PURPOSE: Volatile anesthetic postconditioning reduces apoptosis through antiapoptotic signaling. Whether sevoflurane postconditioning prevents activation of caspase 9 and 3, which are implicated in the initiation and execution step of apoptosis, is not known. METHODS: Isolated perfused guinea pig hearts underwent 30 min global ischemia and 120 min reperfusion [control (CTL)]. Anesthetic postconditioning was elicited with sevoflurane (2%) for 2 min at reperfusion onset (POST). LY294002, phosphatidylinositol-3-kinase (PI3K)/Akt (protein kinase B) inhibitor; and PD98059, extracellular signal-regulated kinase 1/2 (ERK) inhibitor, were administered for 10 min before ischemia and throughout the reperfusion period in POST (POST + LY, POST + PD). Left-ventricular-developed (LVDP) and LV end-diastolic (LVEDP) pressures and infarct size were measured. Western blot analysis determined phosphorylated Akt and ERK expression. Myocardial caspase 3 and 9 were determined immunohistochemically. RESULTS: After ischemia-reperfusion, POST had higher LVDP (57 +/- 9 vs. 38 +/- 7 mmHg, p < 0.05) and lower LVEDP (21 +/- 8 vs. 46 +/- 15 mmHg, p < 0.05) versus CTL. Infarct size was significantly reduced in POST versus CTL (15 +/- 3 vs. 41 +/- 11%, p < 0.001). Phosphorylation of Akt and ERK after reperfusion was significantly increased in POST versus CTL. Immunoreactivity for caspase 3 and 9 was greater in the nucleus of myocytes and endothelial cells in CTL. POST attenuated this increased immunoreactivity. LY294002 and PD98059 abolished the effect of POST on caspase 3 and 9 immunoreactivity. CONCLUSIONS: Sevoflurane postconditioning prevents activation of caspase 3 and 9, mediators of apoptosis in ischemia-reperfusion injury. This caspase activation is mediated by phosphorylation of Akt and ERK.
PURPOSE: Volatile anesthetic postconditioning reduces apoptosis through antiapoptotic signaling. Whether sevoflurane postconditioning prevents activation of caspase 9 and 3, which are implicated in the initiation and execution step of apoptosis, is not known. METHODS: Isolated perfused guinea pig hearts underwent 30 min global ischemia and 120 min reperfusion [control (CTL)]. Anesthetic postconditioning was elicited with sevoflurane (2%) for 2 min at reperfusion onset (POST). LY294002, phosphatidylinositol-3-kinase (PI3K)/Akt (protein kinase B) inhibitor; and PD98059, extracellular signal-regulated kinase 1/2 (ERK) inhibitor, were administered for 10 min before ischemia and throughout the reperfusion period in POST (POST + LY, POST + PD). Left-ventricular-developed (LVDP) and LV end-diastolic (LVEDP) pressures and infarct size were measured. Western blot analysis determined phosphorylated Akt and ERK expression. Myocardial caspase 3 and 9 were determined immunohistochemically. RESULTS: After ischemia-reperfusion, POST had higher LVDP (57 +/- 9 vs. 38 +/- 7 mmHg, p < 0.05) and lower LVEDP (21 +/- 8 vs. 46 +/- 15 mmHg, p < 0.05) versus CTL. Infarct size was significantly reduced in POST versus CTL (15 +/- 3 vs. 41 +/- 11%, p < 0.001). Phosphorylation of Akt and ERK after reperfusion was significantly increased in POST versus CTL. Immunoreactivity for caspase 3 and 9 was greater in the nucleus of myocytes and endothelial cells in CTL. POST attenuated this increased immunoreactivity. LY294002 and PD98059 abolished the effect of POST on caspase 3 and 9 immunoreactivity. CONCLUSIONS:Sevoflurane postconditioning prevents activation of caspase 3 and 9, mediators of apoptosis in ischemia-reperfusion injury. This caspase activation is mediated by phosphorylation of Akt and ERK.
Authors: B Freude; T N Masters; F Robicsek; A Fokin; S Kostin; R Zimmermann; C Ullmann; S Lorenz-Meyer; J Schaper Journal: J Mol Cell Cardiol Date: 2000-02 Impact factor: 5.000
Authors: T S Zheng; S F Schlosser; T Dao; R Hingorani; I N Crispe; J L Boyer; R A Flavell Journal: Proc Natl Acad Sci U S A Date: 1998-11-10 Impact factor: 11.205