Myocardial dysfunction and ultrastructural alterations mediated by oxygen metabolites

Miki, Shinobu; Ashraf, Muhammad; Salka, Samer; Sperelakis, Nicholas

doi:10.1016/0022-2828(88)90578-0

Cited by 61 publications

(10 citation statements)

References 35 publications

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“…Exposure of isolated hearts to free radical generating solutions has been shown to result in decreased mechanical function and myocardial ATP levels, i.e., in changes similar to those observed in the stunned myocardium [44][45][46][77][78][79][80][81]. In most studies [44][45][46]81], the adverse effects on contractility were prevented by catalase or by hydroxyl radical scavengers, but not by superoxide dismutase, suggesting that hydrogen peroxide or its byproduct, the hydroxyl radical, were the oxygen metabolites responsible for the observed depression of mechanical performance. In one study [79], however, superoxide dismutase was protective, whereas catalase had no effect, implying that superoxide anion was the major negative inotro- pic agent.…”

Section: Do Oxygen Radicals Depress Myocardial Function?mentioning

confidence: 99%

Oxygen-derived free radicals and myocardial reperfusion injury: An overview

Bolli

1991

Cardiovasc Drug Ther

266

110

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Reperfusion of acutely ischemic myocardium is associated with various distinctive pathophysiologic derangements, which are collectively referred to as reperfusion injury. Among these, three have been attributed to oxygen radicals: a) arrhythmias, b) transient mechanical dysfunction ("stunning"), and c) cell death. a) Reperfusion-induced arrhythmias. Although the precise mechanism for reperfusion arrhythmias remains to be determined, considerable evidence suggests that oxygen radicals play an important pathogenetic role in these rhythm disturbances. b) Transient mechanical dysfunction ("myocardial stunning"). Studies suggest that this abnormality is caused by events occurring in the initial seconds of reperfusion, and therefore represents a manifestation of sublethal, reversible reperfusion injury. Although our understanding of the mechanism of myocardial stunning is still fragmentary, there is overwhelming evidence for a pathogenetic role of oxygen radicals. c) Cell death. The evidence that reperfusion causes extension of the infarct produced by the antecedent ischemia is highly controversial. Although several studies have reported reduction of infarct size with antioxidants applied at the time of reperfusion, numerous other investigations have failed to reproduce these results. At present, there is no obvious explanation for this discrepancy. What is clear is that short-term administration of antioxidants at the time of reperfusion will not produce sustained limitation of infarct size. However, the possibility that long-term administration of antioxidants will produce sustained limitation of infarct size merits further consideration. In conclusion, there is strong evidence that the generation of oxygen radicals upon reperfusion plays an important pathogenetic role in two manifestations of reperfusion injury, namely, arrhythmias and stunning. Intense controversy persists regarding whether oxygen radicals contribute to extending cell death upon reperfusion and whether reperfusion in itself causes cell death. On the basis of the evidence available at this time, oxygen radicals appear to be important in the genesis of relatively mild, sublethal forms of myocellular damage, but their role in the genesis of lethal myocellular injury remains to be established.

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Section: Do Oxygen Radicals Depress Myocardial Function?mentioning

confidence: 99%

Oxygen-derived free radicals and myocardial reperfusion injury: An overview

Bolli

1991

Cardiovasc Drug Ther

266

110

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“…After intraperitoneal injection of 500 USP units/kg heparin sodium, hearts were removed and retrogradely perfused through the aorta in a noncirculating Langendorff apparatus with Krebs-Henseleit buffer as previously described. 24 The buffer was saturated with 95% 02-5% CO2 (pH 7.4, 37°C) for 1 hour. The millimolar composition of the perfusion buffer was NaCI 118, KCI 4.7, MgSO4 1.2, KH2P04 1.2, CaCI2 2.5, NaHCO3 25, and glucose 5.5.…”

Section: Heart Preparationmentioning

confidence: 99%

Quantification of hydroxyl radical and its lack of relevance to myocardial injury during early reperfusion after graded ischemia in rat hearts.

Takemura

Onodera

Ashraf

1992

Circulation Research

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To elucidate the pathophysiological role of the hydroxyl radical (-OH) during the postischemic reperfusion of the heart, we measured the OH product in the coronary effluent from isolated perfused rat heart during a 30-minute reperfusion period after various ischemic intervals of 5,10,15,20,30, and 60 minutes. Salicylic acid was used as the probe for *OH, and its derivative, 2,5-dihydroxybenzoic acid (2,5-DHBA), was quantified using high-performance liquid chromatography with ultraviolet detection. 2,5-DHBA was negligible in the effluent from nonischemic hearts, but a significant amount was detected from the hearts rendered ischemic for 10 minutes or longer. The peak of 2,5-DHBA was seen within 90 seconds after the onset of reperfusion in every group. The accumulated amount of 2,5 -DHBA was maximal in the group with 15-minute ischemia (6.73±1.04 nmol/g wet heart wt after 30 minutes of reperfusion); it decreased as the ischemic time was prolonged and was 2.38±0.84 nmol/g wet wt after 30 minutes of reperfusion in the group with 60-minute ischemia. In the model of 15-minute ischemia/30 -minute reperfusion, there was no correlation between the accumulated amount of 2,5-DHBA and functional recovery (±dP/dt, heart rate, and coronary flow), lactate dehydrogenase release, and morphological damage. Although treatment with 0.5 mM deferoxamine, an iron chelator, significantly decreased 2,5-DHBA (from 6.73± 1.04 to 2.29±0.80 nmol/g wet wt after 30 minutes of reperfusion, p<0.01), it failed to reduce the postischemic myocardial injury in the group with 15-minute ischemia. The results suggest that OH production is influenced by the preceding ischemic interval and that OH does not exert an immediate direct effect on postischemic damage during early reperfusion in the isolated perfused rat heart, although a possibility remains that the small portion of OH trapped by salicylic acid may not be intimately associated with myocardial injury. (Circulation Research 1992;71:96-105) KEY WORDS * ischemia * reperfusion * hydroxyl radical * salicylic acid P roduction of oxygen-derived radicals and metabolites has been linked to the deleterious effects of reperfusion on the ischemic heart. 1-4 It has become possible to detect free radicals in the postischemic reperfused heart using electron paramagnetic resonance spectroscopy (EPR). Recent studies using EPR have revealed that the peak of the production of radicals appears in the early phase of reperfusion.5-9 EPR is undoubtedly a powerful tool in studying the relation between free radicals and the evolution of ischemia/ reperfusion injury. However, EPR spin trapping has its limitations: the spin adducts of the commonly used spin trap 5,5-dimethyl-1-pyrroline N-oxide are metabolized and unstable in vivo10ull; high concentrations (>20 mM) of the spin trap a-phenyl N-tert-butyl nitrone (PBN) are toxic in in vivo preparations9; and their sensitivity is relatively low.'2 Recently, however, to avoid toxicity,

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“…It has been shown that the latter may play a role in ischaemic damage (Miki et al, 1988). Hydrogenperoxide can generate hydroxyl radicals through an iron catalysed Haber-Weiss reaction (Haber & Weiss, 1934) although it is not clear whether this reaction occurs in vivo (Halliwell, 1978;Weiss, 1989).…”

Section: Discussionmentioning

confidence: 97%

Cytochemical evidence of NADH-oxidase activity in the isolated working rabbit heart subjected to normothermic global ischaemia

1990

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The cytochemical localization of NADH-oxidase, a possible source of oxygen derived toxic species was studied in the isolated working rabbit heart subjected to normothermic global ischaemia. The activity of this oxidase could be important for the damage observed during ischaemia, when cellular defence mechanisms against free radicals are depleted. In non-ischaemic myocardium only small amounts of the NADH-oxidase reaction product were present in the mitochondria. Although the reaction product could already be observed after 45 min of incubation, prolonged incubation times up to 2h were necessary to clearly define these reactive sites. The reaction product is substrate dependent and is not affected by cyanide. Exposure of the hearts to ischaemia resulted in an alteration of the enzyme activity depending on the degree of ischaemic damage. In ultrastructurally slightly altered areas a high degree of activity was observed in the mitochondria. In infarcted tissue, mitochondria contained little or no reaction product. This cytochemical study supports the hypothesis that hydrogen peroxide and oxygen radicals produced in the mitochondria by NADH-oxidase activity may contribute to the mitochondrial damage observed during ischaemia when NADH is no longer oxidized by the respiratory chain and cellular defence mechanisms are impaired.

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Myocardial dysfunction and ultrastructural alterations mediated by oxygen metabolites

Cited by 61 publications

References 35 publications

Oxygen-derived free radicals and myocardial reperfusion injury: An overview

Oxygen-derived free radicals and myocardial reperfusion injury: An overview

Quantification of hydroxyl radical and its lack of relevance to myocardial injury during early reperfusion after graded ischemia in rat hearts.

Cytochemical evidence of NADH-oxidase activity in the isolated working rabbit heart subjected to normothermic global ischaemia

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