Effect of Intracoronary Superoxide Dismutase on Regional Function in Stunned Myocardium

Buchwald, A.; Klein, Hermann H.; Lindert, S.; Pich, Sybille; Nebendahl, Klaus; Wiegand, V.; Kreuzer, H

doi:10.1097/00005344-198902000-00013

Cited by 22 publications

(12 citation statements)

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“…Fourth, Rohmann et al (69) followed the recovery of function for only 30 min after the second reperfusion, an interval which may have been too short to rule out a beneficial effect (36). Finally, these previous studies (68,69) used open-chest swine whereas we used conscious pigs. Since the conditions associated with open-chest preparations markedly exaggerate the severity of stunning and the magnitude of free radical generation in dogs (22), it is possible that a protective effect of antioxidant therapy may be more difficult to demonstrate in open-chest swine.…”

Section: Discussionmentioning

confidence: 91%

“…Attenuation of myocardial stunning was observed, however, in our final protocol, in which two boluses of SOD and catalase were given, suggesting that the higher plasma levels of enzymes obtained with this protocol were important for the protection. Third, the aforementioned studies examined the stunning induced by an 8-min coronary occlusion (68) or by two 10-min occlusions (69), whereas we evaluated the stunning induced by 10 2-min occlusions. Fourth, Rohmann et al (69) followed the recovery of function for only 30 min after the second reperfusion, an interval which may have been too short to rule out a beneficial effect (36).…”

Section: Discussionmentioning

confidence: 99%

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Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs.

Sun¹,

Tang²,

Park³

et al. 1996

J. Clin. Invest.

223

137

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Conscious pigs underwent a sequence of 10 2-min coronary occlusions, each separated by 2 min of reperfusion, for three consecutive days (days 1, 2, and 3). On day 1, pigs received an i.v. infusion of a combination of antioxidants (superoxide dismutase, catalase, and N -2 mercaptopropionyl glycine; group II, n ϭ 9), nisoldipine (group III, n ϭ 6), or vehicle (group I [controls], n ϭ 9). In the control group, systolic wall thickening (WTh) in the ischemic-reperfused region on day 1 remained significantly depressed for 4 h after the 10th reperfusion, indicating myocardial "stunning." On days 2 and 3, however, the recovery of WTh improved markedly, so that the total deficit of WTh decreased by 53% on day 2 and 56% on day 3 compared with day 1 ( P Ͻ 0.01), indicating the development of a powerful cardioprotective response (late preconditioning against stunning). In the antioxidant-treated group, the total deficit of WTh on day 1 was 54% less than in the control group ( P Ͻ 0.01). On day 2, the total deficit of WTh was 85% greater than that observed on day 1 and similar to that observed on day 1 in the control group. On day 3, the total deficit of WTh was 58% less than that noted on day 2 ( P Ͻ 0.01). In the nisoldipine-treated group, the total deficit of WTh on day 1 was 53% less than that noted in controls ( P Ͻ 0.01). On days 2 and 3, the total deficit of WTh was similar to the corresponding values in the control group. These results demonstrate that: ( a ) in the conscious pig, antioxidant therapy completely blocks the development of late preconditioning against stunning, indicating that the production of reactive oxygen species (ROS) on day 1 is the mechanism whereby ischemia induces the protective response observed on day 2; ( b ) antioxidant therapy markedly attenuates myocardial stunning on day 1, indicating that ROS play an important pathogenetic role in postischemic dysfunction in the porcine heart despite the lack of xanthine oxidase; ( c ) although the administration of a calcium-channel antagonist (nisoldipine) is as effective as antioxidant therapy in attenuating myocardial stunning on day 1, it has no effect on late preconditioning on day 2, indicating that the ability of antioxidants to block late preconditioning is not a nonspecific result of the mitigation of postischemic dysfunction on day 1. Generation of ROS during reperfusion is generally viewed as a deleterious process. Our finding that ROS contribute to the genesis of myocardial stunning but, at the same time, trigger the development of late preconditioning against stunning supports a complex pathophysiological paradigm, in which ROS play an immediate injurious role (as mediators of stunning) followed by a useful function (as mediators of subsequent preconditioning). (

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs.

Sun¹,

Tang²,

Park³

et al. 1996

J. Clin. Invest.

223

137

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“…37 Similar protective effects of antioxidants have subsequently been demonstrated in conscious animals. 33,38,39 At the time of this writing, at least 22 full-length articles have been published that have examined the effect of antioxidants on myocardial stunning after a 15-minute coronary occlusion; all of these articles (except those that used superoxide dismutase alone [40][41][42] or catalase alone 40 ) have reported a protective effect of antioxidants against stunning. 37 Furthermore, generation of ROS in stunned myocardium has been demonstrated directly by both spin trapping 9,39,[43][44][45][46][47] and aromatic hydroxylation 48 techniques, and attenuation of ROS generation has repeatedly been shown to result in attenuation of contractile dysfunction.…”

Section: Generation Of Ros (Oxyradical Hypothesis)mentioning

confidence: 99%

Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning

et al. 1998

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“…The inability of SOD alone to mitigate postischemic dysfunction has also been observed in a pig model. 100 Although both *°2-and H202 appear to contribute to stunning, it remains uncertain whether they do so by direct cytotoxicity or via formation of other species. *°2 and H202 can interact through the metal-catalyzed Haber-Weiss reaction to generate the highly reactive *OH radical.10' Consequently, accumulation of *°2 and H202 could produce postischemic dysfunction, at least in part, indirectly through generation of OH.…”

Section: Decreased Sensitivity Of Myofilaments To Calciummentioning

confidence: 99%

Mechanism of myocardial "stunning".

1990

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Among the numerous mechanisms proposed for myocardial stunning, three appear to be more plausible: 1) generation of oxygen radicals, 2) calcium overload, and 3) excitation-contraction uncoupling. First, the evidence for a pathogenetic role of oxygen-derived free radicals in myocardial stunning is overwhelming. In the setting of a single 15-minute coronary occlusion, mitigation of stunning by antioxidants has been reproducibly observed by several independent laboratories. Similar protection has been recently demonstrated in the conscious animal, that is, in the most physiological experimental preparation available. Furthermore, generation of free radicals in the stunned myocardium has been directly demonstrated by spin trapping techniques, and attenuation of free radical generation has been repeatedly shown to result in attenuation of contractile dysfunction. Numerous observations suggest that oxyradicals also contribute to stunning in other settings: after global ischemia in vitro, after global ischemia during cardioplegic arrest in vivo, and after multiple brief episodes of regional ischemia in vivo. Compelling evidence indicates that the critical free radical damage occurs in the initial moments of reflow, so that myocardial stunning can be viewed as a sublethal form of oxyradical-mediated "reperfusion injury." Second, there is also considerable evidence that a transient calcium overload during early reperfusion contributes to postischemic dysfunction in vitro; however, the importance of this mechanism in vivo remains to be defined. Third, inadequate release of calcium by the sarcoplasmic reticulum, with consequent excitation-contraction uncoupling, may occur after multiple brief episodes of regional ischemia, but its role in other forms of postischemic dysfunction has not been explored. It is probable that multiple mechanisms contribute to the pathogenesis of myocardial stunning. The three hypotheses outlined above are not mutually exclusive and in fact may represent different steps of the same pathophysiological cascade. Thus, generation of oxyradicals may cause sarcoplasmic reticulum dysfunction, and both of these processes may lead to calcium overload, which in turn could exacerbate the damage initiated by oxygen species. The concepts discussed in this review should provide not only a conceptual framework for further investigation of the pathophysiology of reversible ischemia-reperfusion injury but also a rationale for developing clinically applicable interventions designed to prevent postischemic ventricular dysfunction.

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Effect of Intracoronary Superoxide Dismutase on Regional Function in Stunned Myocardium

Cited by 22 publications

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Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs.

Evidence for an essential role of reactive oxygen species in the genesis of late preconditioning against myocardial stunning in conscious pigs.

Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning

Mechanism of myocardial "stunning".

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