Platelet activating factor interaction with tumor necrosis factor in myocardial ischaemia-reperfusion injury.

Abstract

The role played by platelet-activating factor (PAF) and tumor necrosis factor (TNF-alpha) in myocardial ischaemia-reperfusion injury was investigated. Pentobarbital anaesthetized rats were subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham-operated rats were used as controls (Sham MI/R). Myocardial ischaemia-reperfusion injury produced a marked myocardial injury (necrotic area/area-at-risk = 60 +/- 5%; necrotic area/total area = 50 +/- 6%), high serum creatine phosphokinase activity (Sham MI/R = 25 +/- 10 U/ml; MI/R = 190 +/- 12 U/ml), a severe leukopenia (Sham MI/R = 10367 +/- 630 WBC x mm3; MI/R = 4123 +/- 120 WBC x mm3) and elevated myocardial myeloperoxidase activity (investigated as an index of leukocytes adhesion and accumulation) in the area-at-risk (6.2 +/- 0.5 U x 10(-3)/g tissue) and in necrotic area (6.6 +/- 0.7 U x 10(-3)/g tissue. Plasma PAF and serum TNF-alpha were significantly increased only during reperfusion. The peak of PAF plasma levels (6.5 +/- 1.2 pmol/ml) occurred earlier (15 min of reperfusion) than the peak of serum TNF-alpha (150 U/ml at 30 min of reperfusion). At the end of reperfusion, macrophage TNF-alpha was also enhanced (Sham MI/R = undetectable; MI/R = 148 +/- 12 U/ml). The administration of CV 6209, a specific PAF receptor antagonist (5 mg/kg, 5 min after occlusion), significantly reduced myocardial injury (necrotic area/area-at-risk = 27 +/- 3%, P < 0.001; necrotic area/total area = 10 +/- 2%, P < 0.001), blunted the increase in serum creatine phosphokinase (70 +/- 12 U/ml), partially restored leukopenia (8234 +/- 143 WBC x mm3) and lowered myeloperoxidase activity in area-at-risk (2.3 +/- 0.3 U x 10(-3)/g tissue; P < 0.001) and in necrotic area (2.8 +/- 0.5 U x 10(-3)/g tissue). In addition, administration of CV 6209 reduced the serum and macrophage levels of TNF-alpha. The results of this study, therefore, suggest that PAF and TNF-alpha are key mediators of myocardial ischaemia-reperfusion injury and that PAF plays a permissive role in inducing the release of other factor(s) relevant to reperfusion injury.