Aprotinin exerts differential and dose-dependent effects on myocardial contractility, oxidative stress, and cytokine release after ischemia-reperfusion.

McEvoy MD, Taylor AG, Zavadzkas JA, Mains IM, Ford RL, Stroud RE, Jeffords LB, Beck CU, Reeves ST, Spinale FG
Ann Thorac Surg. 2008 86 (2): 568-75

PMID: 18640335 · PMCID: PMC2675543 · DOI:10.1016/j.athoracsur.2008.04.025

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 x 10(4) kallikrein inhibitory units (KIU)/kg aprotinin (n = 11), 4 x 10(4) KIU/kg aprotinin (n = 10), and vehicle (saline, n = 10). Based upon a fluorogenic assay, aprotinin doses of 2 and 4 x 10(4) 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 x 10(4) KIU/kg but not 4 x 10(4) KIU/kg aprotinin. Tumor necrosis factor increased by more than 60% from control (p < 0.05) with I/R, but was reduced with 4 x 10(4) KIU/kg aprotinin. Myeloperoxidase increased with I/R, and was reduced to the greatest degree by 2 x 10(4) 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.

MeSH Terms (18)

Animals Aprotinin Cardiac Surgical Procedures Disease Models, Animal Dose-Response Relationship, Drug Elasticity Image Processing, Computer-Assisted Interleukin-6 Mice Mice, Inbred Strains Myocardial Contraction Myocardial Reperfusion Injury Myocardium Oxidative Stress Peroxidase Serine Proteinase Inhibitors Tumor Necrosis Factor-alpha Ventricular Function, Left

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