SUMMARY. Therapy directed against the toxic effects of reactive oxygen species may reduce the final extent of ischemic injury in otherwise viable tissue irreversibly injured by the abrupt reoxygenation of reperfusion. In four groups of dogs, superoxide dismutase plus catalase (groups I-III) or saline (controls) (group IV) was infused into the left atrium. Group I received the infusion for 2 hours, beginning 15 minutes before occlusion of the left circumflex coronary artery (90 minutes) and ending 15 minutes after reperfusion. Group II received the infusion for 1 hour starring 15 minutes before reperfusion. Group III received the infusion for 1 hour beginning 40 minutes after reperfusion. Dogs were killed the next day, and infarct size was determined by dissection and weighing, and confirmed histologically. Infarct size expressed as percent of the anatomic area at risk was: group I, 19.4 ± 5.0; group II, 21.8 ± 3.3; group III, 47.6 ± 10.3; group IV, 43.6 ± 3.5 (mean ± SEM). Analysis of variance followed by Duncan's multiple range test showed that ultimate infarct size as assessed in groups I and II differed significantly (P < 0.05) from that observed in the control animals in group IV, whereas infarct size between groups III and IV did not differ significantly (P > 0.05). The percent of left ventricle at risk did not differ between the four groups. The beneficial effects of superoxide dismutase plus catalase could not be explained by hemodynamic differences. Similar protection of jeopardized myocardium in groups I and II suggest that potentially viable tissue is salvaged by scavenging free radicals during early reperfusion. Lack of protection in group III suggests that injury has occurred within the first 40 minutes of reperfusion. The results of this investigation demonstrate that the '"primary' myqcardial cellular damage due to ischemia is additive to the cardiac cell damage during the phase of reperfusion, and that the "secondary" effects are mediated by toxic metabolites of oxygen. (Che Res 54: 277-285, 1984)

Pain associated with inflammation involves prostaglandins synthesized from arachidonic acid (AA) through cyclooxygenase-2 (COX-2) pathways while thromboxane A 2 formed by platelets from AA via cyclooxygenase-1 (COX-1) mediates thrombosis. COX-1 and COX-2 are both targets of nonselective nonsteroidal antiinflammatory drugs (nsNSAIDs) including aspirin whereas COX-2 activity is preferentially blocked by COX-2 inhibitors called coxibs. COXs are homodimers composed of identical subunits, but we have shown that only one subunit is active at a time during catalysis; moreover, many nsNSAIDS bind to a single subunit of a COX dimer to inhibit the COX activity of the entire dimer. Here, we report the surprising observation that celecoxib and other coxibs bind tightly to a subunit of COX-1. Although celecoxib binding to one monomer of COX-1 does not affect the normal catalytic processing of AA by the second, partner subunit, celecoxib does interfere with the inhibition of COX-1 by aspirin in vitro. X-ray crystallographic results obtained with a celecoxib/COX-1 complex show how celecoxib can bind to one of the two available COX sites of the COX-1 dimer. Finally, we find that administration of celecoxib to dogs interferes with the ability of a low dose of aspirin to inhibit AA-induced ex vivo platelet aggregation. COX-2 inhibitors such as celecoxib are widely used for pain relief. Because coxibs exhibit cardiovascular side effects, they are often prescribed in combination with low-dose aspirin to prevent thrombosis. Our studies predict that the cardioprotective effect of low-dose aspirin on COX-1 may be blunted when taken with coxibs.arachidonic acid | adrenic acid | nonsteroidal antiinflammatory drugs | platelet | prostaglandin

A monoclonal antibody (904) that binds to a leukocyte cell adhesion-promoting glycoprotein, (Mol; CD11b/CD18) was administered (1 mg/kg, iv.) to open chest anesthetized dogs 45 min after the induction of regional myocardial ischemia. Ischemia was produced by occluding the left circumflex coronary artery (LCX) for 90 min and then reperfusing for 6 h. There was no difference between control and antibody treated groups with respect to arterial blood pressure, heart rate, or LCX blood flow. Administration of antibody produced no observable effect on circulating neutrophil counts, suggesting that antibody-bound neutrophils were not cleared from the circulation. The mean size of myocardial infarct expressed as percentage of the area at risk of infarction that resulted was reduced by 46% with anti-Mol treatment (25.8±4.7%, n = 8) compared to control (47.6±5.7%, n = 8; P < 0.01). The area at risk of infarction was similar between groups. Circulating (serum) antibody excess was confirmed in all 8 anti-Mol treated dogs by immunofluorescence analysis. Analysis of ST segment elevation on the electrocardiogram as an indicator of the severity of ischemia suggests that the anti-Mol reduces infarct size independent of the severity of ischemia. An additional group of dogs (n = 5) was tested with a control monoclonal antibody of the same subtype (murine IgGI) and was found to produce no significant reduction in myocardial infarct size. Accumulation of neutrophils within the myocardium was significantly attenuated with 904 treatment when analyzed by histological methods. These data demonstrate that administration of anti-Mol monoclonal antibody after the induction of regional myocardial ischemia results in reduced myocardial reperfusion injury as measured by ultimate infarct size.

No abstract

Myocardial preconditioning with brief coronary artery occlusions before a sustained ischemic period is reported to reduce infarct size. To determine the number of occlusive episodes required to produce the preconditioning effect, we performed single or multiple occlusions of the left circumflex coronary artery (LCx) followed by a sustained occlusion (60 minutes) of the LCx. Anesthetized dogs underwent one (P1), six (P6), or 12 (P12) 5-minute occlusions of the LCx. Each occlusion period was followed by a 19-minute reperfusion period. A 60-minute occlusion of the LCx followed the preconditioning sequences. A control group received a 60-minute occlusion of the LCx without preconditioning. All groups were subjected to 6 hours of reperfusion after which the heart was removed for calculating infarct size (IS), area at risk (AR), and left ventricular mass (LV). The IS/AR ratio for the control group was 29.8±4.4% (n=17), which was substantially greater (p<0.001) than that of the preconditioned groups: P1, 3.9±1.3% (n=14); P6, 0.4±0.3% (n=5); and P12, 2.9±2.8% (n=5). There were no significant differences in the IS/AR ratio among the three preconditioned groups. The AR/LV ratio was comparable among all groups and did not differ statistically: control, 40.4±13%; P1, 36.2±1.7%; P6, 36.1±1.7%; and P12, 37.3±2.1%. Collateral blood flow to the inner two thirds of the risk region determined with radiolabeled microspheres during ischemia did not differ significantly between the control group (0.03 ±0.01 ml/minlg, n=8) and single occlusion group (0.06±0.02 mllmin/g, n=8), indicating that the marked disparity in infarct size could not be attributed to differences in collateral blood flow. The data indicate that preconditioning with one brief ischemic interval is as effective as preconditioning with multiple ischemic periods. (Circulation 1990;82:609-619) T imely reperfusion of the ischemic heart in experimental animals limits the extent of irreversible myocardial injuryl2 and enhances the long-term prognosis for survival in patients with coronary artery disease.