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)

A stable free-radical polymeric derivative of prostaglandin B1 (PGBx) has been synthesized that exhibits regenerative effects on oxidative phosphorylation in aged mitochondria. The molecular weights of the most active preparations fall between 2000 and 2600. PGBx is characterized by a single-line electron spin resonance spectrum that is stable at room temperature. PGBx restores phosphorylating ability and net ATP synthesis in isolated mitochondria aged for 4 days at 0 degrees C and protects against further degradation of phosphorylating activity when such aged mitochondria are preincubated at 28 degrees C in the absence of adenine nucleotide phosphate acceptors. This compound has been reported to exert beneficial effects in vivo in experimental pathological conditions, such as regional ischemia, in which the mitochondria of the ischemic region may have been damaged.
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PMID:Protection and reactivation of oxidative phosphorylation in mitochondria by a stable free-radical prostaglandin polymer (PGBx). 28

The loss of NADH-ubiquinone oxidoreductase activity, the activity of mitochondrial electron transfer complex I, underlies the loss of mitochondrial phosphorylating respiration with NAD-linked substrates observed during myocardial ischemia. In the present study the loss of complex I activity was found to be considerably more rapid during zero-flow ischemia in rat heart, a fast heart-rate heart, than in dog heart, a slow heart-rate heart. Moreover, the greater rapidity of the loss of complex I activity in the ischemic rat heart appeared to reflect the more rapid and more severe decreases in tissue pH and in tissue ATP characteristic of the zero-flow ischemic rat heart compared to zero-flow ischemic dog heart. In vitro enzyme inactivation studies on dog heart electron transfer complex I showed that the enzyme was approximately 40% inactivated after 1 minute by incubation at pH 6.0 in the absence of added ATP. The effect of low pH upon enzyme activity was mitigated considerably by the presence of one to two mM MgATP in the incubation mixtures. Moreover, a portion of the activity-sparing effect of MgATP was still observed in the presence of the uncoupler, FCCP. This latter observation suggests that part of the function-stabilizing effect of ATP was attributable to inner membrane energization and part appeared to have been due to a direct protective effect of ATP upon the complex.
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PMID:Effects of acidosis and ATP depletion on cardiac muscle electron transfer complex I. 174 4

An isolated rabbit heart preparation was used to characterize the effects of hypothermia on the deterioration in mitochondrial respiratory function and on the calcium overload that occurs during ischemia and reperfusion. Hearts were perfused aerobically with an asanguineous solution for 120 minutes or made totally ischemic for 90 minutes at 37 degrees, 34 degrees, 28 degrees, 22 degrees C, respectively, and reperfused for 30 minutes at 37 degrees C. Mitochondrial function was assessed by measuring calcium content, yield, oxygen consumption, and adenosine triphosphate-producing capacities. In addition, the mechanical function of the hearts was measured together with tissue adenosine triphosphate, creatine phosphate, and calcium content. In a separate series of experiments, the effect of temperature on the initial rate of respiration-supported calcium accumulation of mitochondria from freshly excised, nonperfused rabbit hearts was determined. The hearts made ischemic at 37 degrees C were severely depleted of tissue adenosine triphosphate and creatine phosphate. Their mitochondria accumulated calcium and the oxidative phosphorylating activity was impaired. During reperfusion, tissue and mitochondrial calcium levels were substantially increased, state 3 of mitochondrial respiration was further impaired, and the adenosine triphosphate-generating capacities were severely reduced. Diastolic pressure increased and there was no recovery of developed pressure. Isolated mitochondrial function of hearts made ischemic at 28 degrees and 22 degrees C was protected. There was a less marked increase in tissue and mitochondrial calcium, and the initial rate and total production of adenosine triphosphate were maintained. In these hearts there was an almost complete recovery of mechanical performance at reperfusion, whereas the ischemia-induced depletion of tissue adenosine triphosphate and creatine phosphate was not significantly reduced by hypothermia. The hearts made ischemic at 34 degrees C were only partially protected. These data suggest that a decrease in temperature from 37 degrees to 22 degrees C during ischemia did not significantly prevent depletion of adenosine triphosphate at the end of ischemia but reduced tissue and mitochondrial calcium overload, maintaining mitochondrial function. Thus in our experiments the protective effect of hypothermia might be related to a direct reduction of tissue and mitochondrial calcium accumulation rather than to a slowing in rates of energy utilization. This possibility is supported by the finding that in freshly excised, nonperfused rabbit hearts, hypothermia significantly reduced the initial rate of mitochondrial calcium transport.
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PMID:Effects of temperature on myocardial calcium homeostasis and mitochondrial function during ischemia and reperfusion. 232 31

The effect of the beta-adrenoceptor antagonist metipranolol given twice daily in a dose of 0.5 mg/kg body weight for 3 days on respiration, respiratory control index of mitochondria and oxidative phosphorylation was measured in the heart muscle of anesthetized dogs after 60 min of induced ischemia. In control animals pretreated with saline, all measured variables with the exception of the coefficient of oxidative phosphorylation were significantly decreased. In contrast, pretreatment with metipranolol significantly improved all measured myocardial metabolic variables. The effect of metipranolol on the oxidative phosphorylating processes was more pronounced when the metabolic substrate was glutamate than when it was pyruvate.
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PMID:Cardioprotective effect of metipranolol on ischemic heart muscle. 257 Jun 31

To establish if the administration of gallopamil, a derivative of verapamil, protects heart muscle against the deleterious effect of ischemia and subsequent reperfusion, rabbits were injected subcutaneously twice daily with 2 mg/kg of Gallopamil for 5-6 days. The hearts were isolated and perfused with aerobic Krebs-Henseleit buffer solution by the Langendorff method. The hearts were paced (180 b/min) and wall temperature was controlled. Ischemia was induced by reducing coronary flow from 25 ml/min to 1 ml/min for 90 min and then the hearts were reperfused for 30 min. At the end of either the ischemic period or reperfusion, the hearts were assayed for ATP, CP, and calcium. Others were homogenized, their mitochondria harvested and monitored for oxidative phosphorylating and ATP generating activity as well as calcium content and uptake. The mechanical function of the hearts and noradrenaline release was also measured. Hearts that were made ischemic gained calcium, their endogenous stores of ATP and CP were depleted, their mitochondria had reduced RCI and state 3 respiration and increased calcium concentrations. During reperfusion tissue and mitochondrial calcium was significantly increased, the capacity of mitochondria to use oxygen for state 3 respiration was further impaired and their ATP generating capacity reduced. Diastolic pressure increased and there was no recovery of developed pressure and important noradrenaline release. Pretreatment with gallopamil protected the mitochondria against the ischemically induced changes in RCI, state 3 respiration. There was also a less marked rise in tissue and mitochondrial calcium and a reduced increase of diastolic pressure. Gallopamil also diminished the effect of reperfusion on the calcium accumulating activity of mitochondria and on the decline in the ATP generating and oxygen utilizing capacity of the mitochondria. The tissue levels of ATP and CP were better maintained, and noradrenaline release was reduced, the systolic pressure generating capacity was enhanced by the treatment with gallopamil. These results are discussed in accordance with the hypothesis that this drug protects heart muscle against the deleterious effects of ischemia and reperfusion by ensuring that sufficient ATP remains available to maintain homeostasis with respect to calcium.
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PMID:Protective effects of gallopamil against ischemia and reperfusion damage. 263 74

The aim of this study was to investigate if dilazep is able to reduce with a direct protective action on the myocardium the deleterious effects caused by ischaemia and reperfusion. For this purpose we used an isolated rabbit heart preparation. The hearts were either perfused aerobically or made totally ischaemic for 60 min (by abolishing coronary flow) or made ischaemic for 60 min and then reperfused for 30 min. Ischaemic and reperfusion damage was measured in terms of alteration in mechanical function, lactate and CPK release, mitochondrial function and tissue content of Adenosine Triphosphate (ATP), Creatine Phosphate (CP) and calcium. Dilazep (10(-5) M) was administered in the perfusate either 20 minutes before ischaemia or only during post-ischaemic reperfusion. Ischaemia induced a decline of the endogenous stores of ATP and CP, followed by an alteration of calcium homeostasis with increase of diastolic pressure, mitochondria calcium overload and impairment of the oxidative phosphorylating capacities. On reperfusion, tissue and mitochondrial calcium increase the capacity of the mitochondria to use O2 for state III respiration was further impaired and the ATP-generating capacity reduced. Diastolic pressure increased and there was only a small recovery of active tension generation associated with massive CPK release. Administration of dilazep before ischaemia induced a negative inotropic effect which, in turn, resulted in a slowing of the rate of CP and ATP depletion during ischaemia. This protected the hearts against the ischemic, and reperfusion-induced decline in the ATP-generating and O2-utilizing capacities of the mitochondria. In addition, there was a less marked increase in tissue and mitochondrial Ca++, CPK and lactate release were reduced and the recovery of developed pressure on reperfusion was significantly increased. Administration of dilazep during reperfusion failed to modify the exacerbation of ischaemic damage caused by the readmission of coronary flow. These data suggest that dilazep benefits the ischaemic myocardium via an ATP sparing action.
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PMID:Mechanism of myocardial protective action of dilazep during ischaemia and reperfusion. 362 58

Respiratory and phosphorylating capacities of kidney mitochondria were distinctly decreased within early (1.5 hr) and late (1 day) postischemic periods after long-term (2-3 hrs) ischemia of rat kidney. Preadministration of adenine (ADP, AMP) and pyridine (NAD) nucleotides into the animals prevented the decreases, while vitamin E, heparin, trifluoroperazine or aminazine proved to be ineffective. Depletion of mitochondrial nucleotide pool, which occurred during long-term ischemia of kidney and were maintained within the post-ischemic period, appears to be responsible for impairment of oxidative phosphorylation.
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PMID:[Changes in and pharmacological correction of oxidative phosphorylation in regional kidney ischemia]. 376 3

Hemodynamic and mitochondrial function recover following 60 minutes of ischemic arrest and reperfusion in hearts pretreated with verapamil. The present study was carried out to determine whether verapamil prevents the onset of mitochondrial oxidative impairment after 60 minutes of ischemic arrest without reperfusion. Two preparations of mitochondria isolated following Polytron homogenization and subsequent treatment of the myofibrillar pellet with Nagarse were examined for phosphorylating respiration. The Polytron mitochondria were more sensitive to ischemic arrest than were the Nagarse mitochondria with either glutamate-malate (57% vs. 22% inhibition), succinate (+ rotenone) (41% vs. 14% inhibition), or palmitoylcarnitine (57% vs. 27% inhibition) as respiratory substrates. Verapamil pretreatment significantly increased oxidation of all substrates by the subsequently isolated Polytron mitochondria, but only succinate-supported respiration returned to control levels. In contrast, the small amount of respiratory inhibition exhibited by the Nagarse mitochondria after ischemic arrest was insensitive to verapamil pretreatment. We conclude that the Polytron preparation of mitochondria is more susceptible to ischemia than the Nagarse mitochondria, and this susceptibility correlates with a striking sensitivity to verapamil protection. In general, oxidation of NADH-linked substrates, including palmitoylcarnitine, is more affected by ischemic arrest than succinate, and only oxidation of the latter substrate is totally protected by verapamil. The beneficial action of verapamil on mitochondrial function occurs prior to reperfusion. The data suggest that alterations in calcium homeostasis occur during the ischemic period, as well as in the subsequent reperfusion period.
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PMID:Protection of canine cardiac mitochondrial function by verapamil-cardioplegia during ischemic arrest. 399 98

Studies were undertaken to determine the mechanisms leading to altered mitochondrial function in ischemic myocardium. A new procedure has been developed to routinely isolate 60-70% of the total mitochondrial protein from heart tissue. After 1 hour of ischemia, mitochondria exhibit decreases of more than 50% in phosphorylating respiration for both NADH- and succinate-linked substrates compared to controls. However, no significant decreases in the efficiency of mitochondrial ATP synthesis (ADP:0) or ATPase activity are observed. Rates of substrate-driven Ca2+ uptake exhibit decreases greater than that seen with phosphorylating respiration with incomplete uptake and premature release of Ca2+. Spectrophotometric measurements in ischemic heart reveal rapid oxidation or loss of mitochondrial NADH with marked "swelling" of the inner membrane compartment; both changes parallel the loss of Ca2+. Significant losses in intramitochondrial adenine nucleotides also are found. Mitochondrial retention of accumulated Ca2+ can be restored by addition of small amounts of exogenous adenine nucleotides (ATP or ADP) with concomitant attenuation of both NADH oxidation and "swelling." The data indicate that, following 1 hour of ischemia, the efficiency of mitochondrial ATP production is still relatively intact whereas both electron transport chain activity and calcium transport are severely compromised. These decreases appear to be related to selective membrane damage in the mitochondrial inner membrane.
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PMID:Mechanism(s) of altered mitochondrial calcium transport in acutely ischemic canine hearts. 625 87

Left anterior descending coronary artery occlusion in anesthetized pigs produced a stable transmural ischemia characterized by a rapid and then sustained loss of blood flow and mechanical function. After 2 h of occlusion, mitochondria from the ischemic area exhibited a 36 +/- 6% drop in state 3 respiratory activity (QO2) supported by the NAD-linked substrates, glutamate plus malate, but only a 5 +/- 3% decrease in QO2 with succinate plus rotenone. The activity of electron transfer complex I (NADH-CoQ reductase) decreased commensurately by 33 +/- 4% with the decrease in QO2 with NAD-linked substrates. Consistent with the nearly unchanged QO2 with succinate plus rotenone, the activities of electron transfer complexes III and IV decreased only slightly by 9 +/- 5% and 9 +/- 4%, respectively. Mitochondrial ATPase (complex V) activity decreased by 48 +/- 2% with little change in its oligomycin sensitivity. A 48% drop in ATPase activity was shown, by means of oligomycin titrations, to correspond to a 32% decrease in NAD-linked substrate supported QO2. The decreases observed in NADH-CoQ reductase and ATPase activities each account nearly quantitatively for the impaired mitochondrial phosphorylating respiration observed during sustained myocardial ischemia. These results suggest that mitochondrial inner enzyme complexes I and V are important sites of cellular injury in myocardial ischemia.
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PMID:Mitochondrial inner membrane enzyme defects in porcine myocardial ischemia. 645 Nov 85


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