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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cultured chick heart muscle cells degrade ATP during metabolic inhibition via ADP to AMP. Whether AMP is primarily deaminated to IMP or dephosphorylated to adenosine depends on the 'metabolic block' (glycolysis vs. oxidative phosphorylation). Inhibition of glycolysis (deoxyglucose) results in an inosine/adenosine ratio greater than 1 in the supernatant, whereas the nucleoside ratio is less than or equal to 1 during inhibition of oxidative phosphorylation (hypoxia, rotenone). EHNA, a blocker of adenosine deaminase, has little effect on inosine release during metabolic inhibition, consistent with the reported low activity of adenosine deaminase in cardiac muscle cells. The amount of adenosine and inosine released can be largely attenuated by two nucleoside carrier inhibitors, nitrobenzyl-thioinosine and dipyridamole, which suggests that nucleosides are produced intracellularly and subsequently released. These results indicate that the amount of inosine or adenosine released from the cardiomyocyte during impaired energy metabolism (e.g. ischemia) can be controlled by the metabolic state of the cell.
Mol Cell Biochem 1991 Oct 16
PMID:Adenine nucleotide degradation in cultured chick heart muscle cells. 179 25

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.
J Mol Cell Cardiol 1991 Dec
PMID:The relationship between oxygen radical generation and impairment of myocardial energy metabolism following post-ischemic reperfusion. 181 Oct 55

The effects of the vasoconstrictor peptide endothelin-1 were examined in the isolated heart during hypoxia, reoxygenation and reperfusion. Isovolumic rat hearts were perfused with Krebs-Henseleit buffer at constant pressure. Cumulative dose-response curves were obtained for endothelin-1 boluses of 0.04 to 400 pmol in five groups of hearts. Coronary flow declined with increasing dosages and was almost abolished at 400 pmol in control hearts. In hearts subjected to mild hypoxia (perfusate PO2 approximately 150 mmHg), the constrictor effect of endothelin-1 was attenuated at moderate dose compared to control hearts (4 vs. 16% flow reduction at 40 pmol; P less than 0.05). The constrictor effect was unaltered in hearts subjected to either 60 min of severe hypoxia (PO2 approximately 35 mmHg) followed by reoxygenation or to 10 min of total ischemia followed by reperfusion (stunning). When hearts were reperfused following 30 min of total ischemia (irreversible injury), the constrictor response to endothelin-1 was potentiated compared to control (e.g. 36 vs. 16% flow reduction at 40 pmol; P less than 0.05). We conclude that endothelin-1 is a potent coronary constrictor in hypoxic, reoxygenated and reperfused heart. The constrictor effect is attenuated during hypoxia, most likely due to the presence of counteracting vasodilator metabolites. During reperfusion, the constrictor effect is unchanged in stunned myocardium, but is augmented in irreversibly injured heart, due to either increased endothelin-1 binding sites or loss of counteracting vasodilator mechanisms such as prostaglandins and/or endothelium-derived relaxing factor.
J Mol Cell Cardiol 1991 Dec
PMID:Effects of endothelin-1 in the isolated heart in ischemia/reperfusion and hypoxia/reoxygenation injury. 181 Oct 56

We tested the hypothesis that loss of mitochondrial adenine nucleotides during myocardial ischemia is induced by the accumulation of inorganic phosphate (Pi) and a decrease in cytosolic ATP. In the isolated perfused rat heart, loss of mitochondrial adenine nucleotides (ATP + ADP + AMP) was preceded by the rise in tissue Pi and the loss of tissue ATP. After 30 min ischemia, the average rate of loss of mitochondrial adenine nucleotides was c. 1.5% of the initial pool/min. In isolated heart mitochondria, there are two pathways for adenine nucleotide release: a 'fast', phosphate-dependent pathway, which is inhibited by atractyloside; and a 'slow', phosphate-independent pathway, which is insensitive to atractyloside. Decreasing the pH from 7.4 to 6.5 significantly decreased the rate of release by the phosphate-dependent pathway (but not the phosphate-independent pathway). Analysis of release rates indicated that HPO4-2 is responsible for the phosphate-induced release; Vmax = 53.8% of the pool/per minute, Km = 7.5 mM. In vitro, extramitochondrial ATP inhibited adenine nucleotide release in the presence of Pi such that the rate of release was inversely proportional to the extramitochondrial [ATP]; extrapolation to zero ATP indicated a release rate of 2 to 3% of the pool/per minute, which is approximately equal to the rate of the 'slow' phosphate-independent pathway. Moreover, increasing the Pi concentration did not increase the rate of adenine nucleotide release in the presence of extramitochondrial ATP. Accumulation of mitochondrial adenine nucleotides was observed when the mitochondria were incubated in the presence of 4 mM or greater ATP. The results suggest that the rise in intracellular Pi during myocardial ischemia does not induce the loss of adenine nucleotides from the mitochondrial compartment, but rather that degradation of cytosolic ATP results in a slowing of ATP influx such that the rate of efflux (phosphate-independent) exceeds the rate of influx.
J Mol Cell Cardiol 1991 Dec
PMID:Mechanism of loss of adenine nucleotides from mitochondria during myocardial ischemia. 181 Oct 58

The present study was designed to evaluate the effects of POCA, a carnitine palmitoyltransferase I (CPT I) inhibitor, and pyruvate, a substrate inhibiting fatty acid (FA) oxidation, on post-ischemic cardiac FA accumulation on the one hand, and hemodynamic recovery and loss of cellular integrity on the other. To this end isolated, working rat hearts, receiving glucose (11 mM) as substrate, were subjected to 45 min of no-flow ischemia and 30 min of reperfusion. Hearts were perfused with or without POCA (10 microM) and/or pyruvate (5 mM). In the control group the FA content increased significantly during ischemia and remained elevated during reperfusion. Administration of POCA did not affect functional recovery and LDH release significantly, but resulted in about two-fold increased FA levels upon reperfusion as compared to glucose-perfused hearts. Pyruvate markedly improved functional recovery. Addition of this substrate did not affect lactate dehydrogenase (LDH) release, but enhanced FA accumulation during reperfusion. The combined administration of pyruvate and POCA nullified the positive effect of pyruvate on hemodynamic recovery, aggravated LDH release, and further enhanced the accumulation of FAs. The adenine nucleotide content of reperfused hearts was comparable for all groups investigated. In conclusion, during transient ischemia POCA and pyruvate markedly increased cardiac FA accumulation through inhibition of the oxidation of FAs released from endogenous lipid pools. No clear relation was found between the FA content of reperfused hearts and post-ischemic functional recovery.
J Mol Cell Cardiol 1991 Dec
PMID:Fatty acid accumulation during ischemia and reperfusion: effects of pyruvate and POCA, a carnitine palmitoyltransferase I inhibitor. 181 Oct 59

Myocardium which has been preconditioned by one or several brief episodes of ischemia has much slower energy utilization during a subsequent sustained episode of ischemia. Since preconditioned tissue also is 'stunned', the reduced energy utilization of preconditioned tissue may be due to reduced contractile effort. This study was done to assess whether differences in energy utilization persisted or disappeared under conditions of total ischemia, in vitro, when contractile activity was abolished in both control and preconditioned regions by hyperkalemic cardiac arrest. Preconditioned myocardium was produced in open-chest anesthetized dogs by exposing the circumflex bed to four 5-min episodes of ischemia each followed by 5 min of arterial reperfusion. Non-preconditioned anterior descending bed was used as control myocardium. Hearts were arrested with hyperkalemia after the last reperfusion period in order to reduce or eliminate the effects of contractile activity. Metabolite content was measured in sequential biopsies of the tissue. Large differences in the rate of energy metabolism of the two regions were noted during the first 15 minutes of ischemia. During this time, the preconditioned tissue utilized less glycogen, and produced less lactate, glucose-6-phosphate (G6P), glucose-1-phosphate (G1P), and alpha-glycerol phosphate (alpha GP), than did control myocardium. Moreover, there was a much smaller decrease in net tissue ATP in the preconditioned than in the control tissue. Thus, the decrease in the demand of preconditioned tissue for energy, which has been observed in vivo, persisted despite the elimination of differences in contractile effort between control and preconditioned myocardium. Although the cause of this decrease in energy demand in preconditioned myocardium remains unknown, the present results suggest that it is not due to concomitant stunning.
J Mol Cell Cardiol 1991 Dec
PMID:Energy metabolism in preconditioned and control myocardium: effect of total ischemia. 181 Oct 60

Myocardial glycogen and the factors which primarily regulate its metabolism were studied during post-ischemic reperfusion. Myocardial [13C]glycogen was continuously monitored by 13C-NMR spectroscopy in beating rat hearts perfused with oxygenated solutions containing [1-13C]glucose (5 mM) and insulin, during normal flow at 15 ml/min (n = 5), and during reperfusion after 30 min of 1 ml/min (n = 5), or 0 ml/min (n = 4) ischemia. Mean myocardial [13C]glycogen fell during reperfusion from 1.1 +/- 0.6 at the end of zero-flow ischemia to 0.4 +/- 0.4 mumol of [13C]glucosyl units/g wet wt (P less than 0.02) over the first 7 min of reperfusion; it also fell during reflow following 1 ml/min ischemia, from 2.3 +/- 1.4 to 1.7 +/- 1.0 mumol (P less than 0.03) over the same interval. In parallel experiments, glycogen phosphorylase % a (GPA%) content was higher at the end of 30 min of 0 ml/min (37.3 +/- 7.3%, P less than 0.01), and trended higher after 1 ml/min flow (30.8 +/- 12.1%, P = 0.18) than under baseline conditions (20.1 +/- 7.4%). However GPA% returned to baseline values within 1 min of reflow after both 0 and 1 ml/min ischemic periods (20.6 +/- 3.0% and 19.0 +/- 8.0%, respectively). Inorganic phosphate, as determined by simultaneous 31P-NMR, remained elevated during early reperfusion relative to baseline, and significantly correlated with the extent of decline in [13C]glycogen during reperfusion (r = 0.79, P less than 0.01). Thus, glycogen breakdown continues to occur during early post-ischemic reperfusion, but the mechanism is not related to elevated GPA%, and may be due to persistently increased inorganic phosphate at that time.
J Mol Cell Cardiol 1991 Dec
PMID:Regulation of myocardial glycogenolysis during post-ischemic reperfusion. 181 Oct 61

The effects of hypothermic ischemia and reperfusion on sarcolemma and sarcoplasmic reticulum Ca2+ transport were studied in vesicles isolated from rabbit hearts. Hypothermic global ischemia was produced by immersing hearts in saline at 4 degrees C for 3 h. Following hypothermic ischemia, reperfusion was carried out for 40 min using a Langendorff perfusion system for the working heart. Na+,K(+)-ATPase activity of sarcolemmal vesicles (SL), was not depressed by hypothermic ischemia nor by ischemia and reperfusion. The initial rate of Na(+)-Ca2+ exchange in SL vesicles was not depressed, but the maximum amount of Ca2+ uptake was increased both after hypothermic ischemia and after reperfusion. Ca2+ uptake activity of sarcoplasmic reticulum vesicles (SR) isolated from hearts subjected to hypothermic ischemia was slightly lower than that of control, and was further reduced following reperfusion. Ca(2+)-ATPase activity of SR was unaffected by hypothermic ischemia, while it was markedly lowered after reperfusion. Although the phosphoenzyme level in SR vesicles was slightly decreased, the turnover rate was reduced after reperfusion. Reperfusion injury thus took place mainly in SR while SL appeared to be tolerant to ischemia and reperfusion.
J Mol Cell Cardiol 1991 May
PMID:Effect of hypothermic ischemia and reperfusion on calcium transport by myocardial sarcolemma and sarcoplasmic reticulum. 183 91

Using 31P-NMR the existence of Na+/H+ exchange system and its contribution to intracellular pH (pHi) regulation were examined in the isolated isovolumic rat heart under physiological and pathophysiological conditions. Ethylisopropylamiloride (EIPA) was used as a tool to search into the role of Na+/H+ exchange system. In the normal well-oxygenated heart dose-dependent negative chronotropic effects were observed with 10(-6) to 10(-5) M EIPA. After 10(-4) M the heart ceased to beat and a progressive fall of high energy phosphates compounds occurred. However, contrary to expectation pHi did not fall but rose after EIPA. In NH4Cl-loaded hearts removal of NH4Cl resulted in a fall of the pHi followed by a rapid recovery to the normal pHi. After 10(-5) M EIPA the fall of pHi became greater and there was no recovery within 35 min of observation period. This dose of EIPA, however, did not affect the time course of changes in the pHi during 60 min of low-flow ischemia (0.2 ml/min). It is concluded that pHi regulation following an acute acid loading is dependent on amiloride-sensitive Na+/H+ exchange. However, Na+/H+ exchange system does not play an important role in maintenance of the pHi under normoxic or ischemic condition. In the normoxic heart EIPA produced a decrease in heart rate without producing any change either in myocardial energy metabolism or in pHi. Thus, the compound could be categorized as a bradycardic agent.
J Mol Cell Cardiol 1991 Apr
PMID:Na+/H+ exchange is not operative under low-flow ischemic conditions. 183 54

The effect of inhibition of the mitochondrial ATPase with oligomycin on the rate of ATP depletion and anaerobic glycolysis was studied in the totally ischemic dog heart. An oxygenated, buffered crystalloidal solution containing 10 microM oligomycin and 12 mM glucose was delivered at 100 mmHg pressure to the circumflex bed of the excised cooled heart. Buffered solution without oligomycin was delivered simultaneously to the anterior descending bed of the same heart. Little metabolic evidence of ischemia developed until the heart was made totally ischemic by incubating it in a sealed plastic bag at 37 degrees C. Successful inhibition of the mitochondrial ATPase was confirmed by the absence of both mitochondrial ATPase activity and the loss of respiratory control in mitochondria isolated from treated tissue. ATP, glycolytic intermediates and catabolites of the adenine nucleotide pool were measured in the control and treated beds at various intervals during 120 min of ischemia. Inhibition of the ATPase resulted in slowing of the rates of ATP depletion and anaerobic glycolysis (estimated by lactate accumulation). Also, degradation of the adenine nucleotide pool occurred more slowly in the inhibited group. These data establish that about 35% of the ATP utilization observed during the first 90 min of total ischemia in the canine heart is due to mitochondrial ATPase activity.
J Mol Cell Cardiol 1991 Dec
PMID:Effect of inhibition of the mitochondrial ATPase on net myocardial ATP in total ischemia. 183 1


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