Aprotinin Exerts Differential and Dose-Dependent Effects on Myocardial Contractility, Oxidative Stress, and Cytokine Release After Ischemia-Reperfusion

Background Cardiac surgery can result in left ventricular ischemia and reperfusion (I/R), the release of cytokines such as tumor necrosis factor, and oxidative stress with release of myeloperoxidase. Although aprotinin has been used in cardiac surgery, the likely multiple effects of this serine protease inhibitor limit clinical utility. This study tested the hypothesis that different aprotinin doses cause divergent effects on left ventricular contractility, cytokine release, and oxidative stress in the context of I/R. Methods Left ventricular I/R (30 minutes I, 60 minutes R) was induced in mice, and left ventricular contractility (maximal end-systolic elastance) determined. Mice were randomly allocated to 2 × 104 kallikrein inhibitory units (KIU)/kg aprotinin (n = 11), 4 × 104 KIU/kg aprotinin (n = 10), and vehicle (saline, n = 10). Based upon a fluorogenic assay, aprotinin doses of 2 and 4 × 104 KIU/kg resulted in plasma concentrations similar to those of the half and full Hammersmith doses, respectively. Results After I/R, maximal end-systolic elastance fell by more than 40% from baseline (p < 0.05), and this effect was attenuated by 2 × 104 KIU/kg but not 4 × 104 KIU/kg aprotinin. Tumor necrosis factor increased by more than 60% from control (p < 0.05) with I/R, but was reduced with 4 × 104 KIU/kg aprotinin. Myeloperoxidase increased with I/R, and was reduced to the greatest degree by 2 × 104 KIU/kg aprotinin. Conclusions Aprotinin influences left ventricular contractility, cytokine release, and oxidative stress, which are dose dependent. These results provide mechanistic evidence that multiple pathways are differentially affected by aprotinin in a context relevant to cardiac surgery.