Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using direct visualization techniques, we recently confirmed earlier histologic studies that leukocytes accumulate primarily in the coronary capillaries of ischemic hearts during early reperfusion. The purpose of this study was to determine if pentoxifylline (PTX) would reduce leukocyte trapping in postischemic hearts. Isolated rat hearts were subjected to 30 min of 37 degrees C, no-flow ischemia. Hearts were initially reperfused with diluted whole blood containing fluorescent leukocytes. At 5, (R5), 20, and 35 min of reperfusion, the deposition of leukocytes in the coronary capillaries and venules was observed directly using intravital fluorescence microscopy. Three groups were studied: a non-ischemic control group (group I) and postischemic groups reperfused with diluted whole blood treated with vehicle group II or PTX (5 mM; group III). Postischemic reperfusion with unactivated blood caused a significant trapping of leukocytes in coronary capillaries throughout reperfusion (R5, group I = 2.0 +/- 0.3 vs. group II = 5.7 +/- 0.6 leukocytes/capillary field, p < 0.05). The addition of PTX reduced capillary leukocyte trapping below control values throughout reperfusion (R5, group III = 1.6 +/- 0.2 leukocytes/capillary field, p < 0.05). At R5, there was no statistically significant difference in leukocyte accumulation in venules for all groups (group I = 1.5 +/- 0.6, group II = 3.2 +/- 0.4, group III = 3.3 +/- 0.4 leukocytes/100 microns venule). During the reperfusion period, leukocyte persistence in the capillaries of postischemic hearts (36%) was greater than in the venules (13%). These data indicate that early in reperfusion after myocardial ischemia, leukocyte trapping occurs primarily in the coronary capillaries. PTX reduced early leukocyte trapping in the capillaries. The results also demonstrate that during reperfusion, the mechanisms affecting capillary retention are more persistent than those in the venule. These findings suggest that attempts to attenuate the damaging potential of early leukostasis in capillaries consider the biophysical properties of the leukocyte.
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PMID:Pentoxifylline reduces leukocyte retention in the coronary microcirculation early in reperfusion following ischemia. 892 49

Gene transfer as a therapeutic modality for the treatment of myocardial ischemia and/or infarction has been proposed as a revolutionary approach to improve collateral circulation, enhance myocardial viability and amplify healing. Our study was undertaken to assess the feasibility, efficiency, anatomic distribution, timing and localization of adenovirus-mediated gene transfer into the vicinity of infarcted myocardium in the adult mammalian heart. We induced myocardial infarction by subjecting rats to 60 min of coronary artery occlusion followed by sustained reperfusion. Gene transfer into the infarction area was performed using direct injection of a replication-defective adenovirus vector encoding the bacterial reporter gene, beta-galactosidase. A total of 5.0 x 10(9) plaque-forming units of virus was delivered into the left ventricular myocardium either immediately (n = 7) or at 7 (n = 6), 22 (n = 5) or 30 days (n = 5) after reperfusion of rat hearts. Control rats received either 50 microliters of saline 13 days after myocardial infarction (n = 2) or were not subjected to infarction and received Adenovirus carrying the beta-galactosidase gene as described above (n = 4). All rats were killed at 7 days after cardiac injection. Hearts were harvested, frozen and sectioned and stained for beta-galactosidase activity and with hematoxylin and eosin. Sections were evaluated by light microscopy. Relative beta-galactosidase activity was measured by digital planimetry and expressed as the ratio of the maximal area of beta-galactosidase staining relative to the total area of the section examined (% +/- S.E.M.). beta-galactosidase gene expression was limited mainly to viable myocytes at the border of the myocardial infarction. The area of transgene expression in the non-infarcted hearts (28 +/- 7%) was significantly higher (P = 0.02) than at any time point studied in infarcted tissues (3.4 +/- 1.2%, 1.4 +/- 1.0%, 2.8 +/- 0.8% and 3.4 +/- 0.9% at reperfusion and at 7, 22 and 30 days after myocardial infarction, respectively). Hearts injected 7 days after infarction had significantly less transgene activity (P = 0.03) with three of five samples displaying no macroscopically visible beta-gal activity. Following viral injection, an inflammatory response consisting of mononuclear cell infiltration was much less intense seven days following injection in non-infarcted control rat hearts than at any of the time points examined for infarcted hearts. Gene transfer into infarcted myocardium, while feasible, was limited by low transfection efficiency when compared to non-infarcted normal myocardium. Transgene expression in the infarcted myocardium appears restricted to residual cardiomyocytes in the periphery. Nevertheless, the ability to introduce genes into these viable peripheral cells might be a useful therapeutic strategy for enhancing neovascularization, collateral flow and healing.
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PMID:Adenovirus-mediated gene transfer into infarcted myocardium: feasibility, timing, and location of expression. 893 Aug 2

We describe real-time measurement of myocardial oxygen consumption during ischemia in the intact heart. Measurement of extracellular oxygen concentration during myocardial ischemia by spin label oximetry has been limited by ischemia-induced reduction of the neutral, water-soluble nitroxide TEMPONE. We have overcome this problem by encapsulating the nitroxides. Isolated immature (7-10 d old) rabbit hearts (n = 8) were perfused aerobically within the cavity of a loop gap resonator with bicarbonate buffer containing an oxygen-sensitive, lipid-soluble nitroxide (14N-TEMPO laurate in FC-43 perfluorocarbon micelles) and a much less oxygen-sensitive and positively charged nitroxide (15N-TEMPO choline in multilamellar vesicles) as an internal standard. The ratio of the ESR signal amplitudes of these nitroxides was used as a sensitive index of oxygen concentration. Sequestration of the nitroxides decreased their reduction rate by ascorbate in comparison with nonsequestered nitroxides. Hearts were subjected to 60 min of global no-flow ischemia at 20 degrees C. Extracellular oxygen content (mean +/- SD) during aerobic perfusion was 1195 +/- 55 mumol/liter. The electron spin resonance signal from TEMPO laurate increased with the onset and progression of ischemia, consistent with a decrease in extracellular oxygen, while the signal for TEMPO choline was relatively unchanged. Extracellular oxygen content after 40 and 60 min of ischemia was reduced to 393 +/- 27 mumol/liter (p < .05) and 61 +/- 5 mumol/liter (p < .05), respectively. We conclude that spin-label oximetry can directly and precisely measure myocardial oxygen consumption at constant temperature during ischemia in the intact heart.
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PMID:Spin label oximetry to assess extracellular oxygen during myocardial ischemia. 895 35

Coenzyme Q10 (CoQ10, ubiquinone) has been shown to be protective against myocardial ischemia/reperfusion induced injury. The purpose of this study was to investigate the effect of CoQ10 added to cold cristalloid cardioplegia on hypothermic ischemia and normothermic reperfusion using an isolated working rat heart. Hearts (n = 6-9/group) from male Wistar rats were aerobically (37 degrees C) perfused (20 min) with bicarbonate buffer. This was followed by a 3-min infusion of St. Thomas' Hospital cardioplegic solution containing various concentrations of CoQ10 (0, 1, 3, 6, 12, and 58 mumol/L). Hearts were then subjected to 180 min of hypothermic (20 degrees C) global ischemia and 35 min of normothermic (37 degrees C) reperfusion (15 min Langendorff, 20 min working). Ventricular fibrillation (Vf) upon reperfusion was irreversible in the 12 and 58 mumol/ L CoQ10 groups (4/6 and 3/6, respectively). In the hearts which Vf upon reperfusion was not irreversible, the percent recovery of aortic flow (%AF) was 43.3 +/- 5.4% (n = 9) in the control group versus 31.6 +/- 7.7% (n = 6), 38.0 +/- 12.0% (n = 6), 27.2 +/- 6.9% (n = 6), 31.3% (n = 2), and 30.4 +/- 14.2% (n = 3) in the 1, 3, 6, 12, and 58 mumol/L CoQ10 groups, respectively. Creatine kinase leakage during Langendorff reperfusion tended to be greater in the 12 and 58 mumol/L CoQ10 groups than in the control group. Thus, CoQ10 in the cold cristalloid cardioplegic solution induced irreversible Vf upon reperfusion and failed to improve functional recoveries following hypothermic global ischemia.
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PMID:[The effect of coenzyme Q10 and cold cristalloid cardioplegia on hypothermic global ischemia]. 896 87

The effects of L-arginine on ischemia/reperfusion-induced myocardial dysfunction as well as the tissue activity of nitric oxide synthase (NOS) were investigated in rat isolated Langendorff-perfused hearts. Hearts were subjected to nonischemic perfusion or 30 min of global ischemia followed by 30 min of reperfusion. The hearts subjected to ischemia/reperfusion received either vehicle, L-arginine (1 mM), D-arginine (1 mM), the NOS inhibitor NG-nitro-L-arginine (L-NNA, 1 mM), or L-arginine (1 mM) plus L-NNA (1 mM) at the beginning of ischemia. L-Arginine but not D-arginine significantly enhanced the recoveries of left ventricular double product and coronary flow compared with the vehicle group. There was a substantial activity of Ca(2+)-dependent NOS but no significant Ca(2+)-independent NOS activity in the hearts undergoing 60 min of nonischemic perfusion. After ischemia/reperfusion, Ca(2+)-dependent NOS activity significantly decreased (by > 90%) in comparison with that of nonischemic hearts. L-Arginine increased the Ca(2+)-dependent NOS activity compared with the vehicle group to a level that was similar to that observed in nonischemic hearts. There was no difference in Ca(2+)-dependent NOS activity between vehicle- and D-arginine-treated groups. Administration of L-NNA abolished the beneficial effects of L-arginine on functional recovery and on Ca(2+)-dependent NOS activity. There were no significant Ca(2+)-independent NOS activities in any of the ischemic groups. These results suggest that myocardial ischemia/reperfusion reduces Ca(2+)-dependent NOS activity in the heart. Administration of L-arginine enhances myocardial function and preserves Ca(2+)-dependent NOS activity after ischemia/reperfusion through a pathway involving NOS activity.
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PMID:L-arginine enhances functional recovery and Ca(2+)-dependent nitric oxide synthase activity after ischemia and reperfusion in the rat heart. 905 81

Epidemiologic studies indicate that long-term alcohol consumption decreases the incidence of coronary disease and may improve outcome after myocardial infarction. Attenuation of ischemia-reperfusion injury after myocardial infarction improves survival. This study investigates the possibility that alcohol consumption can improve survival after myocardial infarction by reducing ischemia-reperfusion injury. Hearts were isolated from guinea pigs after drinking ethanol for 3-12 weeks and subjected to global ischemia and reperfusion. Hearts from animals drinking ethanol showed improved functional recovery and decreased myocyte damage when compared with controls. Adenosine A1 receptor blockade abolished the protection provided by ethanol consumption. These findings indicate that long-term alcohol consumption reduces myocardial ischemia-reperfusion injury and that adenosine A1 receptors are required for this protective effect of ethanol. This cardioprotective effect of long-term alcohol consumption mimics preconditioning and may, in part, account for the beneficial effect of moderate drinking on cardiac health.
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PMID:Regular alcohol consumption mimics cardiac preconditioning by protecting against ischemia-reperfusion injury. 909 76

ATP sensitive potassium channel (KATP) openers (e.g. cromakalim) are thought to be cardioprotective during ischemia-reperfusion, while KATP blockers (e.g. glibenclamide) may potentiate ischemia-reperfusion damage. We studied cardiac energetics and intracellular pH, by 31P magnetic resonance spectroscopy, during ischemia-reperfusion of buffer perfused, isolated rat hearts in the presence of cromakalim (10 microM) or glibenclamide (1, 10 and 50 microM). Hearts were subjected to 25 min total global ischemia at 36.5 degrees C and reperfused for 45 min. Pre-treatment with cromakalim delayed the time to ischemic contracture (19.3 +/- 1.5 min v 15.3 +/- 0.6 for control, P < 0.05) and significantly improved recovery of function at 45 min reperfusion (84 +/- 11% pre-ischemic rate pressure product (RPP) v 38 +/- 5 for control, P < 0.05). This was accompanied by an attenuation in the loss of ATP during ischemia. Pre-treatment with glibenclamide decreased the time to ischemic contracture: 16.1 +/- 0.8 min. 15.1 +/- 0.7, 12.0 +/- 1.2 (P < 0.01) and 9.5 +/- 0.9 (P < 0.001) for control, 1, 10 and 50 microM glibenclamide respectively. 50 microM glibenclamide significantly improved functional recovery at 45 min reperfusion but 1 and 10 microM were without effect; 24 +/- 6, 22 +/- 4, 29 +/- 4 and 58 +/- 7% (P < 0.05) of pre-ischemic RPP for control, 1, 10 and 50 microM glibenclamide. During ischemia, intracellular ATP was depleted more rapidly in the presence of 50 microM glibenclamide and intracellular acidosis was significantly attenuated (final pH 6.3 v 5.8 for control). 50 microM glibenclamide also decreased tissue lactate content at the end of ischemia (75 +/- 3 mumol/g dry weight v 125 +/- 18 for control, P < 0.05) and this attenuation of lactate accumulation and consequent decreased intracellular acidosis may be responsible for the cardioprotection observed under these conditions. These latter effects are unlikely to be related to glibenclamide's KATP blocking activity. This study demonstrates that blocking of myocardial KATP does not potentiate ischemia-reperfusion injury and, in addition, illustrates the important role played by intracellular acidosis in myocardial ischemia-reperfusion injury.
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PMID:Effects of cromakalim and glibenclamide on myocardial high energy phosphates and intracellular pH during ischemia-reperfusion: 31P NMR studies. 922 Mar 52

Although several studies have demonstrated that nitric oxide appears to be cardioprotective and endothelin-1 (ET-1) deleterious in myocardial ischemia/reperfusion injury, their interactions in the intact heart are unknown. Therefore, coronary effluent and interstitial fluid ("transudate") levels of ET-1 and cyclic GMP, an indirect measure of nitric oxide production, were determined simultaneously in normoxic and reperfused hearts and compared with myocardial and coronary function. Rat hearts were buffer-perfused at 9 ml/min/g heart wet weight for 45 min (baseline), followed either by another 45 min of perfusion (normoxia), or 15 min of total global ischemia and 30 min reperfusion. Hearts received, from 42-90 min, either vehicle, the inhibitor of nitric oxide formation NG-nitro-L-arginine (L-NNA; 200 micromol/l), the nitric oxide donor S-nitroso-N-acetyl-DL-penicillamine (SNAP; 200 micromol/l), or the ET receptor antagonist PD 142893 (200 nmol/l). Both mediators were released preferentially into the vascular lumen which resulted in similar luminal and interstitial concentrations of cyclic GMP, but three-fold higher levels of ET-1 in tissue because of the higher effluent than transudate flow rate. L-NNA increased the release of ET-1 and worsened coronary function, whereas SNAP had opposite effects. On reperfusion, considerable functional impairment was observed, although levels of cyclic GMP both in the vascular and tissue compartment were not reduced, but even increased. Reperfusion functional impairment was aggravated after inhibiting the synthesis of nitric oxide, whereas SNAP restored cardiac and coronary function close to pre-ischemic level. Deterioration of function corresponded with an increased level, and improvement with a decreased level of intersitial ET-1 at the onset of reperfusion. PD 142893 was similarly cardioprotective as SNAP both in normoxia and reperfusion. These results suggest that in reperfusion, cardiac function is depressed, despite increased rather than decreased endogenous nitric oxide production, largely due to the prevalence of the deleterious effects of ET-1 which are overcome by antagonism of ET receptors or exogenous nitric oxide supplied by SNAP.
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PMID:Interaction of nitric oxide and endothelin-1 in ischemia/reperfusion injury of rat heart. 929 60

Myocardial ischemia-reperfusion injury is at least partially mediated by oxygen-derived free radicals. Catalase is a major enzyme involved in the detoxification of hydrogen peroxide. The activity of catalase in the heart is very low, which may be a factor responsible for the high sensitivity of the heart to ischemia-reperfusion injury. The present study was undertaken to determine whether elevation of catalase specifically in the heart of transgenic mice can provide protection against ischemia-reperfusion injury. Hearts isolated from transgenic mice in which catalase in the heart was elevated approximately 60-fold higher than that in nontransgenic heart and from the non-transgenic littermates were subjected to 50 min of warm (37 degrees C) zero-flow ischemia followed by 90 min reflow. Compared with nontransgenic controls, transgenic hearts showed significantly improved recovery of contractile force (75 vs. 25% at the end of 90 min reperfusion, P < 0.01). Efflux of creatine kinase was reduced by approximately 50%, and the zone of myocardial infarction as demarcated by triphenyltetrazolium at the end of reperfusion was reduced by approximately 40% in transgenic hearts compared with nontransgenic controls. These findings support the view that hydrogen peroxide is an important cause of ischemia-reperfusion damage and suggest that protection may be provided by elevation of catalase activity.
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PMID:Catalase-overexpressing transgenic mouse heart is resistant to ischemia-reperfusion injury. 932 93

While the ischemic tolerance of the myocardium has been reported to decrease with senescence, it is not known when and how this occurs. Our objectives were to determine whether the tolerance to myocardial ischemia in rats decreased before the onset of senescence and whether an increase in myocardial ionic imbalance was associated with an enhanced myocardial injury with aging. Hearts were isolated from Fischer 344 rats categorized as young (12 weeks old), mature adult (24 weeks), middle-aged (50 weeks) or senescent (100 weeks). Hearts were perfused isovolumically by the Langendorff procedure and subjected to 25 min of global ischemia followed by 30 min of reperfusion. In the 50- and 100-week-old rats, the recovery of ventricular function and high-energy phosphate levels was lower and there was increased incidence of ventricular fibrillation after 25 min of global ischemia followed by reperfusion. The release of creatine kinase and lactate dehydrogenase during reperfusion was greater in the 50-and 100-week-old rats than in the 12- and 24-week-old rats, indicating the irreversible myocardial damage due to ischemia-reperfusion increased by middle-age. Intracellular levels of Na+ and K+ before ischemia were higher in the 50- or 100-week-old rats than in the 12-week-old rats. The increase in intracellular Na+ at end of ischemia was greater in the older (50-week-old, 215% of the pre-ischemic value; 100-week-old, 232% of the pre-ischemic value) than in the younger rats (12-week-old, 158% of the pre-ischemic value). Results indicated that the rat heart becomes more vulnerable to ischemia in middle-age. This decrease in ischemic tolerance may be caused by an acceleration of myocardial ionic imbalance with aging.
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PMID:Decrease in ischemic tolerance with aging in isolated perfused Fischer 344 rat hearts: relation to increases in intracellular Na+ after ischemia. 940 82


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