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.
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.
Authors: John S Ikonomidis; Jennifer W Hendrick; Andrea M Parkhurst; Amanda R Herron; Patricia G Escobar; Kathryn B Dowdy; Robert E Stroud; Elizabeth Hapke; Michael R Zile; Francis G Spinale Journal: Am J Physiol Heart Circ Physiol Date: 2005-01 Impact factor: 4.733
Authors: W van Oeveren; N J Jansen; B P Bidstrup; D Royston; S Westaby; H Neuhof; C R Wildevuur Journal: Ann Thorac Surg Date: 1987-12 Impact factor: 4.330
Authors: R S Krombach; M J Clair; J W Hendrick; W V Houck; J L Zellner; S B Kribbs; S Whitebread; R Mukherjee; M de Gasparo; F G Spinale Journal: Cardiovasc Res Date: 1998-06 Impact factor: 10.787
Authors: J P Gott; W A Cooper; F E Schmidt; W M Brown; C E Wright; J D Merlino; J D Fortenberry; W S Clark; R A Guyton Journal: Ann Thorac Surg Date: 1998-09 Impact factor: 4.330
Authors: Fien Blancke; Marc J Claeys; Philippe Jorens; Guy Vermeiren; Johan Bosmans; Floris L Wuyts; Chris J Vrints Journal: Mediators Inflamm Date: 2005-12-14 Impact factor: 4.711