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 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deep hypothermic circulatory arrest facilitates repair of congenital cardiac anomalies in infants. It is known empirically that hypothermia protects against central nervous system (CNS) ischemic damage. The Q10O2 is only 2.2 for brain and thus a decrease in metabolic rate does not fully account for protective effects of hypothermia. Since enthalpy of dissociation of H2O is high (approximately 7 kcal/mole), its pH is temperature dependent (7.0 at 25 degrees C, 7.4 at 20 degrees C) and hypothermia may in part protect by its influence on hydrogen ion concentration. A manifestation of CNS susceptibility to ischemia is an obstruction of the microcirculation [no-reflow lesion (NRL)] demonstrated by infusion of carbon black into the cerebral circulation after a period of circulatory arrest. White lesions (NRL) against a gray background on cut section of brain increase in size with increasing time of arrest. The effect of anoxia versus circulatory arrest, brain temperature, and extracellular brain pH on NRL was studied in 45 mongrel dogs, subjected to varying periods of N2-induced anoxia on cardiopulmonary bypass (CPB) at 37 degrees C or 20 degrees C. In some studies jugular venous pH was adjusted by infusion of NaHCO3 or HCl. Control groups included normothermic CPB without anoxic and normothermic CPB, anoxia, and equimolar NaCl infusion. NRL was quantified by planimetry of photographs of cut sections of brain. These results confirm that NRL is abated by hypothermia and suggest that (1) NRL is a function of anoxia and not arrested circulation since perfusion with N2 at 37 degrees C does not protect the brain (i.e., NRL is not solely related to "critical reopening pressure") and (2) NRL is in part a function of extracellular pH.
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PMID:Cerebral anoxia: effect of deep hypothermia and pH. 3 7

A reduction in myocardial oxygen supply during ischemia, not only leads to reduced aerobic ATP production but does not stimulate glycolytic ATP synthesis. The residual aerobically synthesized ATP comes primarily from continued inefficient (i.e., compared to glucose in terms of moles of ATP produced per mole of O2 consumed) oxidation of fatty acids. This leads to elevated tissue levels of long chain fatty acyl-CoA and fatty acyl-carnitine. Both are potentially cell damaging metabolic intermediates. Restriction of glycolysis is due to inhibition of glyceraldehyde-3-phosphate dehydrogenase by accumulated metabolites, such as H+, lactate and NADH. The reduced production of ATP leads to decreased levels of high energy phosphate stores which in turn may impair myocardial mechanical function.
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PMID:Energy metabolism in the ischemic heart. 55 21

Multiple organ failure (MOF) is known to follow systemic inflammatory mediator activation associated with intestinal ischemia-reperfusion injury. In particular, the pulmonary microvasculature appears to be susceptible to MOF-related injury. This study was designed to evaluate the hypothesis that non-cellular plasma factors associated with intestinal ischemia without reperfusion also mediate pulmonary endothelial cell injury. Male Sprague-Dawley rats had intestinal ischemia induced by microvascular clip occlusion of the superior mesenteric artery for 30, 60, 90, or 120 min. Following each period of ischemia, plasma samples were obtained from the protal vein. Time-matched sham-operated animals served as controls. Monolayers of cultured rat pulmonary artery endothelial cells were then incubated with the plasma samples and ATP levels determined using a luciferin-luciferase assay. A 51Cr-release assay using labeled endothelial cells was performed under identical conditions to assess cytotoxicity. Endothelial cell ATP levels were 1.99 +/- 0.23 x 10(-11) mole/micrograms DNA in sham preparations. After a 4-hr incubation in plasma from the 90 and 120 min ischemia groups, cellular ATP levels fell significantly to 1.07 +/- 0.23 x 10(-11) mole/micrograms DNA, respectively (P less than 0.005). No significant cytotoxic injury resulted from incubation with plasma from the 120 min group (1.0 +/- 0.4% versus 0.8 +/- 0.4% in sham group, P = NS). All animals survived 24 hr in the sham, 30, and 60 min groups. However, survival was 40 and 0% in the 90 and 120 min groups, respectively (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pulmonary endothelial cell ATP depletion following intestinal ischemia. 152 42

The epidermal nevus syndrome (ENS) is a sporadic neurocutaneous disorder that consists of epidermal nevi and congenital anomalies involving the brain and other systems. From among over 60 patients with ENS presenting with neurologic manifestations, we identified 17 who had hemimegalencephaly based on pathologic or radiologic studies. Associated brain and neurologic abnormalities included gyral malformations in 12 of 12, mental retardation in 13 of 14, seizures in 16 of 17 (including 9 with infantile spasms), and contralateral hemiparesis in 7 of 12. All had ipsilateral epidermal nevi of the head, and several had ipsilateral facial hemihypertrophy. We concluded that these abnormalities comprise a recognizable neurologic variant of ENS that we believe represents the full expression of primary brain involvement. Several patients also had evidence of acquired brain lesions such as infarcts, atrophy, porencephaly, and calcifications, which are best explained by prior ischemia or hemorrhage. Given repeated observations of blood vessel anomalies in ENS patients, we hypothesize that underlying vascular dysplasia predisposes to these acquired lesions. The same cause may be invoked to explain the wide variety of neurologic symptoms reported in ENS patients without hemimegalencephaly. While the cause of ENS remains unknown, several observations suggest a somatic mutation.
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PMID:Epidermal nevus syndrome: a neurologic variant with hemimegalencephaly, gyral malformation, mental retardation, seizures, and facial hemihypertrophy. 199 73

Myocardial ischemia is associated with profound electrophysiologic derangements which occur within minutes and are rapidly reversible with reperfusion, suggesting that subtle and reversible biochemical alterations within or near the sarcolemma contribute. Our efforts have concentrated on two structurally similar amphipathic metabolites, long-chain acylcarnitine and lysophosphatidylcholine. Studies performed in vitro in isolated tissue indicate that incorporation of either metabolite into the sarcolemma at concentrations of 1-2 mole %, as verified using electron microscopic (EM) autoradiography, elicits profound electrophysiologic derangements analogous to those seen in the ischemic heart in vivo. In isolated myocytes in vitro, the electrophysiologic derangements elicited by hypoxia are associated with a marked 70-fold increase in the endogenous sarcolemmal accumulation of long-chain acylcarnitine. Inhibition of carnitine acyltransferase I (CAT-I) not only prevents the accumulation of long-chain acylcarnitine in isolated myocytes exposed to severe hypoxia, but also markedly attenuates the electrophysiologic alterations. Several lines of experimental evidence, including measurements in venous effluents as well as cardiac lymph, indicate that lysophosphatidylcholine (LPC) accumulates to a large extent in the extracellular space during ischemia. This extracellular accumulation may be secondary to release from vascular endothelium, smooth muscle or blood cell elements. In crude homogenates of myocardial tissue, the total enzymic activity for catabolism of LPC far exceeds the total activity for synthesis of LPC mediated by phospholipase A2 (PLA2) catalyzed hydrolysis of phosphatidylcholine (PC). Therefore, inhibition of catabolism would be required for net accumulation of LPC to occur. Three enzymes responsible for the catabolism of LPC are inhibited by either long-chain acylcarnitine or acidic pH. Thus, accumulation of long-chain acylcarnitine and acidosis contribute to the increase in LPC observed in ischemic tissue. In this report, we provide evidence that accumulation of long-chain acylcarnitine occurs very rapidly in ischemic myocardium in vivo, coincident with the development of electrophysiologic alterations leading to malignant arrhythmias as verified using 3-dimensional cardiac mapping procedures. Following a brief, 2-min period of ischemia, long-chain acylcarnitine content increased four-fold in the ischemic region, concomitant with the development of electrophysiologic abnormalities observed during this period. Additionally, we demonstrate that modification of intracellular lipolysis by beta-adrenergic receptor stimulation or blockade does not influence long-chain acylcarnitine accumulation following this 2-min interval of ischemia. These results suggest that production of long-chain acylcarnitine is not limited by the intracellular free fatty acid concentration early in ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Amphipathic lipid metabolites and their relation to arrhythmogenesis in the ischemic heart. 203 71

The regulation of glycogen phosphorylase and glycogen breakdown in human skeletal muscle has been investigated using the needle biopsy technique. Preliminary studies showed that the activity of phosphorylase in vitro was dependent upon the concentration of inorganic phosphate (Pi) used in the assay system. The Km of phosphorylase a for Pi was found to be 26.2 mmol/l, and that of (a+b) (assayed in the presence of saturating AMP) was 6.8 mmol/l. Because of the difference in Km the apparent percentage of a to (a+b) activity varies with the Pi concentration used in the assay system. Phosphorylase a and (a+b) activities were therefore adjusted to saturating Pi concentrations. The ratio of the activities in this case is independent of the Pi concentration and constitutes a minimal estimate of the fraction of phosphorylase molecules in the a form. The fraction of phosphorylase in the a form in resting muscle was as a mean 22%. Despite nearly a quarter of the phosphorylase being in the a form glycogenolytic activity is extremely low. It is proposed that the concentration of Pi at the active site of the enzyme is low compared to the Km for this of either form of the enzyme, and is limiting to activity. A Pi concentration in resting muscle of 1-3 mmol/l was calculated. During epinephrine infusion at rest 90% of the phosphorylase was transformed to the a form but only a moderate increase in the glycogenolytic rate occurred. This rate approximated to 5-10% of the maximum rate of the enzyme (Vmaxa). During prolonged epinephrine infusion the glycogenolytic rate decreased despite the continuance of 90% or more of the phosphorylase in the a form. In contrast to epinephrine infusion prolonged ischemia resulted in a decrease in the mole fraction of phosphorylase a and simultaneously in an increase of the glycogenolytic rate. During isometric and dynamic exercise there was a rapid transformation of phosphorylase b to a paralleled by pronounced increase in the rate of glycogen breakdown. The increased rate of glycogenolysis during isometric exercise was close to the Vmax of phosphorylase a in vivo. When either form of exercise was continued to fatigue/exhaustion, a re-transformation of phosphorylase a to b was observed. During dynamic exercise cAMP in the muscle increased two fold. This increase was blocked by the prior administration of propranolol.+
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PMID:The regulation of glycogen phosphorylase and glycogen breakdown in human skeletal muscle. 613 34

Eicosapentaenoic acid prevents platelet aggregation and inhibits arachidonate conversion into thromboxane A2 and prostaglandins. Consequently eicosapentaenoic acid might protect the brain from the ischemia that follows cerebral arterial occlusion. We studied the effect of eicosapentaenoic acid on cerebral ischemia in anesthetized gerbils. Ischemia was produced by bilateral carotid occlusion for 10 min, followed by reperfusion for 60 min, in gerbils fed either a standard diet (control) or a diet supplemented with menhaden fish oil for 2 months. The menhaden fish oil contained 17 mole % eicosapentaenoic acid. Regional cerebral blood flow was measured by the hydrogen clearance method and brain water by the specific gravity technique. In control animals cerebral blood flow was decreased 30 and 60 min after reperfusion (p less than .001) and brain water was increased (p less than .001). In the experimental group cerebral blood flow did not fall during reperfusion and edema did not appear. Brain prostaglandins and thromboxane were measured by radioimmunoassay. PGF2 alpha, PGE2, 6-keto PGF1 alpha and TXB2 increased after severe ischemia and reperfusion. The synthesis of brain diene prostaglandins was not altered by eicosapentaenoic acid. Our study indicates that eicosapentaenoic acid prevented post-ischemic cerebral edema and hypoperfusion, without affecting the levels of brain diene prostaglandin and thromboxane.
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PMID:Eicosapentaenoic acid: effect on brain prostaglandins, cerebral blood flow and edema in ischemic gerbils. 632 May 4

It is clear that the combination of 31P NMR studies of muscle and of other organs with biochemical and physiological measurements is an extremely powerful method for studying cellular energetics. We have presented examples of our on-going experiments. Well defined and stable in vitro preparations of mammalian fast-twitch (cat biceps) and slow-twitch (cat soleus) muscles are developed. Erythrocyte-containing perfusate is needed for adequate oxygenation during stimulation. It is not clear why fluorocarbon suspensions are inadequate. Inorganic phosphate levels in the fast-twitch biceps as determined from NRM spectra are close to lmM, that is very much lower than the value (6 mM) derived from chemical measurements of muscle extracts. A similar discrepancy in the slow-twitch soleus cannot yet be established; if it exists, the discrepancy is small. From the metabolite contents, the free energy available from ATP splitting is similar in both muscle types: -63 kJ/mole in biceps and -57 kJ/mole in soleus. Kinetic NMR measurements indicate the creatine phosphokinase reaction is at equilibrium, and in biceps the unidirectional fluxes are 5 mumole per gram per sec. Transient alkalinization of intracellular pH during stimulation periods and acidification during recovery periods are clearly seen. In the biceps the alkalinization is much smaller than in soleus, and suggests a greater buffer capacity in fast-twitch muscles. Both muscles recovery from prolonged ischemic periods upon reperfusion, although the recovery rate is very much slower than that from 10-20 min periods of stimulation in which similar decreases of PCr and increases of Pi occur. The pattern of recovery is however quite similar. Perfused muscles may be a useful model for studying ischemia, anoxia and hypoxia and are useful preparations for a wide variety of metabolic and energetic studies of fast-twitch and slow-twitch mammalian skeletal muscles.
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PMID:Phosphorus NMR spectroscopy of cat biceps and soleus muscles. 663 20

This study was performed to determine the early and delayed metabolic effects of myocardial ischemia on the major membrane phospholipids and to reassess the potential role of lysophospholipids in the genesis of malignant dysrhythmias induced by ischemia. Samples taken from in situ hearts before ant at various intervals up to 40 minutes after abrupt ligation of LAD were extracted by the classical Folch technique with modifications to avoid artifactual lysophospholipid production and losses. Following thin layer chromatography of lipid extracts, phospholipid fractions were quantified by phosphorus estimation and lysophospholipids by a more sensitive method employing gas liquid chromatography. The total phospholipid content with the exception of lysophospholipids remained essentially constant throughout the early phases of acute ischemia, but fell by 6 and 14% after 8 and 24 ours, respectively. At 8 minutes, lysophospholipid levels n ischemic myocardium were significantly increased by 60% compared to pre-occlusion controls in the ischemic zone and by 25% in post-occlusion controls. They changed little thereafter. The molecular species of lysophospholipids remained unchanged throughout the period of ischemia studied. The mole fraction of other phospholipids as well as their fatty acyl and aldehyde profiles also were unchanged. Despite significant elevations in lysophospholipids levels, their absolute quantities were very small (0.6% of total phospholipid P) and 15-fold smaller than that reported in vitro to simulate electrophysiological manifestation of ischemia. However, such small amounts in vivo, if produced in the microenvironment of certain membrane-bound enzymes along with acidosis, hypoxia, and fatty acids, could be potentially deleterious to cell functions.
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PMID:Time course of changes in porcine myocardial phospholipid levels during ischemia. A reassessment of the lysolipid hypothesis. 724 69

The efficacy of benidipine hydrochloride in preventing myocardial ischemia and reperfusion injury was evaluated in isolated rabbit hearts (n = 28). Isovolumic left ventricular function, coronary flow, creatine phosphokinase (CPK) release, and myocardial water content were measured after ischemia during both normothermia (37 degrees C; Group I) and hypothermia (23 degrees C; Group II). After baseline measurements, hearts were induced to arrest by chilled cardioplegic solution. Each group was divided into two subgroups, depending upon whether benidipine hydrochloride (10(-9) mole/liter) was added in the cardioplegia (A, without benidipine; B, with benidipine). After 30 min of ischemia for Group I and 180 min for Group II (which added another cardioplegia every 30 min), hearts were reperfused. Measurements the same as those at baseline were carried out every 15 or 30 min for up to 60 min. Benidipine-treated hearts started beating in a shorter time than did control hearts (Group I-B, 38.7 +/- 3.7 sec vs Group I-A, 59.9 +/- 5.6; Group II-B, 36.7 +/- 2.0 vs Group II-A, 47.8 +/- 3.3). The percentage of recovery of left ventricular developed pressure after 60 min of reperfusion was significantly better in benidipine groups (P < 0.05). With respect to changes in coronary flow and CPK release after reperfusion, benidipine groups were preserved extremely well. We conclude that the addition of benidipine hydrochloride to cardioplegic solution significantly improves ventricular function after myocardial ischemia and reperfusion.
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PMID:Efficacy of benidipine hydrochloride on myocardial ischemia and reperfusion. 764 89


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