UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute myocardial ischemia provokes sensitization of the adenylyl cyclase system. This sensitization can be differentiated in a receptor-specific and an enzyme-specific sensitization. The receptor-linked sensitization is characterized by an increase of beta-adrenergic receptors in the plasma membranes after 15 mins of global ischemia (49.8 +/- 3.6 to 67 +/- 6 fmol/mg protein) followed by a further increase (89 +/- 4 fmol/mg protein) after 50 min of ischemia in isolated perfused hearts. Concomitantly functionally coupled receptors which are able to bind the beta-agonist with high affinity, increased by 32% after 15 min and by 57% after 50 min of ischemia. The affinities of the receptors for their agonists or their antagonists remain unchanged. Maximally isoproterenol-stimulated adenylyl cyclase activity rose from 66 +/- 7 to 101 +/- 10 pmol cAMP/min/mg protein after 15 min of global ischemia indicating the beta-receptor-specific sensitization of the beta-adrenergic system. This sensitization was followed by a gradual decline of the adenylyl cyclase activity after 30 and 50 min of global ischemia. Additionally, 15 min of myocardial ischemia induced an enzyme-linked sensitization of the adenylyl cyclase activity as indicated by an increase of the forskolin-stimulated activity by about 25% (300 +/- 20 vs 378 +/- 25 pmol cAMP/min/mg protein). In contrast after 50 min of ischemia the total adenylyl cyclase activity declined (232 +/- 24 pmol cAMP/min/mg protein) despite the persistent increase of beta-adrenergic receptors in the plasma membranes. These data demonstrate that the enzyme-specific sensitization is only transient. The early sensitization and late inactivation of the adenylyl cyclase activity occurred independently of receptor activation and could not be prevented by beta-blockade (10(-6) M alprenolol). Cyanide perfusion (1 mM), used to block energy metabolism, lead to energy depletion similar to acute myocardial ischemia. This resulted in an increase of functionally coupled receptors with a time course comparable to that of global ischemia. Additional perfusion with desensitizing concentrations of the beta-agonist isoproterenol did not induce uncoupling or internalization of beta-adrenergic receptors in cyanide treated hearts, suggesting that the rise in functionally coupled receptors is due to a redistribution in part caused by the abolition of continuous receptor internalization. In contrast, the enzyme-linked sensitization is independent of cellular localization of the beta-adrenergic receptors. The increased activity was carried by the enzyme even after partial purification with solubilization and wheat germ affinity chromatography. These data suggest an ischemia-induced, covalent modification of the adenylyl cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Dual sensitization of the adrenergic system in early myocardial ischemia: independent regulation of the beta-adrenergic receptors and the adenylyl cyclase. 196 11

Epicardial cells are more susceptible to the electrophysiological effects of ischemia than are endocardial cells. To explore the ionic basis for the differential electrophysiological responses to ischemia at the two sites, we used patch-clamp techniques to study the effects of ATP depletion on action potential duration and the ability of ATP-regulated K+ channels in single cells isolated from feline left ventricular endocardial and epicardial surfaces. During ATP depletion by treatment with 1 mM cyanide (CN-), shortening of action potential durations was significantly greater in epicardial cells than in endocardial cells. Thirty minutes after initiating exposure to 1 mM CN-, action potential duration at 90% repolarization was reduced to 0.70 +/- 0.12 of the control value for endocardial cells versus 0.39 +/- 0.18 for epicardial cells (p less than 0.01), and action potential duration at 20% repolarization was reduced to 0.72 +/- 0.13 for endocardial cells versus 0.12 +/- 0.09 for epicardial cells (p less than 0.01). In both endocardial and epicardial cells, the shortening of action potential by CN- treatment was partially reversed by 0.3 microM glibenclamide; the magnitude of reversal, however, was much greater in epicardial cells. After exposure to 1 mM CN-, the activity of ATP-regulated K+ channels in cell-attached membrane patches was significantly greater in epicardial cells than in endocardial cells. To study the dose-response relation between ATP concentration and open-state probability of the channels, intracellular surfaces of inside-out membrane patches containing ATP-regulated K+ channels were exposed to various concentrations of ATP (10-1,000 microM). The concentration of ATP that produced half-maximal inhibition of the channel was 23.6 +/- 21.9 microM in endocardial cells and 97.6 +/- 48.1 microM in epicardial cells (p less than 0.01). These data indicate that ATP-regulated K+ channels are activated by a smaller reduction in intracellular ATP in epicardial cells than in endocardial cells. The differential ATP sensitivity of ATP-regulated K+ channels in endocardial and epicardial cells may be responsible for the differential shortening in action potentials during ischemia at the two sites.
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PMID:Role of cardiac ATP-regulated potassium channels in differential responses of endocardial and epicardial cells to ischemia. 203 19

Ischemia may cause increased or decreased distensibility of the left ventricle, but the cellular mechanisms involved have not been clarified. We examined the possible contributions of changes in intracellular inorganic phosphate, pH, and Ca2+ concentrations to altered diastolic function in cultured myocytes subjected to partial metabolic inhibition. Paced cultured embryonic chick and adult rabbit ventricular myocytes superfused with 20 mM 2-deoxyglucose (2DG) exhibited an increase in end-diastolic intracellular free calcium concentration ([Ca2+]i) and an upward shift in end-diastolic cell position. These results indicate that glycolytic blockade increases diastolic and systolic calcium in paced ventricular myocytes, and that this elevated diastolic calcium influences the extent of diastolic relaxation. In contrast, paced ventricular myocytes superfused with 1 mM cyanide (CN) exhibited a similar increase in end-diastolic [Ca2+]i but a decrease in end-diastolic cell position and amplitude of motion. Although changes in ATP contents were similar in both groups (2DG, -29.9%; CN, -40.1%), alterations of intracellular pH and inorganic phosphate concentrations were different. In 2DG-treated cells, pHi did not decrease significantly (7.18 +/- 0.04 to 7.12 +/- 0.11, n = 14) but in the CN group it decreased markedly within 6 min (7.18 +/- 0.04 to 6.76 +/- 0.11, n = 11, P less than 0.01). Intracellular inorganic phosphate decreased slightly in the 2DG group (-14.8%, NS) but increased in cells exposed to CN (45.7%, P less than 0.02). We conclude that while a prominent increase in diastolic [Ca2+]i occurs in rapidly paced ventricular myocytes exposed to either inhibitors of glycolysis or oxidative phosphorylation, the effects of this increase in [Ca2+]i on diastolic distensibility may be influenced by intracellular accumulation of metabolites that decrease the sensitivity of myofilament to [Ca2+]i.
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PMID:Contributions of [Ca2+]i, [Pi]i, and pHi to altered diastolic myocyte tone during partial metabolic inhibition. 205 30

In isolated adult rat myocytes, we tested the hypothesis that metabolic inhibition and simulated ischemia regulate the NADH/NAD+ redox couple with concomitant impairment of energy-dependent process, including contraction and maintenance of high-energy phosphate stores. We developed a method to examine the relationship among the redox couple, ATP content, and contractile performance in single cells under several conditions analogous to myocardial ischemia, with and without reperfusion. Myocytes were paced at 1 Hz while cell contraction and NADH fluorescence were determined simultaneously for single cells at 37 degrees C. Cells were exposed to cyanide and 2-deoxy-D-glucose (metabolic inhibition) or to metabolic inhibition plus 12 mM KCl and 20 mM lactate at pH 6.5 (simulated ischemia). Pyridine nucleotide fluorescence signals from single cells studied in this fashion could be modulated by metabolic inhibitors in a manner similar to that classically described for isolated mitochondria. Metabolic inhibition or simulated ischemia quickly produced maximal reduction of NAD+ to NADH. When cells were exposed to simulated ischemia for 10 min, then superfused with glucose-containing control buffer, 28% of cells exposed to conditions of simulated ischemia developed hypercontracture on reperfusion. Hypercontracture developed despite mitochondrial electron transport being reestablished. When myocyte suspensions in a cuvette were studied spectrofluorimetrically, the pyridine nucleotide fluorescence response to metabolic inhibitors was similar to that for a single cell. This permitted correlation of ATP determinations on cells in suspension with contractile and fluorescence measurements from single myocytes. In the absence of glycolysis there is correspondence among loss of electron transport, decline in high-energy phosphate concentration, and decline in contraction. Irreversible disruption of the electron transport process does not appear to be an early event in ischemic injury.
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PMID:NADH measurements in adult rat myocytes during simulated ischemia. 205 13

The ATP-sensitive potassium channel (KATP channel) is a unique ionophore in that it appears to reflect cell metabolism. In the brain, the highest density of binding sites for the KATP channel is the substantia nigra. To evaluate the role of the KATP channel in this key brain area for motor control, we used exposure to cyanide to lower intracellular ATP and thereby mimic anoxia and ischemia. Treatment with cyanide caused the activation of a potassium current in a sub-population of nigral neurones with distinct pharmacological and electrophysiological properties. The response to cyanide was abolished by the sulphonylurea tolbutamide, a potent blocker of the KATP channel. These results suggest that in the substantia nigra, the KATP channel plays a pivotal role in normal mechanisms of neuronal homeostasis in response to anoxia and ischaemia. The significance of these findings for our understanding of the cellular mechanisms in Parkinsonian degeneration is discussed.
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PMID:ATP-sensitive potassium channels counteract anoxia in neurones of the substantia nigra. 206 41

The effects of various metabolic inhibitors on the time course of changes in membrane potential was studied using intracellular recordings from CA1 hippocampal neurons in vitro. Concurrent application of cyanide and iodoacetic acid, agents which block oxidative phosphorylation and glycolysis respectively, result in more rapid loss of membrane function than blockade of either pathway alone. This pharmacological regimen mimics the anoxia and the hypoglycemia encountered during ischemia in vivo, both in terms of the metabolic derangement as well as the time course of changes in membrane function. Thus, this treatment appears to represent a well-controlled pharmacological model of ischemia in vitro.
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PMID:A pharmacological model of ischemia in the hippocampal slice. 228 Aug 93

Previous work in this laboratory has demonstrated a reduction by the nephrotoxic beta-lactam antibiotics cephaloridine, cephaloglycin and imipenem of renal mitochondrial uptake of and respiration with the anionic substrate succinate. The present studies were done to test further the hypothesis that reduced substrate uptake and decreased respiration are causally related. Using cephaloridine in the rabbit, we examined the specificity of this association in regard to the toxic cephalosporin insult, the involvement of renal mitochondria and the reduction of carrier-mediated anionic substrate transport. 1) Specificity of insult in renal cortical mitochondria: cephaloridine (300 mg/kg bwt. i.v., 1 hr before sacrifice) reduces both the uptake of and respiration with succinate, whereas the same dose of cephalexin, which is not nephrotoxic, has neither effect; 25 min of acute unilateral renal artery occlusion reduces both the uptake of and respiration with succinate, but, unlike cephaloridine, ischemia causes a large increase of substrate efflux; and the respiratory toxins cyanide (1 mM) and oligomycin (2 micrograms/g of protein) reduce respiration by a direct effect on the mitochondrial respiratory chain and therefore have no effect on substrate uptake. 2) Specificity of target organ: cephaloridine has no significant effect on either the uptake of or respiration with succinate in hepatic mitochondria.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The renal mitochondrial toxicity of cephalosporins: specificity of the effect on anionic substrate uptake. 229 4

Ischemic induces a nonexocytotic noradrenaline release in the heart, which leads to high and potentially harmful interstitial noradrenaline concentrations. The effect of beta-adrenoceptor antagonists on noradrenaline release in ischemia has been investigated in the present study. DL-Propranolol (1-100 mumol/l) concentration-dependently reduced noradrenaline release during 20 min of global and total ischemia in the perfused rat heart. Other beta-adrenoceptor blocking agents such as atenolol, metoprolol, and timolol (10 mumol/l each), however, did not share this effect. Moreover, both stereoisomers of propranolol were equipotent in suppression of ischemia-induced noradrenaline release, indicating a property of propranolol independent from interaction with beta-adrenoceptors. The well known local anesthetic action of propranolol was not likely to cause its inhibitory effect on ischemia-induced noradrenaline release, as lidocaine (10 mumol/l) did not affect noradrenaline overflow in ischemia. The effect of propranolol was further examined in cyanide intoxication, an experimental model of energy depletion. In this experimental setting the release of dihydroxyphenylethyleneglycol--the major neuronal metabolite of noradrenaline--served as indicator of increased axoplasmic noradrenaline levels which are present during nonexocytotic noradrenaline release. In cyanide intoxication DL-propranolol also reduced noradrenaline overflow but did not affect release of dihydroxyphenylethylene glycol. The latter finding suggests an interaction of propranolol with the neuronal membrane transport of noradrenaline. In ischemia and cyanide intoxication, transport of noradrenaline across the plasma membrane is known to be driven by the noradrenaline carrier (uptake1) working in reverse of its normal direction--from inside to outside. Consequently, inhibitors of the noradrenaline carrier like desipramine were shown to suppress nonexocytotic noradrenaline release in ischemia and cyanide intoxication.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Propranolol inhibits nonexocytotic noradrenaline release in myocardial ischemia. 231 83

To investigate the functional role of renal intrinsic antioxidant enzymes (AOEs), the levels of AOE activities in isolated glomeruli and the changes in renal function to oxidant insults were assessed in normal control rats (NC, N = 23) and rats subjected to 30-minutes of complete renal ischemia for three days (day-3, N = 20) or six days (day-6, N = 23) prior to study. When compared to NC, the activities of total and manganese (cyanide-insensitive) superoxide dismutase, glutathione peroxidase, and catalase were increased more than twofold in day-6 animals, on average, from 36 +/- 4 U/mg protein, 9 +/- 1 U/mg protein, 129 +/- 21 U/mg protein and 1.32 +/- 0.20 k/mg protein, respectively, to 80 +/- 5, 27 +/- 3, 283 +/- 41 and 3.20 +/- 0.20, respectively (P less than 0.05 for all). There were no changes in AOE activities in day-3 animals. In day-6 animals, however, the activities of non-AOEs, LDH and fumarase were found to be unaffected. Separate groups of NC (N = 12), day-3 (N = 5) and day-6 (N = 12) rats were subjected to either 30 minutes of ischemia plus 60 minutes of reperfusion (I/R) or unilateral i.a. infusion of hydrogen peroxide (H2O2, 35 mu moles in 1 hr). The degree of reduction in inulin and para-amino hippurate clearance rates following I/R were significantly less in day-6 (-21 +/- 3% and -12 +/- 2, respectively) compared to NC (-69 +/- 9% and -59 +/- 11, respectively) or day-3 rats (-73 +/- 7% and -62 +/- 10, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of intrinsic antioxidant enzymes in renal oxidant injury. 240 19

Failure of the myocardium to take up Thallium-201 is widely used as a diagnostic marker for ischemia or infarction. Although this is commonly related to a reduction in coronary flow or myocardial perfusion, other possible metabolic factors are poorly understood. The present studies investigated the influence of various interventions, designed to simulate the metabolic consequences of ischemia, on thallium-204 uptake and release in cultured myocardial cells. In these cells, where thallium exchanged rapidly (t 1/2 = 5 min.), and 60% of thallium uptake occurred via the sodium pump, thallium uptake was markedly influence by changes in extracellular potassium. Increasing extracellular potassium from a physiologic level of 5 mM to those levels reported to occur in ischemic myocardium (7.5 mM to 18 mM) effected a 25% to 60% reduction in thallium influx. The decrease in thallium influx produced by increasing extracellular potassium was rapid (30 sec.) in onset and readily reversible by restoring extracellular potassium towards normal. Changes in extracellular pH in the range 6.4 to 8.0 had no demonstrable effect on thallium uptake despite the fact that this was accompanied by similar, although less marked, changes in intracellular pH. Addition of adenine nucleosides, adenosine, inosine and hypoxanthine, to the incubating solution in concentrations from 1 nM to 0.1 mM had no effect on thallium influx or efflux in the cells. This observation held true even when 10 microM dipyridamole was used to inhibit nucleoside uptake by the cells. Addition of 1 mM 2, 4-dinitrophenol or 4 mM potassium cyanide to the cultures maximally inhibited 42% of the thallium influx within 30 min.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of ischemia-related metabolic factors on thallium exchange in cultured rat myocardial cells. 242 79

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