Evidence for a pathogenetic role of xanthine oxidase in the "stunned" myocardium

1987 ◽  
Vol 252 (3) ◽  
pp. H566-H577 ◽  
Author(s):  
M. I. Charlat ◽  
P. G. O'Neill ◽  
J. M. Egan ◽  
D. R. Abernethy ◽  
L. H. Michael ◽  
...  
Keyword(s):  
Free Radicals ◽  
Xanthine Oxidase ◽  
Myocardial Stunning ◽  
Oxygen Free Radicals ◽  
Contractile Function ◽  
Myocardial Dysfunction ◽  
Stunned Myocardium ◽  
Base Line ◽  
Collateral Flow

Recent evidence suggests that postischemic myocardial dysfunction (or myocardial “stunning”) may be mediated by oxygen free radicals, but the mechanism for their production remains unknown. To explore the role of xanthine oxidase as a potential source of free radicals, open-chest dogs undergoing a 15-min occlusion of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion (REP) received intravenously either allopurinol (50 mg/kg 48 h, 20 h, and 30 min before occlusion, 10 mg/kg 1 min before REP, and 6.25 mg X kg-1 X h-1 throughout REP, n = 13) or saline (n = 14). The two groups were similar with respect to occluded bed size (postmortem perfusion) and collateral flow (radioactive microspheres). In controls, the transcardiac difference in plasma uric acid (great cardiac vein - arterial concentration) increased 199 +/- 70% (means +/- SE) during ischemia (P less than 0.02) and remained elevated for 5 min after REP; no increase was observed in treated dogs. Regional myocardial function was assessed by measuring systolic wall thickening with an epicardial Doppler probe. The two groups exhibited comparable systolic thickening under base-line conditions and similar degrees of dyskinesis during ischemia. Following REP, however, recovery of contractile function (expressed as percent of preocclusion values) was considerably greater in allopurinol-treated as compared with control dogs: 57 +/- 14 vs. -22 +/- 16 (P less than 0.01) at 1 h, 70 +/- 13 vs. -15 +/- 15 (P less than 0.001) at 2 h, 65 +/- 14 vs. -28 +/- 13 (P less than 0.001) at 3 h, and 68 +/- 13 vs. -17 +/- 14 (P less than 0.001) at 4 h. These differences could not be ascribed to hemodynamic factors. The results suggest that xanthine oxidase is a source of the oxygen free radicals responsible for myocardial stunning following a brief episode of reversible regional ischemia.

The iron chelator desferrioxamine attenuates postischemic ventricular dysfunction

1987 ◽  
Vol 253 (6) ◽  
pp. H1372-H1380 ◽  
Author(s):  
R. Bolli ◽  
B. S. Patel ◽  
W. X. Zhu ◽  
P. G. O'Neill ◽  
C. J. Hartley ◽  
...  
Keyword(s):  
Myocardial Stunning ◽  
Contractile Function ◽  
Myocardial Dysfunction ◽  
Iron Chelator ◽  
Wall Thickening ◽  
Base Line ◽  
Doppler Probe ◽  
Systolic Thickening ◽  
Catalyzed Reactions

Recent evidence suggests that postischemic myocardial dysfunction ("stunning") may be mediated by oxygen free radicals, but the mechanism by which they produce myocellular damage remains unknown. Since iron catalyzes formation of hydroxyl radicals (HO.) as well as HO.-initiated lipid peroxidation, we explored the potential role of this metal in the pathogenesis of myocardial stunning. Open-chest dogs undergoing a 15-min occlusion of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion (REP) received the iron chelator desferrioxamine intravenously (10 mg/kg over 45 min beginning 30 min before occlusion, then 1.7 mg.kg-1.h-1 throughout REP, n = 19) or normal saline (n = 17). Regional myocardial function was assessed by measuring systolic wall thickening with an epicardial Doppler probe. The two groups exhibited comparable systolic thickening under base-line conditions and similar degrees of dyskinesis during ischemia. After REP, however, recovery of contractile function (expressed as percent systolic thickening) as considerably greater in desferrioxamine-treated compared with control dogs: 5 +/- 3 (mean +/- SE) vs. -3 +/- 2% (P less than 0.05) at 1 h, 6 +/- 3 vs. -2 +/- 3% (P less than 0.05) at 2 h, 5 +/- 3 vs. -6 +/- 2% (P less than 0.005) at 3 h, and 6 +/- 3 vs. -6 +/- 2% (P less than 0.002) at 4 h. These differences could not be ascribed to hemodynamic factors. The results suggest that iron-catalyzed reactions (possibly HO. generation) play a significant role in myocardial stunning after a brief episode of reversible regional ischemia.

Myocardial and endothelial dysfunction after multiple, brief coronary occlusions: role of oxygen radicals

1992 ◽  
Vol 263 (6) ◽  
pp. H1703-H1709 ◽  
Author(s):  
G. J. Gross ◽  
S. T. O'Rourke ◽  
L. R. Pelc ◽  
D. C. Warltier
Keyword(s):  
Free Radicals ◽  
Coronary Artery ◽  
Contractile Function ◽  
Calcium Ionophore ◽  
Endothelial Damage ◽  
Calcium Ionophore A23187 ◽  
Stunned Myocardium ◽  
Ionophore A23187 ◽  
Oxygen Derived Free Radicals

The major objective of the present study was to determine the effect of multiple, brief periods of coronary artery occlusion and reperfusion on postischemic contractile function (sonomicrometry) and endothelium-dependent vasodilator responses in isolated conduit coronary artery rings obtained from anesthetized dogs. The role of oxygen-derived free radicals was also investigated. Dogs were subjected to four 5-min episodes of left anterior descending coronary occlusion interspersed with 5 min of reperfusion followed by a final 60-min reperfusion period. The multiple occlusion-reperfusion protocol resulted in regional segment dysfunction (37 +/- 15% of preocclusion values at 60 min of reperfusion) and attenuated endothelium-dependent responses to acetylcholine, bradykinin, and the calcium ionophore, A23187. Responses to the endothelium-independent vasodilator, sodium nitroprusside, were unaffected. Infusion of superoxide dismutase (5,000 U/kg) and catalase (55,000 U/kg) markedly improved the recovery of myocardial function at 30 and 60 min of reperfusion and completely protected against vascular endothelial damage. These results suggest an important role for oxygen-derived free radicals in the myocardial and endothelial injury that occurs in this model of multiple stunned myocardium.

scholarly journals Xanthine Oxidase Does Not Contribute to Apoptosis after Brain Hypoxia-Ischemia in Immature Rabbits

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Anthony Moretti ◽  
Alma Ramirez ◽  
Richard Mink
Keyword(s):  
Free Radicals ◽  
Xanthine Oxidase ◽  
Caspase 3 ◽  
Oxygen Free Radicals ◽  
Cerebral Injury ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Brain Hypoxia ◽  
Hypoxia Ischemia

Background. The mechanisms involving the initiation of apoptosis after brain hypoxia-ischemia through caspase activation are not fully defined. Oxygen free radicals may be an important mediator of caspase initiation with reactive oxygen species generated by xanthine oxidase (XO) being one potential source. The purpose of this study was to examine the role of XO in apoptosis after global cerebral injury. Methods. Immature rabbits were subjected to 8 minutes hypoxia and 8 minutes ischemia and then 4 hours of reperfusion. In one group (n=5), the XO substrate xanthine was infused to generate more oxygen free radicals to promote apoptosis while in another (n=5), the XO inhibitor allopurinol was given to reduce apoptosis by preventing free radical production (n=5). Control animals (n=4) received the vehicles. Caspase 3, 8, and 9 enzyme activities were measured in the cerebral cortex, hippocampus, cerebellum, thalamus, and caudate. Results. Administration of xanthine increased (P<0.05) caspase 3 activity but only in the hippocampus, and pretreatment with allopurinol did not reduce it. No differences (P>0.05) were found in any other region nor were there any changes in caspases 8 or 9 activities. Conclusion. We conclude that XO is not a major factor in inducing apoptosis after hypoxic-ischemic brain injury.

scholarly journals Minimal role of xanthine oxidase and oxygen free radicals in rat renal tubular reoxygenation injury.

1991 ◽  
Vol 1 (7) ◽  
pp. 959-969
Author(s):  
R B Doctor ◽  
L J Mandel
Keyword(s):  
Free Radicals ◽  
Lactate Dehydrogenase ◽  
Xanthine Oxidase ◽  
Oxygen Radicals ◽  
Oxygen Free Radicals ◽  
Proximal Tubules ◽  
Lactate Dehydrogenase Release ◽  
Reoxygenation Injury ◽  
Isolated Rat

The role of xanthine oxidase and oxygen free radicals in postischemic reperfusion injury in the rat kidney remains controversial. Proximal tubules, the focal segment affected by ischemic renal injury, were isolated in bulk, assayed for xanthine oxidase activity, and subjected to 60 min of anoxia or hypoxia and 60 min of reoxygenation to evaluate the participation of xanthine oxidase and oxygen radicals in proximal tubule reoxygenation injury. The total xanthine oxidase in isolated rat proximal tubules was 1.1 mU/mg of protein, approximately 30% to 40% of the activity found in rat intestine and liver. Lactate dehydrogenase release, an indicator of irreversible cell damage, increased substantially during anoxia (39.8 +/- 2.3 versus 9.8 +/- 1.8% in controls) with an additional 8 to 12% release during reoxygenation. Addition of 0.2 mM allopurinol, a potent xanthine oxidase inhibitor, and dimethylthiourea, a hydroxyl radical scavenger, failed to protect against the reoxygenation lactate dehydrogenase release. Analysis of xanthine oxidase substrate levels after anoxia and flux rates during reoxygenation indicates that hypoxanthine and xanthine concentrations are in a 15-fold excess over the enzyme Km and 0.3 mU/mg of protein of xanthine oxidase activity exists during reoxygenation. Hypoxic tubule suspensions had a minimal lactate dehydrogenase release during hypoxia and failed to demonstrate accelerated injury upon reoxygenation. In conclusion, although xanthine oxidase is present and active during reoxygenation in isolated rat proximal tubules, oxygen radicals did not mediate reoxygenation injury.

Ethane production as a measure of lipid peroxidation after renal ischemia

1986 ◽  
Vol 251 (5) ◽  
pp. F839-F843 ◽  
Author(s):  
M. S. Paller ◽  
R. P. Hebbel
Keyword(s):  
Lipid Peroxidation ◽  
Free Radicals ◽  
Superoxide Radical ◽  
Oxygen Free Radicals ◽  
Tissue Injury ◽  
Renal Ischemia ◽  
Radical Scavenger ◽  
Base Line ◽  
Ethane Production

After renal ischemia, oxygen free radicals are formed and produce tissue injury, in large part, through peroxidation of polyunsaturated fatty acids. We used an in vivo method to monitor lipid peroxidation after renal ischemia, the measurement of ethane in expired gas, to determine the time course of lipid peroxidation and the effect of several agents to limit lipid peroxidation after renal ischemia. In anesthetized rats there was no significant increase in ethane production during 60 min of renal ischemia. During the first 10 min of renal reperfusion, there was a prompt increase in ethane production from 2.9 +/- 1.3 to 6.3 +/- 1.9 pmol/min (P less than 0.05). Ethane production was significantly increased during the first 50 min of reperfusion and then rapidly tapered to base-line levels. Preischemic administration of allopurinol to prevent superoxide radical generation or the superoxide radical scavenger superoxide dismutase prevented the increase in ethane production during postischemic reperfusion. These studies confirm that there is increase lipid peroxidation following renal ischemia that can be prevented by agents which limit the formation or accumulation of oxygen free radicals. This in vivo method for measuring lipid peroxidation could also be employed to study the effects of ischemia on lipid peroxidation in other organs, as well as to monitor lipid peroxidation in other forms of injury.

Molecular and Cellular Mechanisms of Myocardial Stunning

1999 ◽  
Vol 79 (2) ◽  
pp. 609-634 ◽  
Author(s):  
Roberto Bolli ◽  
Eduardo Marbán
Keyword(s):  
Free Radical ◽  
Myocardial Stunning ◽  
Recovery Of Function ◽  
Myocardial Dysfunction ◽  
Calcium Overload ◽  
Global Ischemia ◽  
Stunned Myocardium ◽  
Common Mechanism ◽  
Regional Ischemia

The past two decades have witnessed an explosive growth of knowledge regarding postischemic myocardial dysfunction or myocardial “stunning.” The purpose of this review is to summarize current information regarding the pathophysiology and pathogenesis of this phenomenon. Myocardial stunning should not be regarded as a single entity but rather as a “syndrome” that has been observed in a wide variety of experimental settings, which include the following: 1) stunning after a single, completely reversible episode of regional ischemia in vivo; 2) stunning after multiple, completely reversible episodes of regional ischemia in vivo; 3) stunning after a partly reversible episode of regional ischemia in vivo (subendocardial infarction); 4) stunning after global ischemia in vitro; 5) stunning after global ischemia in vivo; and 6) stunning after exercise-induced ischemia (high-flow ischemia). Whether these settings share a common mechanism is unknown. Although the pathogenesis of myocardial stunning has not been definitively established, the two major hypotheses are that it is caused by the generation of oxygen-derived free radicals (oxyradical hypothesis) and by a transient calcium overload (calcium hypothesis) on reperfusion. The final lesion responsible for the contractile depression appears to be a decreased responsiveness of contractile filaments to calcium. Recent evidence suggests that calcium overload may activate calpains, resulting in selective proteolysis of myofibrils; the time required for resynthesis of damaged proteins would explain in part the delayed recovery of function in stunned myocardium. The oxyradical and calcium hypotheses are not mutually exclusive and are likely to represent different facets of the same pathophysiological cascade. For example, increased free radical formation could cause cellular calcium overload, which would damage the contractile apparatus of the myocytes. Free radical generation could also directly alter contractile filaments in a manner that renders them less responsive to calcium (e.g., oxidation of critical thiol groups). However, it remains unknown whether oxyradicals play a role in all forms of stunning and whether the calcium hypothesis is applicable to stunning in vivo. Nevertheless, it is clear that the lesion responsible for myocardial stunning occurs, at least in part, after reperfusion so that this contractile dysfunction can be viewed, in part, as a form of “reperfusion injury.” An important implication of the phenomenon of myocardial stunning is that so-called chronic hibernation may in fact be the result of repetitive episodes of stunning, which have a cumulative effect and cause protracted postischemic dysfunction. A better understanding of myocardial stunning will expand our knowledge of the pathophysiology of myocardial ischemia and provide a rationale for developing new therapeutic strategies designed to prevent postischemic dysfunction in patients.

Strand scission in DNA induced by dietary flavonoids: role of Cu(I) and oxygen free radicals and biological consequences of scission

1992 ◽  
Vol 111 (1-2) ◽  
Author(s):  
Arshad Rahman ◽  
Fabeha Fazal ◽  
Julie Greensill ◽  
K. Ainley ◽  
J.H. Parish ◽  
...  
Keyword(s):  
Free Radicals ◽  
Oxygen Free Radicals ◽  
Strand Scission ◽  
Dietary Flavonoids

Beneficial actions of superoxide dismutase and catalase in stunned myocardium of dogs

1986 ◽  
Vol 250 (3) ◽  
pp. H372-H377 ◽  
Author(s):  
G. J. Gross ◽  
N. E. Farber ◽  
H. F. Hardman ◽  
D. C. Warltier
Keyword(s):  
Blood Flow ◽  
Superoxide Dismutase ◽  
Free Radicals ◽  
Oxygen Free Radicals ◽  
Ischemia Reperfusion ◽  
Free Radical Scavengers ◽  
Stunned Myocardium ◽  
Regional Myocardial Blood Flow ◽  
Control Group ◽  
Myocardial Segment

Recent evidence suggests that oxygen free radicals may partially mediate irreversible ischemia-reperfusion injury in the myocardium. In the present study, the effect of a combination of two oxygen free radical scavengers, superoxide dismutase plus catalase (SOD + CAT), on the recovery of subendocardial segment function following 15 min of coronary artery occlusion followed by 3 h of reperfusion ("stunned" myocardium) was compared with a control group in barbital-anesthetized dogs. Myocardial segment shortening (%SS) in the subendocardium of nonischemic and ischemic areas was measured by sonomicrometry and regional blood flow by radioactive microspheres. SOD and CAT were infused into the left atrium 30 min before and throughout the occlusion period. Compared with the control group, %SS in the subendocardium of the ischemic region was significantly (P less than 0.05) greater in the SOD plus CAT-treated group during occlusion and throughout reperfusion. Since there were no significant differences in hemodynamics or regional myocardial blood flow between the SOD plus CAT and the control groups, these results suggest that toxic oxygen free radicals may be partially involved in the reversible ischemic injury that occurs during short periods of coronary occlusion followed by reperfusion.

Free radicals in hypoxic rat diaphragm contractility: no role for xanthine oxidase

2001 ◽  
Vol 281 (6) ◽  
pp. L1402-L1412 ◽  
Author(s):  
Leo M. A. Heunks ◽  
Herwin A. Machiels ◽  
Ronney de Abreu ◽  
Xiao Ping Zhu ◽  
Henricus F. M. van der Heijden ◽  
...  
Keyword(s):  
Free Radicals ◽  
Xanthine Oxidase ◽  
Power Output ◽  
Harmful Effect ◽  
Force Generation ◽  
Muscle Performance ◽  
Rat Diaphragm ◽  
Shortening Velocity ◽  
Contraction Pattern

Recent evidence indicates that hypoxia enhances the generation of oxidants. Little is known about the role of free radicals in contractility of the rat diaphragm during hypoxia. We hypothesized that antioxidants improve contractility of the hypoxic rat diaphragm and that xanthine oxidase (XO) is an important source of free radicals in the hypoxic diaphragm. The effects of N-acetylcysteine (NAC; 18 mM), Tiron (10 mM), and the XO inhibitor allopurinol (250 μM) were studied on isometric and isotonic force generation during hypoxia (Po 2 ∼7 kPa). NAC and Tiron decreased maximal force generation, slowed the shortening velocity, and decreased the power output. Fatigue rate was decreased in the presence of either NAC or Tiron. Allopurinol did not alter the contractility or fatigability of the diaphragm. During hyperoxia (Po 2 ∼85 kPa), neither NAC nor allopurinol affected the contractility or fatigability of the diaphragm. Thus free radicals play a significant role in diaphragm contractility during hypoxia. Whether antioxidants exert a beneficial or harmful effect on muscle performance depends on the contraction pattern of the muscle. Free radicals generated by XO do not play a role in diaphragm contractility during either hypoxia or hyperoxia.

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