Reduction of reperfusion injury in the canine preparation by intracoronary adenosine: importance of the endothelium and the no-reflow phenomenon.

Olafsson, Bjarki J.; Forman, Mervyn B.; Puett, David; Pou, Adrienne; Cates, Christopher U.; Friesinger, Gottlieb C.; Virmani, Renu

doi:10.1161/01.cir.76.5.1135

Cited by 369 publications

(145 citation statements)

References 45 publications

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“…Previous work in this laboratory has demonstrated that agents that reduce infarct size in a similar reperfusion model limit microvascular disruption in the subendocardium, suggesting that preservation of the endothelium may be an important mechanism in enhancing myocardial salvage after reperfusion. 28,50 Biochemical analysis failed to support the hypothesis that autocatalytic lipid peroxidation is responsible for postreperfusion myocyte death. Despite the fact that ischemic tissue contained higher levels of the TBA-reactive substance, malondialdehyde levels were elevated (ischemic zone significantly greater than the nonischemic zone) in only three animals.…”

Section: Discussionmentioning

confidence: 99%

“…After 30 minutes of occlusion, a loading dose of N-acetylcysteine (150 mg/kg) was infused via the Swan-Ganz catheter over 1 hour (rate, 1 ml/min; total volume, 60 ml). After this loading dose, a maintenance infusion of Nacetylcysteine (50 mg/kg/hr) was continued until 3 hours after reperfusion (rate, 0.33 ml/min; total volume, 60 ml). Control animals received an equivalent volume of saline over the 4-hour period.…”

Section: Experimental Protocolmentioning

confidence: 99%

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Glutathione redox pathway and reperfusion injury. Effect of N-acetylcysteine on infarct size and ventricular function.

et al. 1988

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Glutathione peroxidase is an important enzyme in the degradative cascade of reactive oxygen free radicals. N-Acetylcysteine (NAC) is a low molecular weight compound that has been used clinically to replenish glutathione. To assess the role of the glutathione redox pathway on reperfusion injury, 23 animals underwent 90 minutes of proximal left anterior descending coronary artery occlusion followed by 24 hours of reperfusion with the administration of NAC (n = 11) or saline (n = 12) beginning 30 minutes into occlusion and continuing for 3 hours after reperfusion. Regional ventricular function was measured with contrast ventriculography, and regional myocardial blood flow was determined with microspheres. At 24 hours, the area at risk was defined in vivo with Monastral Blue, and the area of necrosis was defined by incubation in triphenyltetrazolium. Biopsies were taken from the ischemic and nonischemic zones to determine levels of total glutathione, superoxide dismutase and glutathione peroxidase activity, and reactivity to thiobarbituric acid, an index of lipid peroxidation. The rate-pressure product and myocardial blood flow were similar in the two groups throughout the study. No significant differences were noted in infarct size expressed as a percentage of the area at risk (28.6 5.3% vs. 36.6 6.0%) and of the total left ventricle (14.4 3.2% vs. 16.5 + 3.1%), and no differences were noted between the two groups on examination of the ischemic subendocardium by light and electron microscopy. Both groups exhibited similar degrees of dyskinesis during occlusion; however, treated animals showed significant improvement in regional radial shortening at 3 hours (3.4+2.4% vs. -2.4±2.1%, p<0.02) and 24 hours (9.2±2.2% vs. -2.5 ±6.3%, p

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Section: Discussionmentioning

confidence: 99%

Section: Experimental Protocolmentioning

confidence: 99%

Glutathione redox pathway and reperfusion injury. Effect of N-acetylcysteine on infarct size and ventricular function.

et al. 1988

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“…On reperfusion average flow in both inner and outer layers increased about twofold over preischemic values. This hyperemic response subsided between 30 and 210 minutes of reperfusion (Table 3).…”

Section: Regional Myocardial Blood Flowmentioning

confidence: 97%

Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow.

et al. 1989

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The "no-reflow" phenomenon, the occurrence of areas with very low flow in hearts reperfused after ischemia, is thought to be largely established at the time of reperfusion as a result of microvascular damage induced by ischemia. In the present study we sought to determine whether additional impairment of tissue perfusion might also occur during the course of reperfusion. Open-chest dogs were subjected to 90 minutes of left circumflex coronary artery occlusion and reperfused for 2 minutes (n=7) or 3.5 hours (n=8). Myocardial perfusion was visualized in left ventricular slices following in vivo injection of the fluorescent dye thioflavin-S just before killing. The area of impaired perfusion (absent thioflavin) averaged 9.5+3.0% of the risk region in dogs reperfused for 2 minutes, whereas it was nearly three times as large in dogs reperfused for 3.5 hours (25.9 ±8.2% of the risk region, p<0.05). Serial measurements of flow by microspheres during reperfusion demonstrated zones within the postischemic myocardium that were hyperemic 2 minutes after reperfusion, with adequate flow still present at 30 minutes, but with a subsequent marked fall in perfusion. After 3.5 hours these areas showed negligible flow (0.13 ±0.03 ml/min/g) and no thioflavin uptake. Tissue samples showving postischemic impairment in perfusion had received virtually no collateral flow during ischemia (<0.01 mlUmin/g), whereas collateral flow was significantly higher in adjacent thioflavin-positive zones (0.04±0.01 ml/min/g in endocardial samples and 0.07±0.02 ml/min/g in samples from the midmyocardium, p<0.001 vs. thioflavin-negative areas). Areas that showed late impairment of flow invariably demonstrated contraction band necrosis, which contrasted with the pattern of coagulation necrosis observed in areas of "true" (i.e., immediate) no-reflow. Intracapillary erythrocyte stasis and marked intravascular neutrophil accumulation (to levels >20-fold that found after 2 minutes reperfusion) were typically observed in areas of delayed impairment to flow. Obstruction to flow at the capillary level was confirmed in additional dogs in which the heart was injected postmortem with silicone rubber to delineate the microvascular filling pattern. Areas of absent capillary filling were much more extensive after 3.5 hours than after 2 minutes reperfusion. Thus, this study shows that the occurrence of areas of markedly impaired perfusion in postischemic myocardium is related only in part to an inability to reperfuse certain areas on reflow. A more important factor is represented by a delayed, progressive fall in flow to areas that initially received adequate reperfusion. This phenomenon develops in regions receiving no collateral flow during ischemia and is associated with neutrophil accumulation and capillary plugging late during the course of reperfusion. (Circulation

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“…Of additional interest, isolated rat hearts preconditioned with DPDPE, a delta 1-specific opioid agonist, also demonstrated decreased reperfusion-induced ventricular arrhythmias with contractile dysfunction (negative inotropic effect) upon reperfusion. 42 As was found with adenosine, 43 Deltorphin D administration attenuated the no-reflow phenomenon exhibiting a significant increase in coronary flow in the midmyocardial layer at the 2 h reperfusion time point. The no-reflow phenomenon is a multifactorial syndrome that is potentially caused by leukocyte-mediated endothelial damage; however, it may also present as a secondary consequence of myocyte edema and contracture.…”

Section: Discussionmentioning

confidence: 72%

Featured Article: Pharmacological postconditioning with delta opioid attenuates myocardial reperfusion injury in isolated porcine hearts

Seewald

Coles

Sigg

et al. 2016

Exp Biol Med (Maywood)

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In this study, we found that postconditioning with Deltorphin D significantly improved diastolic relaxation and decreased the incidence of ventricular arrhythmias during early reperfusion. Furthermore, these treated hearts demonstrated increased tissue perfusion after 2 h, suggesting improved microvascular function. Delta opioid agonists attenuated reperfusion injury, suggestive of a postconditioning effect. Such agents may have a potential role in minimizing reperfusion injury associated with coronary stenting, bypass surgery, myocardial infarction, cardiac transplantation, or with the utilization of heart preservation systems. AbstractIschemic preconditioning has been utilized to protect the heart from ischemia prior to ischemia onset, whereas postconditioning is employed to minimize the consequences of ischemia at the onset of reperfusion. The underlying mechanisms and pathways of ischemic pre-and postconditioning continue to be investigated as therapeutic targets. We evaluated the administration of a delta opioid agonist or cariporide on various parameters associated with myocardial reperfusion injury upon reperfusion of isolated porcine hearts. The hearts were reperfused in vitro with a Krebs buffer containing either: (1) 1 mM Deltorphin D (delta opioid specific agonist, n ¼ 6); (2) 3 mM cariporide (sodium-hydrogen exchange inhibitor, n ¼ 4); or (3) no treatment (control, n ¼ 6). Subsequently, postischemic hemodynamic performance, arrhythmia burden, relative tissue perfusion, and development of necrosis were assessed over a 2 h reperfusion period. Postconditioning with Deltorphin D significantly improved diastolic relaxation (Tau, P < 0.05 versus controls) and decreased the incidence of ventricular arrhythmias during early reperfusion. Additionally, these treated hearts demonstrated increased tissue perfusion after 2 h (P < 0.05 versus controls), suggesting improved microvascular function. Delta opioid agonists elicited the potential to attenuate reperfusion injury, suggesting a postconditioning effect of these agents. We hypothesize that the induced benefits of delta opioids, in part, are associated with decreased calcium influx on reperfusion, independent of sodium-hydrogen exchange inhibition. Such agents may have a potential role in minimizing reperfusion injury associated with coronary stenting, bypass surgery, myocardial infarction, cardiac transplantation, or with the utilization of heart preservation systems.

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Reduction of reperfusion injury in the canine preparation by intracoronary adenosine: importance of the endothelium and the no-reflow phenomenon.

Cited by 369 publications

References 45 publications

Glutathione redox pathway and reperfusion injury. Effect of N-acetylcysteine on infarct size and ventricular function.

Glutathione redox pathway and reperfusion injury. Effect of N-acetylcysteine on infarct size and ventricular function.

Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow.

Featured Article: Pharmacological postconditioning with delta opioid attenuates myocardial reperfusion injury in isolated porcine hearts

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