Postischemic myocardial "stunning". Identification of major differences between the open-chest and the conscious dog and evaluation of the oxygen radical hypothesis in the conscious dog.

Abstract

Recent studies suggest that oxygen-derived free radicals contribute to the pathogenesis of postischemic myocardial dysfunction (myocardial "stunning"). This concept, however, is predicated exclusively on results obtained in open-chest preparations, which are subject to the confounding influence of many unphysiological conditions. The lack of supporting evidence in more physiological animal models represents a major persisting limitation of the oxy-radical hypothesis of myocardial stunning. The goal of this study was to address two fundamental (and related) occlusions). Despite the fact that the plasma levels of SOD and CAT declined rapidly after reperfusion, postischemic wall thickening was significantly greater in treated compared with control dogs throughout the first 6 hours of reflow. Thus, a brief (60-minute) infusion of SOD and CAT produced a sustained improvement of recovery of contractility. The magnitude of this beneficial effect was a function of the severity of ischemia: the lower the collateral perfusion, the greater the improvement effected by the enzymes. The accelerated recovery produced by SOD and CAT was not followed by any deterioration of contractility, suggesting that postischemic dysfunction is not a teleologically "protective" phenomenon. In conclusion, the severity of myocardial stunning is greatly exaggerated by the unphysiological conditions present in the barbiturate-anesthetized open-chest dog. However, antioxidant therapy does attenuate myocardial stunning in the conscious dog, indicating that oxygen radicals play a pathogenetic role that is independent of the abnormal conditions associated with the open-chest preparation. (Circulation Research 1991;69:731-747) ecent studiesl-15 suggest that oxygen-derived anesthetized, open-chest preparations.1-15 To our free radicals contribute to the pathogenesis knowledge, no information is available regarding the of postischemic myocardial dysfunction effect of antioxidant therapy on myocardial stunning (myocardial "stunning"'6). The validity of this conafter brief (<20 minutes) ischemia in the conscious cept, however, is limited by the fact that it is predianimal. Several investigators17-28 have pointed out cated exclusively on results obtained in barbiturate-that observations in open-chest models may be con-

Demonstration of free radical generation in the "stunned" myocardium in the conscious dog and identification of major differences between conscious and open-chest dogs.

“…Certain conclusions derived from open-chest preparations have subsequently been found not to be applicable to conscious animals (9,10,15,17,18,20). We have recently observed (21 ) that the severity of myocardial stunning after a 15-min coronary occlusion is greatly exaggerated in the barbiturate-anesthetized open-chest dog, i.e., approximately half of the postischemic depression of contractility observed in this model is not present in the awake dog. The time course of recovery of contractile function is also quite different in the two models.…”

“…The time course of recovery of contractile function is also quite different in the two models. In open-chest dogs, recovery of function ceases at 1 h of reperfusion and no further improvement takes place between 1 and 4 h of reflow (21 ); in contrast, in the conscious dog recovery continues unabated throughout the first 6 h of reperfusion and beyond until complete normalization is achieved (21 ).…”

Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning

“…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.…”

Novel Rat Model of Ischemic Cardiomyopathy Induced by Repetitive Myocardial Ischemia/Reperfusion Injury While Conscious

“…We emphasize that the present study is the first developed rat model with ICM induced by repetitive 30-min ischemic stimuli while conscious. The possible reason for the mild histological findings is considered to be the lack of adverse effects of general anesthesia 9,10 and/or adaptation mechanisms against repeated stimuli. Finally, we observed patchy distribution of myocyte loss and infiltration of fibrosis instead of massive scar formation, but we can not exclude that microscopic infarctions occurred heterogeneously 35,36 and merged with each other.…”

“…8 However, the technical limitation in those animal models is the possible adverse effects of general anesthesia during I/R stimuli, because the alteration of the autonomic nervous system under general anesthesia is considered to exaggerate and jeopardize the I/R injury. 9,10 Therefore, remaining conscious during repetitive I/R stimuli is required as the more appropriate animal model, so the primary purpose of the present study was to establish a novel rat model of ICM induced by repetitive I/R while conscious using an implanted coronary arterial occluder.…”