Abstract
Objectives: This study tested the hypothesis that a recombinant human C5a antagonist, CGS 32359, attenuates neutrophil activation and reduces infarct size in a porcine model of surgical revascularization. Methods: CGS 32359 (0.16-16 μmol/L) dose-dependently inhibited superoxide production by human C5a-activated porcine neutrophils (18 ± 3.7 vs 1.6 ± 0.5 nmol/5 min/5 × 106 neutrophils; P <.05) and reduced neutrophil adherence to coronary endothelium from 194 ± 9 to 43 ± 6 neutrophils/mm2 (P <.05). The left anterior descending coronary artery was occluded for 50 minutes, after which saline solution (n = 8), mannitol-buffer vehicle (n = 9, 102 mg/kg bolus, 102 mg · kg–1 · h–1), or CGS 32359 (CGS, n = 7, 60 mg/kg bolus, 60 mg · kg–1 · h–1) was infused. After ischemia, 1-hour arrest was achieved by means of multidose hypothermic (4°C) blood cardioplegia, followed by 2.5 hours of off-bypass reperfusion. The ligature on the left anterior descending artery was released before the second infusion of cardioplegic solution. Results: Area at risk was similar in all groups (saline solution, 27% ± 2%; mannitol-buffer vehicle, 26% ± 2%; CGS, 26% ± 2% left ventricular mass). Infarct size (area necrosis/area at risk) was significantly reduced by CGS (18% ± 6%, P <.05) versus saline solution (52% ± 3%) and mannitol-buffer vehicle (60% ± 4%). Postischemic systolic shortening (sonomicrometry) in the area at risk was significantly improved with CGS (0.8% ± 0.9%) compared with saline solution (–3.7% ± 1.1%) and mannitol-buffer vehicle (–6.4% ± 1.0%). Myeloperoxidase activity from accumulated neutrophils was less in the ischemic zone of CGS (0.014 ± 0.002 U/100 mg tissue; P <.05) than mannitol-buffer vehicle (0.133 ± 0.012 U/100 mg tissue). Conclusions: We conclude that the recombinant human C5a receptor antagonist CGS 32359 inhibits surgical ischemia-reperfusion injury after coronary occlusion. (J Thorac Cardiovasc Surg 2000;120:350-8)
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