CI-959, a cell-activation inhibitor that prevents the formation of
oxygen-derived
free radicals by inflammatory cells, was studied to determine its effects on
myocardial infarct size and subsequent
scar formation in dogs. The left circumflex coronary artery was occluded for 90 min, followed by 6 h of reperfusion.
Drug infusion was started 15 min before reperfusion at a loading dose of 8 mg/kg i.v., followed immediately by 2 mg/kg i.v. infused over 80 min. The
infarct size, assessed by TTC staining techniques, was significantly reduced in 12 dogs treated with
CI-959 (23.3 +/- 3.6% of the area at risk) when compared to 11 vehicle-treated animals (35.5 +/- 4% of the area at risk, p less than 0.05). This reduction in
infarct size was not attributed to changes in regional myocardial blood flow, as measured by radioactive
microspheres, or to a reduction in myocardial
oxygen demand, as estimated by changes in the rate-pressure product. The
scar thickness, measured after a 6-week recovery period in 9 animals treated with
CI-959, was not significantly reduced in comparison with 11 controls. In vitro,
CI-959 effectively inhibited
oxygen free radical formation by canine neutrophils. The results of this study show that
CI-959 significantly reduces the
myocardial infarct size without causing
scar thinning, which might lead to ventricular
aneurysm, and suggests the most likely mechanism for its beneficial action is the prevention of formation of toxic
oxygen radicals.