Aprotinin modifies left ventricular contractility and cytokine release after ischemia-reperfusion in a dose-dependent manner in a murine model.

McEvoy MD, Sabbagh MJ, Taylor AG, Zavadzkas JA, Koval CN, Stroud RE, Ford RL, McLean JE, Reeves ST, Mukherjee R, Spinale FG
Anesth Analg. 2009 108 (2): 399-406

PMID: 19151263 · PMCID: PMC2675537 · DOI:10.1213/ane.0b013e31818cdb13

BACKGROUND - Periods of ischemia-reperfusion (I/R) during cardiac surgery are associated with transient left ventricular (LV) dysfunction and an inflammatory response. In this study, we examined the potential dose-dependent effects of aprotinin (APRO) on LV contractility and cytokine release in the setting of I/R.

METHODS - An index of LV contractility, LV maximal elastance (E(max)), was measured at baseline, 30 min of ischemia, and 60 min of reperfusion by microtransducer volumetry. Mice were randomized as follows: (a) APRO 20,000 kallikrein-inhibiting units (KIU)/kg (n = 11); (b) APRO 4 x 10(4) KIU/kg (n = 10); (c) APRO 8 x 10(4) KIU/kg (n = 10); and (d) vehicle (saline; n = 10). APRO doses were calculated to reflect half, full, and twice the clinical Hammersmith dosing schedule. After I/R, plasma was collected for cytokine measurements.

RESULTS - After I/R, E(max) decreased from the baseline value by more than 40% in the vehicle group as well as in the APRO 4 x 10(4) KIU/kg and APRO 8 x 10(4) KIU/kg groups (P < 0.05). However, E(max) returned to near baseline values in the APRO 2 x 10(4) KIU/kg group. Tumor necrosis factor (TNF) increased 10-fold after I/R, but it was reduced with higher APRO doses.

CONCLUSIONS - This study demonstrated that a low dose of APRO provided protective effects on LV contractility, whereas higher doses suppressed TNF release. These unique findings suggest that there are distinct and independent mechanisms of action of APRO in the context of I/R.

MeSH Terms (14)

Animals Aprotinin Arrhythmias, Cardiac Cytokines Dose-Response Relationship, Drug Elasticity Hemodynamics Hemostatics Kinetics Mice Myocardial Contraction Myocardial Reperfusion Injury Tumor Necrosis Factor-alpha Ventricular Function, Left

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