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)

It is generally assumed that myocardial adenine nucleotides are broken down (e.g., during ischemia) via AMP----adenosine----inosine, but contribution of the pathway AMP----IMP----inosine cannot be excluded. The catabolism of exogenously added adenosine (1-20 microM) was studied in isolated rat hearts. All catabolites (i.e., inosine, hypoxanthine, xanthine, and uric acid) were measured together with nonmetabolized adenosine. Even at low (1 microM) adenosine concentrations, deamination accounted for 60% of adenosine disappearing from the perfusate. The adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) (5 and 50 microM) was infused together with adenosine (5 microM). These two concentrations of EHNA inhibited deamination of exogenous adenosine by 65 and 91%, respectively. When hearts were made ischemic by reduction of perfusion pressure, addition of EHNA raised the adenosine release from 1.4 to 9.8 nmole/min per gram wet wt., but surprisingly, the release of inosine and oxypurines (8 nmole/min per g wet wt.) did not change. These results suggest that considerable breakdown of myocardial adenine nucleotides can occur via the AMP----IMP----inosine pathway instead of AMP----adenosine----inosine. The rate of total purine release is probably not a good measure of intracellular adenosine formation.
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PMID:Adenosine deaminase inhibition and myocardial adenosine metabolism during ischemia. 399 44

The concept of limiting irreversible damage due to ischemic arrest by inhibiting nucleoside breakdown was tested in the isolated perfused rat heart. Functional recovery measurements were combined with continuous high-energy phosphate measurements by means of 31P nuclear magnetic resonance (NMR) and with nucleoside release measurements in the reperfusion period. The adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and 2'-deoxycoformycin (DCF) were given 5 min before ischemia and for the first 5 min of reperfusion. These treated groups were compared with a control, untreated group. These were further compared with a group of hearts arrested with potassium and to a group combining potassium arrest and EHNA. It was found that all treated groups recovered mechanical function significantly better than the untreated group. DCF, K+, and K+ + EHNA slowed ATP decline and resulted in better ATP recovery than untreated or EHNA-treated, and all treatments decreased nucleoside base release. Intracellular pH fell equally in all groups and recovered to preischemic values. Thus, these adenosine deaminase inhibitors improve functional recovery following ischemia, although this improvement was not well correlated with purine losses observed during reperfusion.
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PMID:Effect of adenosine deaminase inhibitors on the heart's functional and biochemical recovery from ischemia: a study utilizing the isolated rat heart adapted to 31P nuclear magnetic resonance. 619 52

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

This study was designed to determine whether intermittent warm aortic crossclamping induces cumulative myocardial stunning or if the myocardium becomes preconditioned after the first episode of ischemia in canine models in vivo. The role of adenosine triphosphate catabolism and subsequent release of purines on reperfusion-mediated postischemic ventricular dysfunction and arrhythmias was assessed with the use of selective inhibitors of nucleoside transport, p-nitrobenzylthioinosine (NBMPR), and a specific adenosine deaminase inhibitor, erythro-9-[2-hydroxy-3-nonyl] adenine (EHNA). Thirty-two anesthetized dogs were instrumented to monitor left ventricular contractility, off bypass, by sonomicrometry. During cardiopulmonary bypass dogs were treated before ischemia with either saline solution (control group, n = 8) or EHNA (100 mumol/L) and NBMPR (25 mumol/L) (EHNA/NBMPR group, n = 8). Hearts were subjected to either 60 minutes of global ischemia and 120 minutes of reperfusion (n = 16) or 6 episodes of 10 minutes of global ischemia and 10 minutes of reperfusion, followed by 60 minutes of reperfusion (n = 16). Sixty minutes of sustained ischemia resulted in 80% loss of adenosine triphosphate and induced reperfusion-mediated ventricular fibrillation and severe left ventricular dysfunction in the control group. EHNA/NBMPR treatment augmented myocardial adenosine trapping during ischemia, attenuated ventricular fibrillation, and enhanced left ventricular functional recovery, despite similar depletion of adenosine triphosphate (80% loss). In the intermittent ischemia experiment, the first episode of 10 minutes of ischemia and reperfusion caused significant adenosine triphosphate depletion, ventricular fibrillation, and left ventricular stunning in both control and drug-treated groups. The prevalence of ventricular fibrillation was greater in the control group than in the drug-treated group after the first episode of ischemia (p < 0.05). Adenosine was the major nucleoside accumulated in the myocardium at the end of 10 minutes of ischemia in the EHNA/NBMPR-treated group (p < 0.05 versus control). Subsequent episodes of ischemia prevented ventricular fibrillation and did not cause cumulative left ventricular stunning in either group. Left ventricular function fully recovered in the EHNA/NBMPR-treated group after intermittent ischemia, but remained stunned in the control group. Unlike sustained ischemia, intermittent ischemia and reperfusion preserved myocardial adenosine triphosphate, limited purine release, and prevented ventricular fibrillation and cumulative stunning. These results suggest that intermittent ischemia and reperfusion augmented the endogenous protective mechanism or mechanisms of "preconditioning." Nucleoside trapping improved functional recovery after sustained or repetitive ischemia. It is concluded that adenosine triphosphate preservation or blockade of nucleoside transport may play an important role in the activation of endogenous myocardial protective mechanisms that "precondition" against subsequent ischemic stress.
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PMID:Intermittent aortic crossclamping prevents cumulative adenosine triphosphate depletion, ventricular fibrillation, and dysfunction (stunning): is it preconditioning? 869 80

Because adenine nucleotide catabolites may be important during postischemic lung reperfusion, we examined the pathway of adenosine monophosphate (AMP) degradation in ischemic lung tissue. Once the pattern of degradation is known, pharmacological interventions can be considered, offering new methods of reducing lung reperfusion injury. For this purpose we used the isolated rabbit lung. Rabbit lungs were flushed in situ with a modified Krebs Henseleit solution (60 ml/kg). The lungs were removed and stored deflated, immersed in saline solution at 37 degrees C. At regular times, biopsies were taken, and adenine nucleotides, nucleosides, and bases were measured in these biopsies using high performance liquid chromatography (HPLC). During lung ischemia, a very significant increase of inosine monophosphate (IMP) was found. Adenosine levels on the other hand did not increase. Hypoxanthine was the major end catabolite of ischemic lung tissue (constituting 92% of the nucleoside and purine base fraction at 4 hours ischemia). To further determine the pathway of AMP degradation, 400 mM of the adenosine deaminase inhibitor erythro-9-[2-hydroxy-3-nonyl]adenine (EHNA) was added to the lung flush solution. During ischemia, adenosine triphosphate (ATP) breakdown was unaltered but adenosine became the major catabolite (2.8 times the concentration of hypoxanthine at 4 hours ischemia). These data suggest that: 1) in rabbit lung tissue, dephosphorylation of AMP to adenosine is more important than deamination to IMP; 2) hypoxanthine is the major end catabolite of ischemic lung tissue. By inhibiting the enzyme deaminase, reduced hypoxanthine levels and increased adenosine levels were obtained. Pharmacological interventions are now available to interfere with the formation of adenine nucleosides and bases in ischemic lung tissue. The importance of adenine nucleotide catabolites to postischemic lung reperfusion injury is discussed.
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PMID:Pattern of AMP degradation in ischemic rabbit lung tissue. 773 34

A previous study has shown that endogenous adenosine trapping during ischemia (by blocking adenine nucleoside transport and inhibiting adenosine breakdown) prevents myocardial stunning. In this study, we tested the hypothesis that delay of administration of inhibitors until reperfusion would similarly prevent myocardial stunning in the absence of entrapped adenosine. In both studies, a selective nucleoside transport blocker, p-nitrobenzyl-thioinosine, was used in combination with a potent adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine, to entrap adenosine (preischemic treatment) or inosine (postischemic treatment) in an in vivo canine model of reversible global ischemia. Twenty-five anesthetized adult dogs were instrumented (by sonomicrometry) to monitor left ventricular performance from the relationship between stroke work and end-diastolic length as a sensitive and load-independent index of contractility. Hearts of animals supported by cardiopulmonary bypass were subjected to 30 minutes of normothermic global ischemia and 60 minutes of reperfusion. Saline solution containing the pharmacologic agents were infused into the bypass circuit before ischemia (group 1) or during reperfusion (group 2). Control group (group 3) received saline before and after ischemia. Myocardial biopsy specimens were obtained before, during, and after ischemia, and levels of adenine nucleotides, nucleosides, oxypurines, and the oxidized form of nicotinamide-adenine dinucleotide were determined. Left ventricular contractility fully recovered within 30 minutes of reperfusion in the groups treated with erythro-9-(2-hydroxy-3-nonyl)adenine and p-nitrobenzyl-thioinosine (p < 0.05 versus control group). Myocardial adenosine triphosphate was depleted by 50% in all groups at the end of ischemia. Adenosine triphosphate recovered during reperfusion only in the group that was treated with inhibitors before ischemia (group 1). At the end of ischemia, adenosine levels were low (< 10% of total nucleosides) in the control group (group 3) and in the group treated only after ischemia (group 2). A high level of adenosine (> 90% of total nucleosides) was present in group 1. We infer that selective pharmacologic blockade of nucleoside transport, only after ischemic injury, accelerated functional recovery during reperfusion, even without trapping of endogenous adenosine during ischemia and without adenosine triphosphate recovery during reperfusion. Recovery of myocardial adenosine triphosphate required preischemic treatment and adenosine entrapment during ischemia and reperfusion. Therefore, nucleoside trapping may be used to prevent reperfusion-mediated injury after reversible ischemic injury.
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PMID:Nucleoside trapping during reperfusion prevents ventricular dysfunction, "stunning," in absence of adenosine. Possible separation between ischemic and reperfusion injury. 804 Nov 75

We investigated the effect of the adenosine deaminase inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and coformycin on high-energy phosphate metabolism, tissue nucleotides and nucleosides, and recovery of contractile function in isolated, perfused guinea pig hearts. EHNA and coformycin (10 microM) improved postischemic recovery of contractile function approximately 85% and enhanced coronary flow rate in reperfused tissue approximately 40%. The protective effect of EHNA on recovery of contractile function was concentration dependent. Although adenosine (10 microM) increased coronary flow rate on reperfusion approximately twofold over vehicle, it failed to improve postischemic recovery of contractile function. EHNA and coformycin preserved cardiac ATP levels and increased endogenous tissue adenosine during ischemia. During reperfusion, these agents enhanced recovery of high-energy phosphates approximately twofold and potentiated adenosine release into the perfusate with concentration dependency. Furthermore, EHNA and coformycin reduced the extent of myocardial ischemia-reperfusion injury, as indicated by the approximately 55% reduction in creatine phosphokinase release. We conclude that inhibitors of adenosine deaminase attenuate myocardial ischemic injury and improve postischemic recovery of contractile function and metabolism through endogenous myocardial adenosine enhancement and ATP preservation.
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PMID:Adenosine deaminase inhibitors attenuate ischemic injury and preserve energy balance in isolated guinea pig heart. 823 12

Human cardiac valves are increasingly used in the reconstruction of ventricular outflow tracts and offer performance advantages over porcine and mechanical prostheses; the durability of these replacements has been associated with leaflet interstitial cell viability and a presumed sustained function after implantation. Preimplantation tissue preparation entails sequential steps that are potentially cytotoxic and may therefore affect functional cell survival at thaw. We defined the metabolic consequences of each interval using semilunar cusps from 118 porcine valves to model a homograft preparation with 40 minutes of fixed cadaveric (harvest) ischemia. Fifty-eight valves served as controls and were first processed according to standard cryopreservation protocol; nucleosides were extracted at the end of each step to differentiate independent contributions to high-energy phosphate depletion. Sixty simultaneously harvested leaflets were administered the nucleoside transport inhibitor p-nitrobenzy-thionosine (NBMPR) and the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) at procurement, to attempt adenosine salvage and restitution of processing-incurred adenine nucleotide losses. High-performance liquid chromatography was used to compare adenosine triphosphate, diphosphate, and monophosphate and diffusible nucleopurines of the control and EHNA/NBMPR-treated groups. Control results indicate that disruption of the adenosine triphosphate-diphosphate cycle occurs independently with antibiotic disinfection and cryopreservation. However, throughout all preparation steps, adenine nucleotides were maintained at harvest (baseline) concentrations in the EHNA/NBMPR valves. This suggests that salvage therapy may protect a significant number of cells from net high-energy phosphate catabolism. If, with further study, the durability of transplanted valves is concluded to benefit from retained leaflet interstitial cell viability, such enhancement of metabolic tolerance to the obligatory processing may facilitate functional recovery.
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PMID:Inhibition of adenosine deaminase and nucleoside transport. Utility in a model of homograft cardiac valve preimplantation processing. 850 37

In the presence of its substrates hypoxanthine and xanthine, xanthine oxidase generates oxygen free radicals that cause postischemic injury. Recently, it has been demonstrated that the burst of xanthine oxidase-mediated free radical generation in the reperfused heart is triggered by a large increase in substrate formation, which occurs secondary to the degradation of adenine nucleotides during ischemia. It is not known, however, whether blocking this substrate formation is sufficient to prevent radical generation and functional injury. Therefore, studies were performed in isolated rat hearts in which xanthine oxidase substrate formation was blocked with the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), and measurements of contractile function and free radical generation were performed. Chromatographic measurements of the intracellular adenine nucleotide pool showed that preischemic administration of EHNA blocked postischemic hypoxanthine, xanthine, and inosine formation. Electron paramagnetic resonance spin trapping measurements of free radical generation showed that inhibition of adenosine deaminase with EHNA blocked free radical generation and that it also increased the recovery of contractile function by more than 2-fold. Exogenous infusion of hypoxanthine and xanthine totally reversed the protective effects of EHNA. These results demonstrate that blockade of xanthine oxidase substrate formation by adenosine deaminase inhibition can prevent free radical generation and contractile dysfunction in the postischemic heart.
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PMID:Adenosine deaminase inhibition prevents free radical-mediated injury in the postischemic heart. 862 67

We previously reported that adenosine A1 receptor activation protects against the cardiodepressant effects of hydrogen peroxide in isolated rat hearts. The present study examined whether a transient ischemic period of 5 min duration, which preconditions the heart against ischemic and reperfusion-induced dysfunction, can bestow protection against 30-min exposure to hydrogen peroxide in isolated rat hearts. Transient ischemia on its own failed to alter the cardiac response to hydrogen peroxide. However, when transient ischemia was carried out in the presence of the nucleoside transport inhibitor S-(4-Nitrobenzyl)-6-thioguanosine and the adenosine deaminase inhibitor erythro-9-(2-Hydroxy-3-nonyl)adenine, a significant attenuation of the hydrogen peroxide-induced loss in contractility was evident and this was associated with significant preservation of tissue glycogen content. The protective effect of the transient ischemia/drug combination on both functional changes and glycogen levels was abolished by the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine as well as by glibenclamide, a blocker of the ATP-sensitive potassium channel (KATP). To further assess the role of glycogen in the protection against hydrogen peroxide, we compared the effects of the adenosine A1 agonist N6-cyclopentyl adenosine (CPA) and insulin. While both treatments protected against hydrogen peroxide the effect of insulin was superior to any other treatment. Moreover, while all protective modalities preserved glycogen stores after hydrogen peroxide treatment, the protection afforded by insulin was also associated with significantly elevated glycogen levels prior to hydrogen peroxide administration. No protection by either CPA or insulin was evident in the absence of exogenous glucose. Taken together, our results demonstrate that a brief period of ischemia with concomitant administration of agents which increase interstitial adenosine levels protects against hydrogen peroxide toxicity. The effect is mediated by activation of adenosine A1 receptors and is linked to KATP stimulation. Moreover, our results are strongly suggestive of an important role of glycogen preservation in bestowing protective effects against hydrogen peroxide cardiotoxicity.
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PMID:Transient ischemia in the presence of an adenosine deaminase plus a nucleoside transport inhibitor confers protection against contractile depression produced by hydrogen peroxide. Possible role of glycogen. 876 52


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