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

Cardiac microdialysis is a recently developed technique that allows intramyocardial interstitial fluid (ISF) to be sampled via the implantation and perfusion of a small, hollow dialysis fiber within the myocardium. The purpose of this paper is to describe initial studies using cardiac microdialysis in the isolated perfused heart. Microdialysis probes, constructed in the laboratory, were implanted in the left ventricular myocardium of isolated perfused rat hearts and perfused at 0.5 microliter/min with Krebs-Henseleit buffer. The effluent dialysate, assayed for adenosine, inosine, hypoxanthine, xanthine, and uric acid, was used as an index of intramyocardial levels of these purine metabolites. All metabolites were elevated initially after implantation, declined rapidly in the first 45 min, and were then stable for the next 90 min. Based on in vitro percent recovery data, baseline dialysate concentrations were extrapolated to yield estimates of intramyocardial ISF (in microM) 0.47 adenosine, 0.85 inosine, 0.29 hypoxanthine, 0.49 xanthine, and 8.6 uric acid. During global zero-flow ischemia (37 degrees C), dialysate levels of all purine metabolites were elevated, with inosine being the predominant compound. Pretreatment of the hearts with 50 microM erythro-9-(2-hydroxy-3-nonyl)adenine, an adenosine deaminase inhibitor, markedly enhanced ISF adenosine accumulation and attenuated the accumulation of inosine, hypoxanthine, and xanthine. The simplicity and versatility of cardiac microdialysis in the isolated perfused heart suggest that this technique may be a valuable adjunct to the many studies performed using this preparation.
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PMID:Cardiac microdialysis in isolated rat hearts: interstitial purine metabolites during ischemia. 162 49

Reversible myocardial dysfunction associated with transient ischemia has been termed the stunned myocardium. Because exogenous adenosine has been shown to protect the ischemic myocardium, we hypothesized that augmentation of endogenous adenosine levels would attenuate myocardial stunning. To induce stunning, anesthetized dogs were subjected to 15 minutes of ischemia (left anterior descending artery occlusion) followed by 60 minutes of reperfusion. Erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA; 5 mg/kg/hr), an adenosine deaminase inhibitor, was used to augment adenosine levels. The effect of EHNA on interstitial fluid (ISF) adenosine levels, coronary blood flow, and regional systolic wall thickening was compared with that of an untreated group (n = 8). EHNA increased preischemia ISF adenosine levels threefold and was associated with a corresponding increase in coronary blood flow. EHNA administration did not alter preischemia systolic wall thickening. Although ISF adenosine increased fourfold during ischemia in the untreated group, ISF adenosine increased nearly sixtyfold above preischemia values in the EHNA-treated group and remained elevated throughout reperfusion. Postischemic regional function was enhanced significantly in the group treated with EHNA. These data show that adenosine deaminase inhibition increased ISF adenosine levels and attenuated myocardial stunning. Metabolic manipulation of myocardial ISF nucleoside levels may be beneficial in limiting postischemic myocardial dysfunction.
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PMID:Enhanced interstitial fluid adenosine attenuates myocardial stunning. 185 25

The effects of Erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) on Langendorff perfused rat hearts subjected to ischemia-reperfusion injury were studied. Results showed that EHNA can inhibit the increase of cardiac resting tension during ischemia period and decreasing the incidence of ventricular fibrillation and its duration. The contraction amplitude, resting tension and heart rate could be recovered to preischemic level, and the coronary flow even greater than before. The authors thought that EHNA can block the breakdown of adenosine to inosine and hypothanxine, and, therefore, cut off the pathway and production of oxygen free radicals during ischemia-reperfusion injury.
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PMID:[Adenosine deaminase inhibitor (EHNA) on ischemia-reperfusion injury in isolated perfused rat hearts]. 220 2

The aim of this study was to determine the dual role of ATP as an energy substrate and as a major source of oxygen-derived free-radical-mediated reperfusion injury by using adenine nucleoside blocker, p-nitrobenzylthioinosine (NBMPR), and adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). In a randomized study, 16 dogs were instrumented with minor-axis LTZ-piezoelectric crystals and intraventricular pressure transducers to monitor, off bypass, left ventricular performance by using a sensitive and load-independent index of contractility (slope of the stroke work-end-diastolic length relation). Hearts were subjected to 60 minutes of normothermic global ischemia and 120 minutes of reperfusion. Normal saline without (Group 1, n = 8) or with (Group 2, n = 8) NBMPR and EHNA was infused in three boluses into the cardiopulmonary bypass reservoir before ischemia and reperfusion. Transmural serial biopsies were obtained before and during ischemia and reperfusion and analyzed for myocardial adenine nucleotide pool intermediates by using high-performance liquid chromatography. In the control group, three hearts developed ischemic contracture and another three hearts exhibited cardiogenic shock during reperfusion. In the EHNA/NBMPR-treated group, left ventricular performance recovered within 30 minutes of reperfusion (p less than 0.05 vs. control). Myocardial ATP was depleted to 20% of normal in both groups by the end of ischemia (p less than 0.05). Intramyocardial adenosine in the EHNA/NBMPR-treated group was 12-fold greater (15.09 +/- 1.6 nmol/mg protein) than the control group at the end of the ischemic period (p less than 0.05). Inosine was about fourfold higher in the control group (19.07 +/- 1.50 nmol/mg protein) compared with the drug-treated group (p less than 0.05). During reperfusion, myocardial ATP levels increased to approximately 50% of normal in the EHNA/NBMPR group while remaining depressed (20% of normal) in the control group. Thus, despite the dramatic loss of myocardial ATP during ischemia, complete recovery of ventricular performance and significant repletion of ATP during reperfusion were observed when adenosine transport and deamination were modulated during ischemia and reperfusion. These results suggest that 1) the myocardium may have more ATP than is needed for basic cardiac functions and 2) washout of ATP diffusible catabolites is detrimental to ventricular performance during reperfusion. Specific blockade of nucleoside transport resulted in complete functional recovery despite low but critical ATP levels.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Is adenosine 5'-triphosphate derangement or free-radical-mediated injury the major cause of ventricular dysfunction during reperfusion? Role of adenine nucleoside transport in myocardial reperfusion injury. 193 94

Adenosine is known to induce rapid cardioplegic arrest and to improve postischemic recovery in the isolated rat heart. Long exposures to high doses of adenosine impair postischemic recovery, however. In this paper we tested the combination of low-dose adenosine (1 mmol/L) with potassium (26 mmol/L), with the aim of achieving rapid arrest (as with high-dose adenosine) but eliminating the need for postarrest washout of adenosine. Cardioplegic solutions studied were (1) Krebs-Henseleit potassium (26 mmol/L) (K); (2) K plus adenosine (1 mmol/L) (KA); (3) K plus an adenosine deaminase inhibitor [erythro-9-(2-hydroxy-3-nonyl)adenine] (0.1 mmol/L) (KE); and as control (4) Krebs-Henseleit potassium (6 mmol/L) (C). We induced cardiac arrest in Langendorff-perfused rat hearts by infusing the cardioplegic solution for 3 minutes at 3 ml/min. Total ischemia lasted 20 minutes at 37 degrees C, followed by reperfusion for 30 minutes. High potassium decreased the arrest time from 260 +/- 16 seconds (group C, mean values +/- standard error of the mean) to 22 +/- 4 seconds (group K). A further decrease to 10 +/- 2 seconds was observed with KA (p = 0.016 versus K). KE, which increased endogenous adenosine, gave intermediate effects. All hearts recovered during reperfusion; the product of developed tension and heart rate (grams per minute) was superior in KA hearts (6250 +/- 740 versus K hearts 4380 +/- 390; p = 0.050). KE gave an intermediate result (5290 +/- 900), while C showed the worst recovery (3180 +/- 830). Our electrophysiologic studies with sinus node and atrial tissue suggest that adenosine induced hyperpolarization and an increase in potassium permeability, thereby arresting the sinus node before depolarization of the membrane by potassium (26 mmol/L). We conclude that low-dose adenosine as an adjunct to potassium shortens the arrest time in this model and improves postischemic recovery.
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PMID:Adenosine as adjunct to potassium cardioplegia: effect on function, energy metabolism, and electrophysiology. 239 80

We tested the effect of the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenosine (EHNA) on ischemia-reperfusion injury in isolated perfused rat heart. In the ischemia-reperfusion group (n = 10), ventricular fibrillation occurred within 3 min of reperfusion after the 40-min ischemic period. The incidence of ventricular fibrillation was 90% with a mean duration of 3.15 +/- 0.97 (SE) min. Resting tension increased significantly. By contrast, the incidence of ventricular fibrillation after reperfusion in the EHNA-treated (5 microM) group (n = 10) was 20% (P less than 0.01), and the duration was 0.30 +/- 0.21 min (P less than 0.01). Resting tension was significantly lower and around the normal level in the EHNA-treated group (P less than 0.01). Contraction amplitude and heart rate recovered to nearly normal compared with the ischemia-reperfusion group (P less than 0.01). Coronary flow was greater in the EHNA-treated group (P less than 0.01). It is concluded that EHNA protects the heart, possibly by accumulation of adenosine that benefits the hearts and by blocking the xanthine oxidase pathway for free radical generation.
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PMID:Protective effects of an adenosine deaminase inhibitor on ischemia-reperfusion injury in isolated perfused rat heart. 239 91

We tested the hypothesis that inhibition of adenosine transport by dipyridamole and inhibition of adenosine deamination by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) prevents nucleoside loss and stimulates postischemic ATP-repletion. In an open chest canine model, dipyridamole (0.5 mg/kg/h) and EHNA (5 mg/kg/h) were infused intra-atrially during a coronary occlusion period of 45 min and a reperfusion period of 180 min. Transmural needle biopsies, obtained during the ischemic period and within the reperfusion period, were analyzed using high performance liquid chromatography for adenine nucleotides and adenosine, inosine, xanthine, and hypoxanthine as well as creatine phosphate. During ischemia and under the influence of dipyridamole plus EHNA, 56% of the catabolized adenine nucleotides were recovered stoichiometrically as adenosine, whereas in the untreated group less than 10% of the nucleotides were recovered as adenosine because of rapid deamination to inosine. In the control group, ATP levels decreased during ischemia from control values of 5.25 +/- 0.28 microns/g to 2.01 +/- 0.18 microns/g. In the group treated with dipyridamole and EHNA, ATP levels fell to 2.2 +/- 0.22 microns/g but rose to 3.22 +/- 0.29 microns/g within 180 min of reperfusion, whereas in the untreated control group tissue levels of ATP did not increase. However, a significant proportion of the adenosine accumulated during ischemia under the influence of dipyridamole plus EHNA was not used for the restoration of the ATP level during reperfusion. A significant amount of adenosine was probably trapped in the interstitial space and could not be transported back into the myocytes in the presence of dipyridamole during reperfusion. In both groups, creatine phosphate levels were restored to normal levels during reperfusion.
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PMID:Enhanced postischemic ATP repletion by pharmacological inhibition of nucleoside washout and catabolism. 245 65

The effects of inhibitors of adenosine catabolism on contractile function and metabolites were assessed during 15 minutes of ischemia followed by 30 minutes of reperfusion in the open-chest dog heart. As compared to sham treatment, pretreatment with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and dipyridamole (DP) protected contractile function during ischemia, and improved recovery of high energy phosphate content and contractile function during reperfusion following ischemia. Testing EHNA and DP in a free-radical generating system indicated both compounds have some scavenging ability, suggesting the effect of EHNA + DP may not be on adenosine nucleotide metabolism alone. Comparison of end diastolic segment lengths to contractile function indicated the results were not affected by changes in preload resulting from peripheral vasodilation.
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PMID:Inhibitors of adenosine catabolism improve recovery of dog myocardium after ischemia. 277 Jul 8

The loss of the catabolic products of adenosine triphosphate in the form of purine nucleosides and oxypurines during ischemia and subsequent reperfusion may limit adenine nucleotide regeneration. This study compared the effects of infusion of inhibitors of the major reactions involved in the degradation of adenosine triphosphate to inosine on the postischemic recovery of high energy phosphate and myocardial function. Isolated rat hearts were made totally ischemic after a 5-min infusion of p1,p5-diadenosine pentaphosphate, alpha, beta-methylene adenosine diphosphate, nitrobenzyl-6-thioinosine, or erythro-9-(2-hydroxy-3-nonyl) adenine, which are inhibitors of adenylate kinase, 5'-nucleotidase, adenosine translocase, and adenosine deaminase, respectively. Following 30 min of ischemia, only hearts infused with alpha, beta-methylene adenosine diphosphate recovered significantly better ventricular function than did the control (P less than 0.05), but all hearts had increased adenosine triphosphate and creatine phosphate regeneration (P less than 0.05). The formation and washout of greater than 30% of the total adenine pool metabolites were not prevented by any drug. Nevertheless all manipulations of adenine metabolism resulted in recruitment of high energy phosphate during preischemic infusion which may have potential benefits in elective ischemic arrest.
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PMID:Influence of inhibitors of ATP catabolism on myocardial recovery after ischemia. 304 Nov 5

The aim of this study was to differentiate myocardial reperfusion injury from that of ischemia. We assessed the role of the myocardial adenosine 5'-triphosphate (ATP) catabolites, hypoxanthine and xanthine, generated during ischemia and the early phase of reperfusion, in reperfusion injury by modulating adenosine transport and metabolism with specific metabolic inhibitors. This was followed by intracoronary infusion of exogenous hypoxanthine and xanthine. Twenty-four dogs instrumented with minor-axis piezoelectric crystals and intraventricular pressure transducers were subjected to 30 minutes of normothermic global myocardial ischemia and 60 minutes of reperfusion. In Group 1 (n = 7), normal saline was infused into the cardiopulmonary bypass reservior before ischemia and before reperfusion. Saline solution containing 25 microM p-nitrobenzylthioinosine (NBMPR) and 100 microM erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) was infused in Group 2 (n = 10) dogs. Group 3 (n = 7) dogs were treated exactly like those in Group 2 except, at the end of the ischemic period and immediately before releasing the cross-clamp, a solution of EHNA-NBMPR containing 100 microM hypoxanthine and 100 microM xanthine was infused into the aortic root. Left ventricular performance and myocardial adenine nucleotide pool intermediates were determined before and after ischemia. ATP was depleted by about 50% (p less than 0.05 vs. preischemia) in all groups after 30 minutes of ischemia. Inosine was the major ATP catabolite (9.29 +/- 1.2 nmol/mg protein) in Group 1, while adenosine (9.91 +/- 0.7 nmol/mg protein) was the major metabolite in EHNA-NBMPR-treated dogs (Groups 2 and 3). Hypoxanthine levels were fivefold more in Group 1 compared with Groups 2 and 3 (p less than 0.05). Left ventricular performance in Group 1 decreased from 76.8 +/- 7.6 to 42.9 +/- 9.8 and 52.3 +/- 8.4 dynes/cm2 x 10(3) (p less than 0.05), while myocardial ATP decreased from 30.9 +/- 2.2 to 17.2 +/- 1.0 and 16.5 +/- 1.0 nmol/mg protein during 30 and 60 minutes of reperfusion, respectively (p less than 0.05 vs. preischemia). Ventricular function in Group 2 dogs completely recovered within 30 minutes of reperfusion, and myocardial ATP recovered to the preischemic level at 60 minutes of reperfusion. In Group 3, left ventricular performance was depressed by 39% and 30% during 30 and 60 minutes of reperfusion (p less than 0.05), respectively, and myocardial ATP did not recover during reperfusion despite a significant intramyocardial adenosine accumulation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Myocardial reperfusion injury. Role of myocardial hypoxanthine and xanthine in free radical-mediated reperfusion injury. 318 Apr 2


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