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)

We studied the effect of selected metabolic substrates on recovery of myocardial function and ATP concentration when added to the reperfusate after normothermic ischemia. The hearts of 30 anesthetized, open-chest mongrel dogs were subjected to 45 min of global ischemia at 37 degrees C followed by 90 min of reperfusion. Left ventricular function curves were generated on right heart bypass before and at 30 min intervals after the ischemic period. ATP concentration was measured before, at the end of, and 90 min after the ischemic period. Experiments were randomized into five groups distinguished by the content of the myocardial reperfusate during the first 10 min of the reperfusion period. Hearts received either unmodified oxygenated pump blood (control; group I), normothermic oxygenated 28 mmol/liter potassium-blood cardioplegic solution (KBC; group II), 25 mmol/liter glutamate in KBC (group III), 250 mumol/liter adenosine with 1 mg erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA) and glutamate in KBC (group IV), or 2 mmol/liter ribose and glutamate (group V) in KBC. Hearts reperfused with KBC showed improvement early (group II vs group I; p less than .02) but not late recovery of left ventricular function over control. Glutamate, which replenishes Krebs cycle intermediates lost during ischemia, increased functional recovery (group III vs group II; p less than .002). Ribose, which is important in purine salvage and resynthesis, added to glutamate-KBC further improved functional recovery (group V vs group III; p less than .01). Adenosine, a precursor of ATP, with EHNA, an inhibitor of rapid adenosine catabolism, added to glutamate-KBC depressed early recovery (group IV vs group III; p less than .01); however, recovery improved with time. Both glutamate and ribose with glutamate in KBC improved ATP recovery (groups III and V vs group II; p less than .002). Thus selective substrate repletion during initial reperfusion after severe normothermic ischemia can improve recovery of myocardial function and ATP concentration.
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PMID:Reduction of postischemic myocardial dysfunction by substrate repletion during reperfusion. 643 May 93

We studied the role of adenosine in modulating pacemaker activity in normal and infarcted ventricular tissues. We used standard microelectrode techniques to study the effects of adenosine on impulse initiation in Tyrode's superfused normal canine Purkinje fibers (PF), PF obtained from experimentally infarcted hearts, and BaCl2-superfused PF. Adenosine reduced automaticity of normal PF, whereas beta, gamma-methylene ATP did not. In infarcted and in Ba2+-depolarized PF, adenosine had no effect on automaticity or the action potential. We then used intracellular current injection to vary the membrane potentials of normal PF and found adenosine to depress automaticity more at high than at low membrane potentials. The ability of adenosine to counteract the effects of epinephrine on automaticity also was related to membrane potential. We conclude that adenosine depresses normal automaticity but has little effect on abnormal impulse initiation at low membrane potentials. It therefore appears that in the setting of myocardial infarction or ischemia the extent to which adenosine release will modify the function of normal and ectopic pacemakers will be influenced by the membrane potentials of those pacemakers.
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PMID:Actions of adenosine on normal and abnormal impulse initiation in canine ventricle. 684 60

Right ventricular failure during acute pressure overload has been attributed to ischemia which occurs when maximal coronary vasodilation is achieved so that further increases in myocardial blood flow cannot occur. To test the hypothesis that coronary vasodilator reserve is exhausted during acute right ventricular pressure overload, right and left ventricular myocardial blood flow was measured in 14 awake dogs during progressive pulmonary artery occlusion; coronary vasodilator reserve was tested by infusion of adenosine (4 microM/kg per min) before and during pulmonary artery occlusion. Right ventricular myocardial blood flow rose from 0.77 +/- 0.09 ml/min per g (mean +/- SEM) during control conditions to 1.69 +/- 0.27 ml/min per g during moderate pulmonary artery occlusion (P less than 0.01). With further pulmonary artery occlusion to cause increased right ventricular end-diastolic pressure and decreased aortic pressure, a selective decrease in myocardial blood flow to the right ventricular subendocardium was observed, and the right ventricular subendocardial-to-subepicardial blood flow ratio fell from 1.36 +/- 0.14 to 0.77 +/- 0.06 (P less than 0.05). With restoration of mean aortic pressure to control levels, right ventricular systolic pressure increased, right ventricular end-diastolic pressure decreased, and the right ventricular subendocardial-to-subepicardial ratio increased to 1.36 +/- 0.18 (P less than 0.01). Adenosine infusion during pulmonary artery occlusion in five dogs caused an increase in mean right ventricular blood flow (1.11 +/- 0.10 to 2.25 +/- 0.30; P less than 0.05). This increase was most marked in the outer layers but, nevertheless, was also significant in the subendocardium. These data indicate that acute severe right ventricular pressure overload may be associated with right ventricular subendocardial hypoperfusion, even when coronary vasodilator reserve is not exhausted.
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PMID:Transmural right ventricular blood flow during acute pulmonary artery hypertension in the sedated dog. Evidence for subendocardial ischemia despite residual vasodilator reserve. 709 29

To determine the value of lactate and the adenosine metabolites inosine and hypoxanthine as indicators of myocardial ischemia, we measured the levels of these metabolites in arterial and coronary sinus blood of nine chronically instrumented dogs subjected to exercise stress before and during reversible circumflex coronary artery occlusion. The degree of circumflex bed hypoperfusion was measured by 15-mu microspheres and the reduction in circumflex coronary flow was measured with a proximal flow probe. Adenosine metabolites, although below the level of accurate detection in our laboratory in arterial blood (i.e., 0.5 microM/l), were detected in coronary sinus blood (range 2.7--18.7 microM/l) in 26 of 33 studies with partial circumflex occlusion when circumflex flow was reduced to less than 80% of that seen during exercise without occlusion and when only subendocardial perfusion was reduced. Global left ventricular flow and transmural flow in nonischemic beds did not correlate with positive studies. Myocardial lactate extraction was a less accurate test for determining circumflex bed hypoperfusion. Thus, myocardial production of adenosine metabolites is a sensitive qualitative test of exercise-induced ischemia responding to a modest fall in coronary flow when only subendocardial hypoperfusion is present.
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PMID:Myocardial lactate and adenosine metabolite production as indicators of exercise-induced myocardial ischemia in the dog. 709 67

The accumulation of adenosine during a brief coronary occlusion has been proposed to mediate the infarct size-limiting effect of ischemic preconditioning. The purpose of this study was to compare the effects of ischemic preconditioning and a transient adenosine infusion on myocardial interstitial fluid (ISF) adenosine levels and infarct size. Microdialysis fibers (10.0 mm length) were placed in the left ventricular myocardium of pentobarbital sodium-anesthetized rabbits to estimate ISF adenosine. Ischemic preconditioning was induced by 5 min of coronary artery occlusion and 10 min of reperfusion before 45 min of occlusion. Adenosine preconditioning was induced with 5 min of intravenous adenosine infusion (140 micrograms.kg-1.min-1) followed by a 10-min washout before the prolonged occlusion. Myocardial infarct size was determined by triphenyltetrazolium chloride staining after 3 h of reperfusion. Five minutes of ischemia and 5 min of adenosine infusion produced comparable increases in dialysate adenosine levels (from 0.19 +/- 0.02 to 0.69 +/0- 0.11 and 0.28 +/- 0.10 to 0.71 +/- 0.18 microM, respectively) that decreased to baseline before the prolonged ischemia; however, ischemic-preconditioned hearts exhibited elevated dialysate adenosine levels for the first 5 min of reperfusion. Ischemic-preconditioned hearts exhibited significantly reduced dialysate adenosine concentrations for the first 20 min of the prolonged occlusion (P < 0.05 vs. control), and infarct size was reduced from 41 +/- 6 to 10 +/- 4% of risk area. Adenosine preconditioning had no effect on dialysate adenosine levels during prolonged ischemia but did reduce infarct size to 25 +/- 5% of risk area. These results indicate that a transient increase in ISF adenosine can reduce myocardial infarct size, but adenosine alone does not fully replicate the protective effects of ischemic preconditioning.
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PMID:Effects of ischemic and adenosine preconditioning on interstitial fluid adenosine and myocardial infarct size. 748 81

Both ischemia and hypoxia increase adenosine production in the heart. This study tested whether hypoxia increases adenosine production in the coronary artery via ecto-5'-nucleotidase and the role of protein kinase C in this condition. Canine left circumflex coronary artery was rapidly removed and incubated in 10 mL Krebs-Henseleit solution for 30 minutes. The Krebs-Henseleit solution contained 5'-iodotubercidin and 2'-deoxycoformycin, which inhibit adenosine kinase and adenosine deaminase, respectively. Adenosine production was measured in intact coronary arteries under normoxic conditions (16.2 +/- 1.2 pmol/mg protein). Adenosine production was reduced by 27% after removal of endothelium. Ecto-5'-nucleotidase activity of coronary arteries with and without endothelium was 51 +/- 6 and 41 +/- 4 nmol/mg protein per minute under normoxic conditions. Hypoxia increased adenosine production to 27.0 +/- 2.3 and 20.0 +/- 0.8 pmol/mg protein with and without endothelium. Hypoxia also increased ecto-5'-nucleotidase activity of coronary arteries with and without endothelium (74 +/- 8 and 53 +/- 5 nmol/mg protein per minute; P < .05). Increases in adenosine production under hypoxic conditions were blunted by both an inhibitor of ecto-5'-nucleotidase and inhibitors of protein kinase C. Activation of ecto-5'-nucleotidase was blunted by an inhibitor of protein kinase C. These results indicate that hypoxia increased extracellular adenosine production and activated ecto-5'-nucleotidase via activation of protein kinase C in coronary arterial smooth muscle and endothelial cells. Increased adenosine production in coronary arteries during hypoxia may contribute to coronary vasodilation and cardioprotection against ischemic injury.
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PMID:Activation of protein kinase C increases adenosine production in the hypoxic canine coronary artery through the extracellular pathway. 748 56

The effect of ischemic preconditioning (IPC) on glycolysis, glucose oxidation, adenine nucleotide and nucleoside levels, and mechanical function was studied in isolated paced working rat hearts under aerobic conditions or when reperfused following sustained ischemia. IPC inhibited glycolysis in aerobic hearts (4.48 +/- 0.66 vs. 3.18 +/- 0.39 mumol.min-1.g dry wt-1) and calculated proton production attributable to exogenous glucose (7.79 +/- 1.31 vs. 4.73 +/- 0.81 mumol.min-1.g dry wt-1). In hearts subjected to ischemia and reperfusion, IPC decreased, relative to controls, glycogen content before the onset of ischemia (116.6 +/- 4.3 vs. 158.0 +/- 8.4 mumol/dry wt) and decreased consumption of glycogen during ischemia (54 +/- 6 vs. 76 +/- 7 mumol/dry wt). During reperfusion, glycolysis was lower in IPC hearts (2.45 +/- 0.16 vs. 4.4 +/- 0.46 mumol.min-1.g dry wt-1), as was calculated proton production (3.57 +/- 0.30 vs. 8.38 +/- 0.93 mumol.min-1.g dry wt-1). Glucose oxidation was similar in control and IPC hearts. Adenosine and ATP content of IPC hearts, relative to controls, were higher at the end of ischemia, being 0.86 +/- 0.08 vs. 0.34 +/- 0.15 mumol/g dry wt and 11.3 +/- 0.8 vs. 5.0 +/- 1.6 mumol/g dry wt, respectively. IPC enhanced recovery of ventricular work during reperfusion of ischemic hearts from 37 to 68%. These results indicate that IPC is associated with a reduction in glycogen content, inhibition of glycolysis during ischemia and reperfusion, and a decrease in proton production from glucose. These changes may, in part, explain the enhanced recovery of mechanical function observed in IPC hearts.
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PMID:Ischemic preconditioning inhibits glycolysis and proton production in isolated working rat hearts. 750 76

Adenosine is released during brain ischemia and provides neuroprotection by actions on nerve and glial cells. Activation of the adenosine A1 receptor enhances the K+ and Cl- conductance in neurons, leading to membrane hyperpolarization and postsynaptic reduction of neuronal Ca2+ influx through voltage- and NMDA receptor-dependent channels. In addition adenosine A1 receptor activation decreases excitatory amino acid release, possibly via inhibition of N- and P-type Ca2+ channels. The A1 and A2 receptors, coupled to Gi/G(o) and Gs proteins respectively, often co-exist and interact with the phospholipase C-dependent activation of the protein kinase C and the adenylyl cyclase. Activation of the A1 receptor may mimic metabotropic receptor stimulation in activating intracellular Ca2+ mobilization and PKC. A2 receptor mediated cAMP formation is depressed by high intracellular Ca2+ but enhanced by PKC activation. By modulating these metabolic signaling events, adenosine may influence acute cell functions, gene transcription and sustained changes of nerve and glial cells relevant for the development of ischemic damage. The neuroprotective adenosine effect seems to be amplified by treatment with propentofylline, which enhances adenosine release, influences the balance between A1 and A2 receptor mediated actions, depresses the free radical formation in activated microglia and influences astrocyte reactions.
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PMID:Modulation of nerve and glial function by adenosine--role in the development of ischemic damage. 753 56

Effects elicited by adenosine and substance P on ventricular sensory endings of 14 dorsal root ganglion afferent neurons were studied in situ in anesthetized dogs. Sensory-field application of adenosine (1 microM) increased the activity of these neurons by 179%. Application of a nonspecific adenosine antagonist to epicardial sensory fields suppressed ongoing activity in all 14 neurons by 39%. Application of an A1- or A2-adenosine-receptor antagonist suppressed activity generated by 10 of these neurons by 44 and 59%, respectively. Adenosine applied after A1- or A2-receptor blockade increased activity in 10 neurons by 131 and 145%, respectively, indicating that A1- and A2-receptor effects were not additive. Application of substance P (1 microM) to identified sensory fields increased activity in 12 of these neurons by 169%, whereas application of a substance P-receptor antagonist reduced activity generated by these neurons by 75%. Myocardial ischemia increased activity of nine neurons associated with left ventricular sensory fields by 320%, an effect that was counteracted by the nonspecific adenosine-receptor antagonist. It is concluded that A1- and A2-adenosine receptors, as well as substance P receptors, are present on ventricular epicardial sensory nerve endings of dorsal root ganglion neurons that are tonically active during normal states, becoming further activated during ischemia.
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PMID:Ventricular sensory neurons in canine dorsal root ganglia: effects of adenosine and substance P. 754 44

ATP-sensitive K+ (KATP) channels are present at high density in membranes of cardiac cells where they regulate cardiac function during cellular metabolic impairment. KATP channels have been implicated in the shortening of the action potential duration and the cellular loss of K+ that occurs during metabolic inhibition. KATP channels have been associated with the cardioprotective mechanism of ischemia-related preconditioning. Intracellular ATP (ATPi) is the main regulator of KATP channels. ATPi has two functions: 1) to close the channel (ligand function) and 2) in the presence of Mg2+, to maintain the activity of KATP channels (presumably through an enzymatic reaction). KATP channel activity is modulated by intracellular nucleoside diphosphates that antagonize the ATPi-induced inhibition of channel opening or induce KATP channels to open. How nucleotides will affect KATP channels depends on the state of the channel. K+ channel-opening drugs are pharmacological agents that enhance KATP channel activity through different mechanisms and have great potential in the management of cardiovascular conditions. KATP channel activity is also modulated by neurohormones. Adenosine, through the activation of a GTP-binding protein, antagonizes the ATPi-induced channel closure. Understanding the molecular mechanisms that underlie KATP channel regulation should prove essential to further define the function of KATP channels and to elucidate the pharmacological regulation of this channel protein. Since the molecular structure of the KATP channel has now become available, it is anticipated that major progress in the KATP channel field will be achieved.
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PMID:Cardiac ATP-sensitive K+ channels: regulation by intracellular nucleotides and K+ channel-opening drugs. 757 82


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