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CARDIOVASCULAR ANESTHESIOLOGY

Aprotinin Modifies Left Ventricular Contractility and Cytokine Release After Ischemia-Reperfusion in a Dose-Dependent Manner in a Murine Model

Matthew D. McEvoy, MD^*, Michel J. Sabbagh, MD^*, Anna Greta Taylor, MD^*, Juozas A. Zavadzkas, MD, Christine N. Koval, BS, Robert E. Stroud, MS, Rachael L. Ford, BS, Julie E. McLean, BA, Scott T. Reeves, MD^*, Rupak Mukherjee, PhD, and Francis G. Spinale, MD, PhD

From the *Departments of Anesthesiology and Perioperative Medicine, and Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina; and Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina.

Address correspondence and reprint requests to Francis G. Spinale, MD, PhD, Division of Cardiothoracic Surgery, Medical University of South Carolina, 114 Doughty St., Rm. 625, Charleston, SC 29403. Address e-mail to: wilburnm{at}musc.edu.

Abstract

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 10⁴ KIU/kg (n = 10); (c) APRO 8 x 10⁴ 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 10⁴ KIU/kg and APRO 8 x 10⁴ KIU/kg groups (P < 0.05). However, E_max returned to near baseline values in the APRO 2 x 10⁴ 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.