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)

The quantification of adenine nucleotides released from the heart is hampered by their rapid dephosphorylation to adenosine in the extracellular space catalyzed by highly active ectonucleotidases. To determine the total release of adenine nucleotides from isolated Langendorff-perfused guinea pig hearts, ecto 5'-nucleotidase was effectively blocked by infusion of alpha, beta-methylene-ADP (AOPCP, 50 microM). Adenine nucleotides were measured in the coronary venous effluent by the luciferin-luciferase method after enzymatic rephosphorylation to ATP. In hearts perfused at a constant flow rate (10 ml/min) with normoxic buffer (95% O2, 5% CO2) the release +/- SEM of adenine nucleotides and adenosine was 0.06 +/- 0.01 (n = 11) and 0.04 +/- 0.01 (n = 13) nmol/min. In the presence of AOPCP, the release of adenine nucleotides increased to 0.43 +/- 0.04 nmol/min (n = 9; p less than 0.05), whereas adenosine remained unchanged. Hypoxic perfusion (10% O2, 85% N2, 5% CO2) caused a threefold increase in adenine nucleotide release but a 40-fold increase in adenosine. In contrast, global ischemia (30 seconds) caused adenine nucleotide and adenosine release to rise to similar values of 1.06 +/- 0.10 and 0.80 +/- 0.14 nmol/min (n = 9). Stimulation of hearts with isoproterenol (4 nM) likewise increased the release of adenine nucleotides (0.50 +/- 0.04 nmol/min) and adenosine (0.87 +/- 0.21 nmol/min) (n = 6). To determine the cellular source of adenine nucleotides released from the heart, the coronary endothelial adenine nucleotide pool was selectively prelabeled by [3H]adenosine. Global ischemia increased the specific radioactivity of released adenine nucleotides by 57%. The findings indicate that 1) adenine nucleotides and adenosine are released at the same order of magnitude from the well-oxygenated heart; 2) beta-adrenergic stimulation and ischemia stimulate the release of adenine nucleotides and adenosine, both purines reaching vasoactive concentrations in the effluent perfusate; 3) during hypoxic perfusion only the release of adenosine is greatly enhanced; and 4) the coronary endothelium preferentially contributes to the ischemia-induced adenine nucleotide release.
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PMID:Adenine nucleotide release from isolated perfused guinea pig hearts and extracellular formation of adenosine. 174 67

To evaluate the effects of pulsatile reperfusion (PR) on the postischemic myocardial phosphometabolites, 17 sheep were put on cardiopulmonary bypass (CPB) and randomly divided into a pulsatile group (P group) and nonpulsatile group (NP group). The heart was arrested by global ischemia for 45 minutes, then defibrillated and reperfused for 2 hours while the circulation was supported by CPB. Myocardial needle biopsies were obtained, and ATP, ADP, and AMP were measured with high performance liquid chromatography. There were no significant differences between the two groups in myocardial ADP and AMP. However, after 120 minutes of reperfusion, the myocardial ATP was restored in the P group, but continued to decrease further in the NP group. Experimental results imply that PR might reduce reperfusion injury and promote recovery of the ischemic myocardium.
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PMID:Effect of pulsatile reperfusion on myocardial high energy phosphates following global ischemia. 175 Dec 46

Modeling of ischemic phenomena in vitro has been hindered by the inability to create specific alterations in the variables of interest over a defined time-frame. In particular, changes in the adenine nucleotide pool have been quite difficult to mimic because of the putative low metabolic rate in culture and the long times necessary to achieve even partial chemical energy depletion. Here we present evidence for a rapid method of producing a profound chemical energy depletion with the combination of a NADH dehydrogenase inhibitor (amytal) and a mitochondrial proton ionophore (CCCP). Treatment with our protocol in enriched spinal cultures results in a 40% decrease in ATP within 2 min and a fall to one-third of control values by 15 min. The overall pool size of the total adenine nucleotides is decreased 46% by 15 min and does not completely recover after 5 min of reenergization. The ATP/ADP ratio declines to one-third of control values during deenergization and returns to control values after 5 min in control buffer. Such a loss of the total adenylate pool closely mimics that seen in vivo during ischemia and provides an in vitro model system in which the effects of the combination of this means of cellular injury with others (e.g., excitotoxins) may be examined.
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PMID:Energy depletion in culture. Adenine nucleotides are altered as in vivo. 177 32

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.
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PMID:Adenine nucleotide degradation in cultured chick heart muscle cells. 179 25

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.
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PMID:Mechanism of loss of adenine nucleotides from mitochondria during myocardial ischemia. 181 Oct 58

Experiment with recirculating blood perfusion device showed that nicorandil 0.15 mmol/L significantly counteracted the harmful effect of ischemic and reperfused injury on the respiratory function of myocardial mitochondria. The oxidative phosphorylation efficiency (ADP/O) was increased 19% (p less than 0.01), the respiratory control rate(RCR) was also increased 40% (p less than 0.01); while the content of myocardial calcium and Ca/Mg were decreased; and the ischemia and reperfusion-induced increase of myocardial water content was abolished as compared with solvent control. The results indicate that nicorandil has protective effect on myocardial mitochondria function during ischemia and reperfusion, which may be the result of blocking Ca2+ from entering the cell and prevent lipid peroxidation.
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PMID:[Protective effects of nicorandil on myocardial mitochondria function during ischemia and reperfusion]. 183 46

Replantation of major extremities after long periods of ischemia can lead to viable replants in many cases, but functional restoration is often poor owing to fibrosis of the muscle. In this study, maximum hypothermic time in tissue transfers containing skeletal muscle using hindlimbs of Lewis rats preserved in 4 degrees C Euro-Collins solution was investigated. After preserving midthigh amputated legs in this solution for 6, 9, and 12 hours, the legs were transplanted to other inbred rats using microsurgical technique, and 1 week later, gastrocnemii were obtained to analyze ATP, ADP, and AMP using high-performance liquid chromatography. The values were compared with those for healthy legs, nonischemic operated control legs, and legs preserved in the same manner for 6, 9, and 12 hours. Histologic and serologic examinations were conducted. ATP values of the 9-hour preservation group resumed those of the nonischemic operated control group, with the values of the 12-hour preservation group remaining at 61 percent. Histologically, focal necrosis, hyaline degeneration, and regeneration processes were the most characteristic manifestations in the muscles transplanted after cold ischemia of 12 hours. It was concluded that skeletal muscle could be preserved for 9 hours in 4 degrees C Euro-Collins solution.
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PMID:Preservation of skeletal muscle in tissue transfers using rat hindlimbs. 144 16

Effects of pretreatment with L-propionylcarnitine (50 mg/kg, n = 9) or saline (n = 10) were studied in open-chest anesthetized pigs, in which ischemia was induced by decreasing left anterior descending coronary artery blood flow to 20% of baseline. After 60 min of ischemia, myocardium was reperfused for 2 h. In both groups, flow reduction abolished contractile function of the affected myocardium and caused similar decreases in ATP (by 55%) and energy charge [(ATP + 0.5ADP)/(ATP + ADP + AMP); decrease from 0.91 to 0.60], mean arterial blood pressure (by 10-24%), the maximum rate of rise in left ventricular pressure (by 26-32%), and cardiac output (by 20-30%). During reperfusion, "no-reflow" was attenuated by L-propionylcarnitine, because myocardial blood flow returned to 61 and 82% of baseline in the saline- and L-propionylcarnitine-treated animals, respectively. Cardiac output of the saline-treated animals further decreased (to 52% of baseline), and systemic vascular resistance increased from 46 +/- 3 to 61 +/- 9 mmHg.min.l-1, thereby maintaining arterial blood pressure. In L-propionylcarnitine-treated pigs, cardiac output remained at 75% of baseline, and systemic vascular resistance decreased from 42 +/- 3 to 38 +/- 4 mmHg.min.l-1. In both groups, energy charge but not the ATP level of the ischemic-reperfused myocardium tended to recover, whereas the creatine phosphate level showed significantly more recovery in saline-treated animals. We conclude that L-propionylcarnitine partially preserved vascular patency in ischemic-reperfused porcine myocardium but had no immediate effect on "myocardial stunning." Potential markers for long-term recovery were not affected by L-propionylcarnitine.
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PMID:L-propionylcarnitine increases postischemic blood flow but does not affect recovery of energy charge. 185 18

The effect of dipyridamole (DYP) on postischemic myocardial function and metabolism was studied using the isolated rabbit heart model. Twenty-one isolated rabbit heart preparations were divided into two groups: KH (control N = 10) were reperfused after 24 min normothermic hyperkalemic arrest with modified Krebs-Henseleit buffer (KH) while DYP (N = 11) were reperfused with KH and 5 X 10(-6) M DYP. Hearts were analyzed for myocardial function (DP, developed pressure, +dp/dt, -dp/dt) and metabolic function (ATP, CrP, ADP, AMP, purines, and lactate levels). Data analysis revealed significant reperfusion depression in DYP myocardial function compared with KH (P less than 0.05): DP (42 +/- 6 vs 89 +/- 7 mm Hg), +dp/dt (390 +/- 21.6 vs 1227 +/- 48.4), and -dp/dt (280 +/- 20.1 vs 677 +/- 19.8). Comparison of DYP to KH metabolic parameters was also significantly different (P less than 0.05): ATP (5.8 +/- 0.7 vs 9.5 +/- 1.4), ADP (2.1 +/- 0.2 vs 3.2 +/- 0.6), CrP (9.6 +/- 0.3 vs 17.2 +/- 1.3). Tissue purines (adenosine and inosine) were significantly elevated (P less than 0.01) in the DYP group, while coronary sinus purines and lactate loss were similar. Thus, the data suggest that DYP, present during postischemic reperfusion, depresses myocardial function by inhibiting adenosine phosphorylation, thereby decreasing the generation of high-energy phosphates without increased substrate loss or ischemia.
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PMID:Metabolic and functional cardiac impairment after reperfusion with persantine. 186 75

Noninvasive 31P nuclear magnetic resonance measurements indicate that during the initial reperfusion phase myocardial tissue contents of phosphocreatine (PCr) recover rapidly, while ATP levels remain low and recover slowly. There is also a burst of H2O2 during the first 10 min of reperfusion, as indicated by the in vivo inactivation of catalase that occurs only when H2O2, and the inactivator 3-aminotriazole (AMT), are simultaneously present. Neither H2O2 production nor CK inactivation was discernable after ischemia alone. In excitable tissue the PCr and ATP pools are equilibrated by the enzyme creatine kinase (CK), but myocardial CK activity is decreased by 20% after reperfusion, though not by simple washout. Extrapolating from the well-known air sensitivity of CK, we find that limited exposure in vitro to small concentrations of H2O2 can markedly diminish CK activity. We postulate that failure of certain CK isoenzymes at energy-using termini may decouple the relative rates of PCr production and ATP regeneration and hence cause elevated PCr-to-ATP ratios. The assumptions of 1) CK equilibrium during the reperfusion period to calculate free ADP levels and 2) cardiac recovery deduced from the elevation of PCr levels may require reexamination.
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PMID:Oxygen metabolite effects on creatine kinase and cardiac energetics after reperfusion. 187 84


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