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)

Depletion of high-energy phosphates, accumulation of inorganic phosphate and intracellular acidosis have each been proposed as important events in the transition from reversible to irreversible ischemic injury. To assess whether each variable is predictive of functional recovery on reperfusion, these were measured in the isolated isovolumic rat heart using 31P NMR. Perfused hearts were subjected to either 10, 12 or 40 min of normothermic ischemia followed by 40 min of reperfusion. Hearts were then freeze-clamped for further analysis of phosphate metabolites by NMR and ion chromatography. High-energy phosphates, Pi, phosphomonoesters and pH were measured by 31P NMR spectroscopy at 2 minute intervals. Heart rate and developed pressure were monitored simultaneously. All hearts undergoing 10 min of ischemia and 40% of hearts subjected to 12 min of ischemia demonstrated good functional recovery. The remainder of hearts ischemic for 12 min went into contracture on reperfusion with little return of function. Hearts subject to 40 min of ischemia went into ischemic contracture and showed no recovery on reperfusion. Intracellular pH, [ATP], and [Pi] measured prior to reperfusion did not predict the extent of recovery. However, phosphomonoesters were detected prior to reperfusion in all hearts that did not recover well, but were not observed in hearts that showed good mechanical recovery. Analysis of tissue extracts by 31P NMR and ion chromatography indicated that the most prominent components of the phosphomonoesters were glucose 6-phosphate, alpha-glycerol phosphate and AMP. In conclusion, of the various phosphorus metabolites that can be measured by 31P NMR, only one group, the phosphomonoesters, was predictive of functional recovery.
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PMID:Predicting functional recovery from ischemia in the rat myocardium. 148 87

The effects of prolonged hypothermic ischemia and subsequent normothermic perfusion on the energetic metabolism and intracellular pH (pHin) of isolated rat livers were studied by phosphorus-31 nuclear magnetic resonance spectroscopy. Nucleoside triphosphate (NTP) depletion and intracellular pH were studied within an 18-h-storage phase, by using the following preservation media: Eurocollins (EC), UW Lactobionate (UW) and Bretschneider's solution (HTK). Values obtained after 8-h ischemia were chosen to estimate the performance of the various media: NTP levels were 37 +/- 7%, 10 +/- 5% and 0% of control levels, respectively, in livers stored in UW, HTK and EC solutions. pHin reached values of 7.15 +/- 0.10 in UW and HTK, and 6.96 +/- 0.10 in EC-stored livers. Ischemic damage was assessed by reperfusing the stored organ with Krebs medium: NTP recovery was around 70 +/- 20% for the three solutions used. Recovery of pHin was near the control value (7.23 +/- 0.08), except for EC solution (7.05 +/- 0.20). The main results are that (i) the rates of NTP and pHin decrease are strongly dependent on the nature of the preservation solution, whereas (ii) NTP recovery is not significantly different during post-ischemic reperfusion. With regard to animal survival, UW solution is at present considered largely superior to EC medium for liver preservation. Thus, our data suggest that the rates of NTP depletion and pHin fall during cold preservation could be both considered as better indicators assessing liver injury than the post-ischemic NTP recovery.
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PMID:Phosphorus-31 nuclear magnetic resonance of isolated rat liver during hypothermic ischemia and subsequent normothermic perfusion. 150 39

The age-related response of the myocardium to 30 min of 37 degrees C global ischemia and 120 min of 37 degrees C reperfusion, measured by phosphorus-31 magnetic resonance spectroscopy and the recovery of isovolumic function, was evaluated by using perfused neonatal (3-8 days old, n = 10), immature (24-30 days old, n = 10), and adult (2-4 mo old, n = 5) rabbit hearts. Basal intracellular pH (pHi) was highest in neonatal hearts and decreased with age. The basal phosphocreatine (PCr)-to-ATP ratio differed in each group, increasing with age. Rapid depletion of PCr occurred in all groups during ischemia; ATP retention was greater in adults than in neonates. Reperfusion resulted in no measurable recovery of ATP in any group. Postischemic pHi stabilized above preischemic values in neonatal and immature hearts and below preischemic values in adult hearts. Recovery of PCr and cytosolic Pi (Pcyi) content, heart rate, and coronary flow during reperfusion was greater in neonatal and immature than in adult hearts. During the final 20 min of ischemia, pHi was lower in immature than in neonatal or adult hearts. Postischemic recovery of left ventricular maximum rate of pressure rise (+dP/dtmax) was depressed in immature compared with neonatal and adult hearts. These results demonstrate increased tolerance of the neonatal heart and increased susceptibility of the immature heart to unprotected normothermic ischemic injury relative to the adult heart and suggest that maturational changes in myocardial pHi regulation may be responsible for the observed age-related response.
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PMID:Age-related response of rabbit heart to normothermic ischemia: a 31P-MRS study. 153 98

In vivo 31P nuclear magnetic resonance (NMR) spectroscopy of the right ventricular (RV) free wall was employed to determine (a) whether phosphorus energy metabolites vary reciprocally with workload in the RV and (b) the mechanisms that limit RV contractile function in acute pressure overload. In 20 open-chest pigs, phosphocreatine (PCr)/ATP ratio (an index of energy metabolism inversely related to free ADP concentration), myocardial blood flow (microspheres), and segment shortening (sonomicrometry, n = 14) were measured at control (RV systolic pressure 31 +/- 1 mm Hg), and with pulmonary artery constriction to produce moderate pressure overload (RV systolic pressure 45 +/- 1 mm Hg), and maximal pressure overload before overt RV failure and systemic hypotension (RV systolic pressure 60 +/- 1 mm Hg). With moderate pressure overload, PCr/ATP declined to 89% of control (P = 0.01), while contractile function increased. Adenosine (n = 10, mean dose 0.16 mg/kg-min) increased RV blood flow by an additional 41% without increasing PCr/ATP, indicating that coronary reserve was not depleted and that the decrease in PCr/ATP from control was not due to ischemia. With maximal pressure overload and incipient RV failure, PCr/ATP fell further to 81% of control and RV blood flow did not increase further, even with adenosine. Thus: (a) The decline in PCr/ATP with moderate RV pressure overload, without evident ischemia or contractile dysfunction, supports the positive regulation of oxidative phosphorylation by ATP hydrolysis products. (b) Depletion of RV coronary flow reserve accompanies the onset of RV failure at maximal pressure overload.
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PMID:Energetics of acute pressure overload of the porcine right ventricle. In vivo 31P nuclear magnetic resonance. 154 81

To determine the ability of extracellular myocardial tissue pH measured with an intramural electrode to reflect myocardial intracellular metabolic status during normothermic ischemia, we studied 14 open-chest dogs with in vivo phosphorus 31-nuclear magnetic resonance spectroscopy during left anterior descending coronary artery occlusion (experimental group, group I, n = 7) or after a sham operation (control group, nonischemic, group II, n = 7). Phosphorus nuclear magnetic resonance spectra were acquired every 5 minutes at 4.7 tesla (256 averages, TR = 1000 msec, pulse width = 30 microseconds) with a 2 cm two-turn radiofrequency surface coil. Intracellular myocardial adenosine triphosphate peak area was normalized to an external phosphate standard. The change in adenosine triphosphate peak area was expressed as percent of baseline value. During 3 hours of normothermic ischemia the observed extracellular myocardial pH correlated with nuclear magnetic resonance-calculated myocardial pH in the ischemic dogs with an average r value of 0.94 (p less than 0.0001). During this same interval, the fall in extracellular myocardial pH correlated with the loss of adenosine triphosphate peak in each ischemic dog, with an average r value of 0.91 (p less than 0.0001). Thus extracellular myocardial pH, measured with an intramural electrode, correlated with nuclear magnetic resonance-derived myocardial pH and loss of myocyte adenosine triphosphate peak content and reflected the metabolic status of the myocyte during ischemia. These data validate the use of extracellular myocardial pH to assess the adequacy of myocardial preservation during aortic crossclamping for cardiac operations.
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PMID:Electrode-derived myocardial pH measurements reflect intracellular myocardial metabolism assessed by phosphorus 31-nuclear magnetic resonance spectroscopy during normothermic ischemia. 156 73

The optimal level of hypothermia during myocardial preservation for cardiac transplantation is not known. Phosphorus 31 nuclear magnetic resonance spectroscopy was used to assess the effect of different preservation temperatures (15 degrees C in group 1, 4 degrees C in group 2) on the myocardial high-energy phosphate profiles during prolonged global ischemia and subsequent reperfusion of isolated rat hearts. Adenosine triphosphate depletion during ischemia was more gradual in group 2, leading to significant differences in myocardial adenosine triphosphate concentrations between the two groups after 3 hours of ischemia. The fall in intracellular pH during ischemia was significantly less pronounced in hearts preserved at 4 degrees C as compared with those at 15 degrees C. The postischemic recovery of both the left ventricular peak systolic pressure and the maximum rate of increase of left ventricular pressure was enhanced in group 2, although the ischemic period was 3 hours longer than in group 1. Hypothermia at 4 degrees C as compared with 15 degrees C appears to prolong myocardial protection with respect to adenosine triphosphate preservation, prevention of the fall in intracellular pH, and the enhancement of postischemic hemodynamic recovery.
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PMID:Optimal level of hypothermia for prolonged myocardial protection assessed by 31P nuclear magnetic resonance. 163 31

To elucidate the mechanism of acute contractile failure induced by adriamycin, the intracellular concentrations of free calcium ([Ca2+]i) and energy-related phosphate compounds were determined in isolated ferret hearts. The time-averaged [Ca2+]i was measured at 10 min resolution using fluorine nuclear magnetic resonance (NMR) spectroscopy and the NMR-sensitive Ca2+ indicator 5F-BAPTA. [Ca2+]i significantly increased from a control of 381 +/- 66 nM (mean +/- SEM, N = 5) to 789 +/- 171 nM during 30 min of perfusion with adriamycin (30 mg/L), and remained elevated for at least 30 min after washout. The isovolumic LV pressure decreased to 80.7 +/- 8.9% of control (N = 12, p less than 0.05) and did not recover after washout. Intramyocardial contents of energy-related phosphates were determined by phosphorus NMR spectroscopy in seven other hearts. No significant change in myocardial energy metabolism was observed during adriamycin exposure and after washout; inorganic phosphate did not increase, and phosphocreatine and ATP did not decrease. These results indicate that Ca overload induced by adriamycin is associated with acute contractile failure. Adriamycin has been reported to inhibit Na-Ca exchange and to affect the gating of Ca2+ release channels in sarcoplasmic reticulum. Whatever the cause of the calcium overload, the fact that dysfunction persists as an aftereffect of adriamycin is consistent with the hypothesis that calcium overload, in the absence of ischemia, can leave behind long-lasting contractile dysfunction.
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PMID:Alterations of intracellular calcium homeostasis and myocardial energetics in acute adriamycin-induced heart failure. 172 Aug 44

This study was undertaken to determine whether or not prostaglandin I2 (PGI2) analog pretreatment could successfully preserve organ viability after warm hepatic ischemia in rats. Although 120-min ischemia of the liver did not permit survival in rats administered normal saline solution (NS group) before warm ischemia, the survival rate of PGI2 analogue (500 ng/kg/min)-treated rats (PG group) significantly improved to 57% (P less than 0.05). Recirculation following 120-min hepatic ischemia in the NS group resulted in no improvement of B-phosphorus of the ATP (B-ATP)/inorganic phosphate (Pi) ratio measured by 31P nuclear magnetic resonance, a marked increase in the serum aspartate aminotransferase (SAST) level, and an increase in the malondialdehyde (MDA) level in liver tissue. In the PG group, the B-ATP/Pi ratio was significantly improved (P less than 0.05), the elevation in SAST was also markedly suppressed (P less than 0.05), and the MDA level of the liver was lowered more than that in the NS group. Severe congestion and extensive vacuolization of hepatocytes from the peripheral to the midzonal areas were histologically exhibited with single-cell necrosis in the NS group. There were fewer histological alterations of the liver and these coincided with the changes in other parameters in the PG group. Our results indicate that PGI2 analog reduces warm ischemic injury of the liver and provides greater protection for organs to be transplanted.
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PMID:The beneficial effect of a prostaglandin I2 analog on ischemic rat liver. 175 84

Timely reperfusion with intravenous thrombolytic agents has been shown to reduce mortality in patients with acute myocardial infarction. However, the magnitude of improvement in left ventricular function has always been less than expected. Reperfusion in fact causes a specific form of tissue injury, termed reperfusion injury, which would subtract from the benefit obtained by terminating ischemia. Oxygen free radical generation has been proposed to be a major mechanism in the pathogenesis of reperfusion injury. Using an isolated perfused rabbit heart model we have demonstrated that administration of oxygen free radical scavengers, such as recombinant human superoxide dismutase (h-SOD) and iron chelators, such as deferoxamine, beginning at the time of reperfusion, reduce the severity of reperfusion injury, as judged by recovery of ventricular function and high energy phosphate metabolism, assessed quantitatively using 31-phosphorus nuclear magnetic resonance spectroscopy. Using electron paramagnetic resonance spectroscopy we have documented a burst of oxygen free radical generation during the early minutes of reperfusion and that this burst can be eliminated by superoxide radical scavengers, such as h-SOD, hydroxyl radical scavengers, such as mannitol, as well as agents that inhibit generation of oxygen free radicals, such as the iron chelator, deferoxamine. Taken together these results strongly support the role of oxygen free radicals in the pathogenesis of reperfusion injury. We have recently completed the first randomized placebo controlled clinical trial of a free radical scavenger (h-SOD) in patients with acute myocardial infarction, undergoing urgent angioplasty of their occluded coronary artery with preservation of left ventricular function as the major study endpoint.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of oxygen radicals in myocardial reperfusion injury: experimental and clinical evidence. 179 80

Oxygen radical toxicity has been implicated in the pathogenesis of myocardial reperfusion injury. In the present study we sought to document the existence of a precise temporal relationship between the time course of free radical generation and the time course of alterations of myocardial energy metabolism during early reperfusion. Rabbit hearts perfused within the bore of a 31-Phosphorous NMR spectrometer were subjected to 30 min of total global ischemia at 37 degrees C. At reflow, 12 control hearts received a bolus of normal perfusate and 12 hearts recombinant human superoxide dismutase (h-SOD) as a 60,000 IU bolus followed by a 100 IU/ml infusion for 15 min. Ischemia resulted in similar depletion of tissue ATP and phosphocreatine (PCr) in the two groups. During the first minute of reflow, recovery of PCr was similar in both groups. However, PCr recovery arrested in control hearts after 2 min, at 63% of baseline, and averaged 64 +/- 4% after 45 min of reperfusion. In contrast, h-SOD treated hearts recovered 86.7% of baseline PCr content after 2 min, 102% after 10 min of reperfusion (P less than 0.001), and 93 +/- 6.4% at the end of the 45 min of reflow (P less than 0.01). The time course of free radical formation during reperfusion was assessed by EPR spectroscopy using both the frozen tissue and the spin trapping methodologies. In control hearts, peak generation of oxygen radicals was reached after 20 s of reflow. h-SOD treatment decreased concentrations of the oxygen-centered radicals in myocardial tissue and of the radical-adducts in the coronary effluent by approximately 80%. Thus, in reperfused hearts peak oxygen radical generation is followed by the occurrence of alterations in the recovery of high energy phosphate metabolism. Both events were largely prevented by administration of h-SOD at reflow. These results provide strong support for a link between oxygen free radical generation and post-ischemic reperfusion injury.
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PMID:The relationship between oxygen radical generation and impairment of myocardial energy metabolism following post-ischemic reperfusion. 181 Oct 55


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