na(+)-H+ exchange. The results provide further evidence in support of a role for Na(+)-H+ exchange. The results provide further evidence in support of a role for Na(+)-H+ exchange in determining ischemia-reperfusion injury in the heart.
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PMID:Effect of amiloride and selected analogues on postischemic recovery of cardiac contractile function. 839 55

There is controversy over whether the cardioprotective effects of Na+/H+ exchanger inhibitors are exerted primarily during ischemia or during subsequent reperfusion, possibly because of interstudy differences in experimental conditions. We studied the impact of perfusate buffer composition on the relative degree of protection afforded by Na+/H+ exchanger inhibition during ischemia vs. reperfusion. Isolated rat hearts (n = 8/group) were perfused (37 degrees C, 75 mmHg) with bicarbonate- or N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered medium and subjected to 20 min of global zero-flow ischemia and 45 min of reperfusion. One of two structurally distinct Na+/H+ exchanger inhibitors [5-(N,N-dimethyl)amiloride (DMA) or (3-methylsulfonyl-4-piperidinobenzoyl)guanidine methanesulfonate (HOE-694), 10 mumol/l] was transiently (5 min) infused 1) immediately before ischemia, 2) during initial reperfusion, or 3) during both of these periods. With bicarbonate-buffered medium, neither drug improved the postischemic recovery of left ventricular developed pressure (LVDP) when given only during reperfusion. In contrast, HOE-694 improved the postischemic recovery of LVDP from 39 +/- 5% in control to 66 +/- 6% (P < 0.05) when given before ischemia and from 33 +/- 4% in control to 65 +/- 4% (P < 0.05) when given before ischemia plus during reperfusion. With the latter protocol, the cardioprotective effect of HOE-694 occurred in a dose-dependent manner at 0.1-10 mumol/l. In contrast to the results with bicarbonate-buffered medium, in the presence of N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered medium, DMA and HOE-694 significantly improved recovery of LVDP (from 34 +/- 5% in controls to 56 +/- 3 and 71 +/- 8%, both P < 0.05) when given only during reperfusion. They also provided significant protection when given before ischemia or before ischemia plus during reperfusion; with the latter protocol, HOE-694 produced an almost complete recovery of LVDP (88 +/- 9 vs. 30 +/- 7% in controls, P < 0.05). In conclusion, our results suggest that the influence of Na+/H+ exchanger activity during reperfusion on the extent of functional recovery is modulated significantly by perfusate buffer composition. As a consequence, the cardioprotective efficacy of Na+/H+ exchanger inhibitors may be overestimated under bicarbonate-free conditions.
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PMID:Impact of extracellular buffer composition on cardioprotective efficacy of Na+/H+ exchanger inhibitors. 877 47

Cardiac efficiency is decreased in hearts after severe ischemia. We determined whether reducing the production of H+ from glucose metabolism or inhibiting the clearance of H+ via Na(+)-H+ exchange could increase cardiac efficiency during reperfusion. This was achieved using dichloroacetate (DCA) to stimulate glucose oxidation and 5-(N,N-dimethyl)-amiloride (DMA) to inhibit Na(+)-H+ exchange, respectively. Isolated working rat hearts were subjected to 30 minutes of global ischemia and 60 minutes of reperfusion. Glycolysis and oxidation rates of glucose, lactate, and palmitate were measured. Recovery of cardiac work, O2 consumption (MVO2), and rates of acetyl-coenzyme A and ATP production during reperfusion were determined. After ischemia, cardiac work recovered to 35 +/- 5% of preischemic values in control hearts (n = 23), although MVO2, tricarboxylic acid (TCA) cycle activity, and ATP production from glycolysis and oxidative metabolism rapidly recovered to preischemic levels. This decrease in cardiac efficiency was accompanied by a substantial production of H+ from glucose metabolism DCA caused a 2.2-fold increase in glucose oxidation, a 46 +/- 17% decrease in H+ production, a 1.6-fold increase in cardiac efficiency, and a 2.0-fold increase in cardiac work during reperfusion (n = 17). Inhibition of Na(+)-H+ exchange with DMA did not alter TCA cycle activity and ATP production rates but did result in a 1.8-fold increase in cardiac efficiency and a 1.7-fold increase in cardiac work (n = 12). These data show that cardiac efficiency and the contractile function after ischemia can be improved by either reducing the rate of H+ production from glucose metabolism during reperfusion or inhibiting the clearance of H+ via Na(+)-H+ exchange. Our data suggest that an increased requirement for ATP to restore ischemia-reperfusion-induced alterations in ion homeostasis contributes to the decrease in cardiac efficiency and contractile function after ischemia.
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PMID:Cardiac efficiency is improved after ischemia by altering both the source and fate of protons. 888 86

To help resolve the controversy as to whether or not Na(+)-H+ exchange is functioning during reperfusion of the ischemic myocardium we assessed the effects of dimethylamiloride (DMA, an amiloride analogue possessing selectivity for inhibition of the Na(+)-H+ exchanger) on cardiac function and intracellular pH during ischemia-reperfusion. Studies were performed in the presence of bicarbonate (modified Krebs-Henseleit buffer) or in the nominal absence of bicarbonate (HEPES buffer) in order to determine if similar cardioprotection and effects on intracellular pH were observed in the presence and absence of bicarbonate dependent transport processes. Isovolumic rat hearts were perfused in the Langendorff mode at a constant pressure of 80 mm Hg and subjected to 28 min total global ischemia at 37 degrees C. Intracellular pH was determined from the pH dependent shift of the inorganic phosphate peak in 31P nuclear magnetic resonance spectra. DMA (20 microM) was infused for either 2.5 min before ischemia, for the initial 5 min of reperfusion, or at both time intervals. DMA had no effect on the intracellular pH during ischemia. Intracellular pH returned to pre-ischemic levels within 2.5 min of reperfusion in bicarbonate buffer. This normalization of pH was slower in HEPES perfusate. In both bicarbonate and HEPES perfused hearts all drug dosing regimens caused a significant increase in the recovery of mechanical function after reperfusion and slowed the recovery of intracellular pH during reperfusion. These results suggest that the Na(+)-H+ exchanger is activated during reperfusion of the ischemic myocardium, that this activation of the exchanger contributes to ischemia-reperfusion induced cardiac dysfunction and that administration of an inhibitor of Na(+)-H+ exchange at reperfusion significantly attenuates the deleterious effects of exchanger activation.
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PMID:Na(+)-H+ exchange inhibition at reperfusion is cardioprotective during myocardial ischemia-reperfusion; 31P NMR studies. 940 70

Stimulation of Na(+)/H(+)exchange during ischemia-reperfusion results in cardiac damage. However, it is unclear whether the Na(+)/H(+)exchanger is active during the ischemic period or during reperfusion. Adult beating cardiomyocytes were exposed to an ischemia mimetic solution for 90 min and then reperfused with a normal solution for 30 min. 5-(N,N-dimethyl)-amiloride (DMA), a blocker of the Na(+)/H(+)exchanger, was administered during ischemia and the first 3 min of reperfusion or only during the first 3 min of reperfusion. Administration of DMA only upon reperfusion resulted in increased cell survival (81+/-1%, P<0.05) compared to using the drug during ischemia and reperfusion (63+/-3%) and in the absence of drug (60+/-1%). During ischemia, pH(i)was lower when DMA was present in the ischemic solution. The inhibition of the Na(+)/H(+)exchanger retarded the recovery of pH during reperfusion. The highest recovery of active cell shortening was observed when DMA was used at the beginning of reperfusion. The use of DMA also reduced the level of passive cell shortening during reperfusion, and when used at the beginning of reperfusion significantly increased the recovery of Ca(2+)transients. Our results demonstrate that the exchanger is primarily active during reperfusion and that inhibition of the exchanger solely at this time has a strong cardioprotective effect.
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PMID:Inhibition of Na(+)/H(+) exchange at the beginning of reperfusion is cardioprotective in isolated, beating adult cardiomyocytes. 1101 33

PURPOSE:The scope of endovascular surgical techniques has expanded to include the treatment of diseases considered at one time to be amenable only to surgical treatment. The development of the biodegradable template follows as an extension of current permanent stent technology. The goal of our project is to develop and test chitosan as an absorbable template for the vascular system.Ultrapure chitosan, heparin sodium salt and lysozyme, and contrast agents MD-76R and Oxilan-350 were used to give radioopaque quality. Prototype chitosan vascular templates were obtained by a dip coating method in which alternate layers of chitosan were coagulated with nonsolvents or heparin. The amount of loaded and released heparin was determined using Azure II colorimetric assay. In vitro enzymatic degradation of templates was evaluated using lysozyme solutions in phosphate buffered saline. Mechanical properties were analyzed using the Dynamic Mechanical Analyzer, DMA-7 (Perkin Elmer, Foster City, Calif.). The microstructure of freeze-dried templates was investigated by field emission scanning electron microscopy (FE SEM) using an LEO 982 electron microscope (Zeiss, Thornwood, NY).In vivo deployment of the templates was undertaken in 10 full-sized pigs (Sus scrofa). After open expose and control of the iliac artery, a closed balloon catheter technique was used to advance and place the balloon catheter and template. The balloon was then expanded, deploying a Palmaz stent with a chitosan template anchored distally. Patency and deployment of the stent-template complex was confirmed by an arteriogram. The animals were sacrificed at 1, 2, 3, 4, and 5 weeks poststent placement, and arterial sections were taken for microscopic analysis. The amount of chitosan remaining was estimated to determine an in vivo rate of absorption.On hematoxilyn and eosin staining of the section arterial samples, a marked inflammatory response was noted and progressed with duration of in vivo contact. A giant cell foreign body reaction coupled with intense intimal hyperplasia and organized thrombus was also noted and progressed with duration of time in vivo. Also noted was the degradation of the template material with only small remnants of material noted within the giant cell by week 4. Clinically, none of the pigs developed limb ischemia or evidence of thromboembolic events.In this in vivo study, the chitosan template proved to be biodegradable but elicited an intense thrombotic and foreign body reaction despite heparin bonding. Further investigation is ongoing as to decreasing the thrombogenic and antigenic qualities of the template materials by either alteration of the base material or addition of bioactive side chains.
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PMID:Bioabsorption qualities of chitosan-absorbable vascular templates(1). 1122 42


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