Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0599766 (functional recovery)
 13,441 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the pathophysiological role of the hydroxyl radical (.OH) during the postischemic reperfusion of the heart, we measured the .OH product in the coronary effluent from isolated perfused rat heart during a 30-minute reperfusion period after various ischemic intervals of 5, 10, 15, 20, 30, and 60 minutes. Salicylic acid was used as the probe for .OH, and its derivative, 2,5-dihydroxybenzoic acid (2,5-DHBA), was quantified using high-performance liquid chromatography with ultraviolet detection. 2,5-DHBA was negligible in the effluent from nonischemic hearts, but a significant amount was detected from the hearts rendered ischemic for 10 minutes or longer. The peak of 2,5-DHBA was seen within 90 seconds after the onset of reperfusion in every group. The accumulated amount of 2,5-DHBA was maximal in the group with 15-minute ischemia (6.73 +/- 1.04 nmol/g wet heart wt after 30 minutes of reperfusion); it decreased as the ischemic time was prolonged and was 2.38 +/- 0.84 nmol/g wet wt after 30 minutes of reperfusion in the group with 60-minute ischemia. In the model of 15-minute ischemia/30-minute reperfusion, there was no correlation between the accumulated amount of 2,5-DHBA and functional recovery (+/- dP/dt, heart rate, and coronary flow), lactate dehydrogenase release, and morphological damage. Although treatment with 0.5 mM deferoxamine, an iron chelator, significantly decreased 2,5-DHBA (from 6.73 +/- 1.04 to 2.29 +/- 0.80 nmol/g wet wt after 30 minutes of reperfusion, p less than 0.01), it failed to reduce the postischemic myocardial injury in the group with 15-minute ischemia. The results suggest that .OH production is influenced by the preceding ischemic interval and that .OH does not exert an immediate direct effect on postischemic damage during early reperfusion in the isolated perfused rat heart, although a possibility remains that the small portion of .OH trapped by salicylic acid may not be intimately associated with myocardial injury.
 ...
PMID:Quantification of hydroxyl radical and its lack of relevance to myocardial injury during early reperfusion after graded ischemia in rat hearts. 131 98

U74006F, a novel 21-amino steroid is a potent inhibitor of iron-mediated lipid peroxidation and has been shown to be of therapeutic benefit in central nervous system ischemia. As oxygen radicals have been implicated in the development of postischemic myocardial dysfunction, we examined the efficacy of U74006F to enhance the recovery of function in a canine model of stunned, reperfused myocardium. Twenty-six dogs were randomized to either a vehicle (n = 11), U74006F (n = 10), or U74006F-paced group (n = 5). U74006F (6 mg/kg i.v.) was administered 15 min prior to coronary artery occlusion. Myocardial blood flows were measured by the microsphere technique, and function data were obtained by sonomicrometry. Both U74006F-treated groups demonstrated a significant increase in posterior wall thickening as compared to the vehicle treatment (U74006F-paced, 27.0 +/- 12.8%; U74006F, 22.4 +/- 11%; vehicle, -13.5 +/- 9.9%, p less than 0.001 following 3 h of reperfusion). Enhanced function recovery was accompanied by lower heart rates in the U74006F-treated group following reperfusion (treated versus vehicle, 109 +/- 6.7 versus 131 +/- 8.8 beats/min, p = 0.004). The U74006F-paced group was maintained at the same rate as the vehicle group, with no diminution in function recovery compared to the unpaced group. No effects in systemic hemodynamics or nutrient blood flow were evident as a function of drug treatment. We conclude that pretreatment with U74006F enhances the recovery of function in stunned canine myocardium via the inhibition of oxygen radicals and lipid peroxidation products. This activity suggests that this compound represents a new therapeutic adjunct in reperfusion and recanalization therapies.
 ...
PMID:Effects of U74006F, a novel inhibitor of lipid peroxidation, in stunned reperfused canine myocardium. 168 19

This study tests the hypothesis that an iron chelator, deferoxamine, can reduce oxygen-mediated myocardial injury and avoid myocardial dysfunction after cardiopulmonary bypass by its action on the iron-catalyzed Haber-Weiss pathway. Twenty-one immature 2- to 3-week-old piglets were placed on cardiopulmonary bypass for 120 minutes, and five piglets served as biochemical controls without cardiopulmonary bypass. Five piglets underwent cardiopulmonary bypass without hypoxemia (cardiopulmonary bypass control). Sixteen others became hypoxemic while undergoing cardiopulmonary bypass for 60 minutes by lowering oxygen tension to about 25 mm Hg, followed by reoxygenation at oxygen tension about 400 mm Hg for 60 minutes. Oxygen delivery was maintained during hypoxemia by increasing cardiopulmonary bypass flow and hematocrit level. In seven piglets deferoxamine (50 mg/kg total dose) was given both intravenously just before reoxygenation and by a bolus injection (5 mg/kg) into the cardiopulmonary bypass circuit; nine others were not treated (no therapy). Myocardial function after cardiopulmonary bypass was evaluated form end-systolic elastance (conductance catheter) and Starling curve analysis. Myocardial conjugated diene production and creatine kinase leakage were assessed as biochemical markers of injury, and antioxidant reserve capacity was determined by measuring malondialdehyde in postcardiopulmonary bypass myocardium incubated in the oxidant, t-butylhydroperoxide. Cardiopulmonary bypass without hypoxemia caused no oxidant or functional damage. Conversely, reoxygenation (no therapy) raised myocardial conjugated diene levels and creatine kinase production (conjugated diene: 3.5 +/- 0.7 absorbance 233 nm/min/100 g, creatine kinase: 8.5 +/- 1.5 U/min/100 g; p < 0.05 versus cardiopulmonary bypass control), reduced antioxidant reserve capacity (malondialdehyde: 1115 +/- 60 nmol/g protein at 4 mmol/L t-butylhydroperoxide; p < 0.05 versus control), and produced severe post-bypass dysfunction (end-systolic elastance recovered only 39% +/- 7%, p < 0.05 versus cardiopulmonary bypass control). Deferoxamine avoided conjugated diene production and creatine kinase release and retained normal antioxidant reserve, and functional recovery was complete (95% +/- 11%, p < 0.05 versus no treatment). These findings show that iron-catalyzed oxidants may contribute to a reoxygenation injury and imply that deferoxamine may be used to surgical advantage.
 ...
PMID:Studies of hypoxemic/reoxygenation injury: without aortic clamping. IV. Role of the iron-catalyzed pathway: deferoxamine. 747 70

Recognition of the central role of iron in the generation of toxic, oxygen-derived species through the Haber-Weiss reaction, the ability of desferrioxamine (DFX) to prevent the damage associated with free radical generation in reperfusion injury, and its inhibitory effect on cell proliferation by inactivation of the iron dependent enzyme ribonucleotide reductase, resulted in an increasing number of studies exploring the novel therapeutic applications of iron chelating drugs: (a) Animal models of reperfusion injury have shown that DFX is able to decrease post-anoxic damage to the brain and heart as manifested in decreased infarct size and improved functional recovery. Iron chelators may be particularly useful in improving the preservation of organs intended for transplantation such as the heart, lung or kidney. (b) Anthracycline cardiotoxicity is aggravated by iron and inhibited by iron chelators. Because the mechanism of its antineoplastic effect differs from its cardiotoxic effect, it is possible to inhibit anthracycline cardiotoxicity without interfering with therapeutic efficacy. In vivo and in vitro animal studies have yielded encouraging results but much additional experimental work is still required before iron chelating therapy may be advocated for use in patients on anthracycline therapy. (c) Cell proliferation can be inhibited by iron chelators through the reversible inhibition of ribonucleotide reductase, a rate-limiting enzyme in DNA synthesis. This may be exploited for the treatment of malignant disease, and preliminary studies have already shown that DFX in combination with multidrug chemotherapy is effective in controlling neuroblastoma and other tumours. However, the contribution of DF to the overall clinical effect is unclear. Prospective controlled clinical studies are required in order to establish whether the antiproliferative, or cell synchronizing properties of DFX may be of practical usefulness in the control of malignant disease. (d) Control of protozoal infection: Experimental in vivo and in vitro models have shown that malarial infection may be inhibited by iron chelating therapy. This useful effect of DFX and other iron chelators is most probably related to ribonucleotide reductase inhibition. Clinical studies of asymptomatic P. falciparum malaria and of cerebral malaria have shown both an accelerated rate of parasite clearance and earlier recovery from coma. These observations lend new meaning to the term 'nutritional immunity' and open new channels for exploring the possibility of controlling infection by means of selective intracellular iron deprivation. Experimental models for studying the effect of iron chelators on other intracellular pathogens such as Toxoplasma gondii, Chlamydia psittaci, or Mycobacterium tuberculosis should be established.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Control of disease by selective iron depletion: a novel therapeutic strategy utilizing iron chelators. 788 Nov 62

Recently we have shown that intracellular low molecular weight (LMW) iron increases during ischemia. It is hypothesized that this increase in LMW iron during ischemia underlies the reported hydrogen peroxide toxicity toward ischemic hearts. To investigate this hypothesis, rat hearts were subjected to 15 min of no-flow ischemia and reperfused with buffer saturated against 95% N2 and 5% CO2 (anoxic reperfusion) for 7 min. Hearts were then switched to buffer saturated against 95% O2 and 5% CO2 (reoxygenation) to assess functional recovery. The cardiac function recovered to 80 +/- 7% of the preischemic value. When the anoxic reperfusion was applied in the presence of 10 microM hydrogen peroxide, functional recovery after reoxygenation was 47 +/- 7%. Hearts that were perfused with deferoxamine before ischemia and then subjected to ischemia and anoxic reperfusion in the presence of 10 microM hydrogen peroxide recovered to 78 +/- 8%. Immediate reoxygenation after ischemia led to only 45 +/- 6% recovery of function. During ischemia, LMW iron increased from 49 +/- 45 to 183 +/- 45 pmol/mg protein (p < .05) and decreased to 58 +/- 38 pmol/mg protein (p < .05) during the subsequent anoxic perfusion. Rat hearts preloaded with deferoxamine showed a slightly higher LMW iron content than normal (85 +/- 23 and 49 +/- 45 pmol/mg protein, respectively; n.s.), which showed a small, nonsignificant increase up to 136 +/- 42 pmol/mg protein after 15 min of ischemia. No significant changes were found in reduced and oxidized glutathione content and glutathione peroxidase or catalase activities under those conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The increased susceptibility to hydrogen peroxide of the (post-)ischemic rat heart is associated with the magnitude of the low molecular weight iron pool. 800 30

In this study deferoxamine (DF), a strong iron chelator, was administered either before storage or during reperfusion, in an attempt to inhibit the iron-dependent hydroxyl radical production and improve the functional recovery of the cold-stored/reperfused cardiac explant. Excised rat hearts were flushed with Krebs-Henseleit buffer (KHB), arrested with a cardioplegic solution, CP11-EB, with or without DF, and immersion stored in CP11-EB at 0 degree C for 16 hr. To assess function, the stored hearts were reperfused in the working mode with KHB for 30 min. Experimental groups included: (i) DF treatment during prestorage flush [CP11-EB + 0.01 mM (n = 5), 0.05 mM (n = 13), 0.1 mM (n = 5), 0.2 mM (n = 5), or 0.75 mM DF (n = 5)]; (ii) DF treatment during reperfusion [KHB + 0.3 mM (n = 5), 0.6 mM (n = 7), 0.75 mM (n = 11), 1.0 mM (n = 6), 1.5 mM (n = 4), or 2.5 mM DF (n = 7)]; and (iii) untreated group (n = 8) received no DF during flush or reperfusion. Function of unstored hearts (n = 7) including aortic flow (AF, 54.6 +/ 2.6 ml/min); cardiac output (CO, 76.5 +/- 3.3 ml/min), systolic pressure (SP, 135.7 +/- 1 mm Hg), diastolic pressure (DP, 70.7 +/- 3.8 mm Hg), and work (96.7 +/- 6.4 g-meter/min) served as controls. Functional recovery of the untreated group was AF, 59%; CO, 58%; SP, 71%; DP, 73%; work, 41% of control values. DF treatment at any dose during the initial flush did not improve functional recovery.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Deferoxamine given at reperfusion improves function of the cold-stored rat heart. 804 Nov 32

Acute renal failure (ARF) is associated with erythropoietin (EPO) deficiency anemia. The present study was designed to determine whether the course of ARF can be altered by preventing EPO deficiency and the associated anemia. Sprague-Dawley rats were injected with a single dose of cisplatin (CP), 7 mg/kg intraperitoneally, and randomized into recombinant EPO-treated (EPO), placebo-treated (control), recombinant EPO-treated pair-fed (EPO-PF), and EPO-treated anemic (EPO-anemic) groups. They were then treated with daily injections of recombinant EPO, 100 U/kg, or placebo for 9 days. Animals in the EPO-anemic group received daily phlebotomies gauged to maintain hematocrits equal to those in the control group. Rats in the EPO-PF group were pair fed with the controls. The control and EPO-anemic groups showed a fall, whereas the EPO and EPO-PF groups showed a rise in hematocrit on day 9. Although blood volume on day 9 was significantly greater in the EPO group than in either the EPO-anemic group or the control group, it was comparable in the latter groups. An equally severe reduction in creatinine clearance (CCr) was found in all groups on day 4. However, measurements of CCr and inulin clearance on day 9 revealed a significantly greater functional recovery in the EPO, EPO-PF, and EPO-anemic groups than in the controls. The enhanced functional recovery with EPO administration was accompanied by an increased tubular regeneration and [3H]thymidine incorporation in the cortical tissue. No significant difference was found in either cortical tissue iron content or arterial blood pressure in the study groups.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Erythropoietin enhances recovery from cisplatin-induced acute renal failure. 816 Jul 83

It has been suggested that iron might play a pivotal role in the development of reperfusion-induced cellular injury through the activation of oxygen free radical producing reactions. The present study examined the effects of myocardial iron overload on cardiac vulnerability to ischemia and reperfusion. Moreover, the effect of the iron chelator deferoxamine in reversing ischemia-reperfusion injury was studied. Animals were treated with iron dextran solution (i.m. injection, 25 mg every third day during a 5 week period). The control group received the same treatment without iron. Isolated rat hearts were perfused at constant flow (11 ml/min) and subjected to a 15 minute period of global normothermic ischemia followed by reperfusion for 15 minutes. The effects of iron overload were investigated using functional and biochemical parameters, as well as ultrastructural characteristics of the ischemic-reperfused myocardium compared with placebo values. The results suggest that (a) a significant iron overload was obtained in plasma and hepatic and cardiac tissues (x2.5, x16, and x8, respectively) after chronic intramuscular administration of iron dextran (25 mg); (b) during normoxia, iron overload was associated with a slight reduction in cardiac function and an increase in lactate dehydrogenase (LDH) release (x1.5); (c) upon reperfusion, functional recovery was similar whether the heart had been subjected to iron overload or not. However, in the control group left ventricular end-diastolic pressure remained higher than in preischemic conditions, an effect that was not observed in the iron-overloaded group. Moreover, LDH release was markedly increased in the iron-loaded group (x4.2); (d) iron overload was associated with a significant worsening of the structural alterations observed during reperfusion, particularly at the mitochondrial and sarcomere level; (e) after 15 minutes of reperfusion, the activity of the anti-free-radical enzyme, glutathione peroxidase (GPX), was significantly reduced in iron-overloaded hearts, whereas catalase activity was increased; (e) the overall modifications observed in the presence of iron overload were prevented by deferoxamine. In conclusion, this study underlines the possible role of cardiac iron in the development of injury associated with ischemia and reperfusion, and the possible importance of the use of an iron-chelating agent in anti-ischemic therapy.
 ...
PMID:Effect of iron overload in the isolated ischemic and reperfused rat heart. 824 Oct 14

Lazaroid, an inhibitor of iron-mediated lipid peroxidation, has been shown to reduce free radical-mediated injury after ischemia and reperfusion. We thus examined the efficacy of pretreatment with lazaroid (U74500A) in enhancing functional recovery after 24-hr heart preservation. An isolated rabbit heart model perfused with the blood from a support rabbit was used. Before preservation, either U74500A (4 mg/kg, group L; n = 6) or solvent (group S; n = 7) was given to the donor rabbit. After 24-hr preservation with UW solution at 0 degrees C, all hearts were perfused with cross-circulated blood for 60 min with the Langendorff mode followed by 40 min of the working mode. In group S, ventricular fibrillation (Vf) after reperfusion was observed in all hearts, whereas no Vf was observed in the U74500A-pretreated group. In group L, the serum creatine phosphokinase; its isozyme, troponin-T; and serum lipid peroxide levels after 10 min of reperfusion were all significantly (P < 0.05) lower than those in group S. The Frank-Starling curve (indicating the left atrial pressure-aortic flow relationship) showed a significant left and upward shift in group L compared with that in group S (P < 0.0001). The heart pretreated with U74500A showed less ischemia-reperfusion injury, better ventricular function, and a lower lipid peroxide level. We thus conclude that the inhibition of lipid peroxidation with lazaroid appears to offer some potential benefits for long-term heart preservation.
 ...
PMID:The effect of lazaroid (U74500A), a novel inhibitor of lipid peroxidation, on 24-hour heart preservation. A study based on a working model using cross-circulated blood-perfused rabbit hearts. 860 Jun 22

Heme oxygenase (HO)-1 converts heme to bilirubin, carbon monoxide, and iron. Our prior work has suggested a cardioprotective role for HO-1 in heart failure. To test whether HO-1 (heat shock protein 32) prevents cardiomyocyte apoptosis and cardiac dysfunction after ischemia-reperfusion (I/R), we generated transgenic mice overexpressing HO-1 in the heart under the control of the alpha-myosin heavy chain promoter. HO-1 transcript and protein increased markedly in the heart only. In an isolated heart preparation, we observed an enhanced functional recovery during reperfusion after ischemia in the transgenic hearts compared with nontransgenic controls. I/R injury was also performed in intact animals by coronary ligation and reperfusion to assess the protective role of HO-1 overexpression on heart apoptosis. HO-1 overexpression reduced cardiac apoptosis, as evidenced by fewer terminal deoxynucleodidyl transferase-mediated dUTP nick-end labeling-positive or in situ oligo ligation-positive myocytes, compared with nontransgenic mice. Our results indicate that cardioselective overexpression of HO-1 exerts a cardioprotective effect after myocardial I/R in mice, and this effect is probably mediated via an antiapoptotic action of HO-1.
 ...
PMID:Cardioselective overexpression of HO-1 prevents I/R-induced cardiac dysfunction and apoptosis. 1212 17


1 2 3 4 5 6 Next >>