SUMMARY Accumulation of polymorphonuclear neutrophils during the acute inflammatory response may exacerbate tissue injury through the release of activated oxygen products or proteolytic enzymes or both. To assess the role of neutrophils in acute myocardial infarction, circulating neutrophil levels in dogs were reduced by 77 + 2% (mean SEM) by administering rabbit antiserum to dog neutrophils. Acute myocardial infarction was induced in open-chest anesthetized dogs by 90 minutes of left circumflex coronary artery occlusion followed by 6 hours of reperfusion. Dogs treated with neutrophil antiserum (n = 8) developed myocardial infarcts that were an average of 43% smaller' than infarcts in dogs treated with nonimmune rabbit serum (n = 7) (27.0 ± 4.5% vs 47.1% 7.5% of the area at risk, p < 0.05). In a salinetreated control group (n = 8), infarct size was 48.0 ± 4.7% of the area at risk, a value not significantly different from that of the nonimmune serum group but significantly greater than that in the neutrophil antiserum dogs (p < 0.05). There were no major hemodynamic differences between groups. Histopathologic examination revealed that infarcted myocardium from dogs given saline or treated with nonimmune serum had a substantial neutrophilic infiltrate, which was virtually absent in infarcted tissue from dogs treated with neutrophil, antiserum. These observations suggest that neutrophil accumulation in response to myocardial ischemia may be responsible for a substantial portion of the irreversible myocardial' injury resulting from temporary coronary artery occlusion.THE MIGRATION of polymorphonuclear neutrophils into recently infarcted myocardium represents the initial phase of a process that leads to demolition and subsequent organization of injured tissue and culminates in the replacement of necrotic myocardium with fibrous scar." 2 Infiltration of neutrophils into irreversibly injured myocardium facilitates the breakdown of necrotic myocardium, which promotes resorbtion or phagocytosis by macrophages.2 After the removal of tissue debris, capillaries and fibroblasts invade the infarcted area and lead to the formation of collagen-rich scar tissue, which replaces the necrotic area.2 During the early acute inflammatory response, polymorphonuclear neutrophils undergo a complex series of functional and biochemical alterations that promote tissue lysis. Although these events are important to the repair process, they may also result in the destruction of potentially viable tissue elements. Stimulated neutrophils release highly reactive and cytotoxic activated oxygen species such as superoxide anion, hydroxyl radical, hydrogen peroxide and singlet oxygen. These activated oxygen radicals degrade extracellular macromolecules, attack membrane phospholipids and, thus, promote cell injury or death. idonic acid, which is converted by specific lipoxygenases to potent chemotactic hydroxy-eicosatetraenoic acids (HETEs).6 These chemoattractant substances promote the further recruitment of neutrophils into the acute inflammatory re...

A simple technique for the reliable induction of coronary artery thrombosis in a conscious dog by delivery of low amperage electric current to the intimal surface of the artery io described. Ibuprofen, an agent known to inhibit platelet function and ptostaglandin synthesis is evaluated in this model. Comparison of myocardial infarct site, throabur weight, arrhythmia development and scanning electron nicrographs of drug treated and control animals indicate that Ibuprofen is capable of protecting against the deleterious effects of coronary artery thrombosis produced by this technique. This method holds considerable potential as an ;iD. vivq model of coronary artery thrombosis and one in which evaluation of anti-thrw botic agents is possible.

SUMMARY To assess the ability of ibuprofen to influence the extent of platelet aggregation and leukocyte infiltration during acute myocardial infarction, autologous indium-111 ("IIn)-labeled platelets or leukocytes were injected before 60 minutes of left circumflex coronary artery (LCx) occlusion, followed by 24 hours of reperfusion in the canine heart. Myocardial infarct size, as a percent of the area at risk, was reduced in the ibuprofen-treated group (12.5 mg/kg i.v. every 4 hours beginning 30 minutes before LCx occlusion) by 40%, from 48 4% in control animals to 29 4% in ibuprofen-treated dogs (p = 0.005).Quantification of the platelet-associated "l'In radioactivity in irreversibly injured myocardium indicated that ibuprofen did not alter the accumulation of platelets in infarcted myocardium. In contrast, leukocyte accumulation in infarcted tissue was reduced significantly. In tissue samples with 0.414.60 gram infarct, the in'farcted/normal ratio of leukocyte radioactivity was 12 ± 2 in control dogs and 4 + 1 in ibuprofentreated dogs, which represents a 67% reduction in leukocyte accumulation in ibuprofen-treated compared with control dogs. Similar reductions were found in other gram-infarct-weight categories. Although both platelets and leukocytes accumulate in infarcted canine myocardium, ibuprofen may exert its beneficial effect on ischemic myocardium by suppressing the inflammatory response associated with myocardial ischemia and infarction.THE GOAL of much cardiovascular research has been to develop pharmacologic means of managing patients before or soon after an acute ischemic insult to minimize the extent of irreversible myocardial injury and subsequent loss of ventricular function. Several agents are effective in reducing the extent of myocardial infarction resulting from experimentally induced acute myocardial ischemia in a variety of animal models.1 One such agent, ibuprofen, is a nonsteroidal antiinflammatory compound that has been reported to exert cardioprotective effects by significantly reducing the extent of irreversible myocardial injury to experimental ischemia in the dog,2'3 the cat,4 and the rat.5 Ibuprofen renders its cardioprotective effects administered orally,3 intravenously2 or intramuscularly.5Several independent investigators have demonstrated protective effects in a variety of experimental models of myocardial ischemia and infarction, but little is known about ibuprofen's mechanism of action. Apparently, the beneficial effects of ibuprofen do not derive from alteration of the balance of myocardial oxygen supply and demand in a favorable manner. Intravenous ibuprofen reportedly has negligible hemodynamic effects2' 6 and almost no effect on the calculated ratepressure product, an accepted approximation of myocardial oxygen consumption,7 during myocardial ischemia in the dog.6 Moreover, in the nonischemic, isolated, blood-perfused cat heart, an animal model that permits careful control of hemodynamic variables, ibuprofen did not alter myocardial oxygen consumption as measured by art...

The effect of altering the abundance of precursors and inhibitors of prostaglandin formation by dietary supplements of fish oil was investigated in dogs with experimentally induced myocardial infarction. Prior to induction, 10 male mongrel dogs were fed standard dog chow supplemented with 25% of the total calories as menhaden oil for 36 to 45 days. The fatty acid composition of th lipids in plasma and platelets changed to reflect the increased intake of polyunsaturated fatty acids of the n-3 type. Thrombosis and subsequent infarction was induced by electrical stimulation of the left circumflex coronary artery of ambulatory dogs that were monitored by telemetry. Upon stimulation of control animals, the frequency of ectopic beats rose from less than 10% at the beginning to about 80% after 19 hours. In contrast, the oil-fed dogs maintained a more normal ECG pattern, showing less than 30% ectopic beats after 19 hours. In these animals, the size of infarction (measured by formazan formation) was 3% of the left ventricle compared to 25% in the control animals. The results suggest that dietary supplementation with fish oil may be beneficial in reducing myocardial damage associated with coronary artery thrombosis.

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