BACKGROUND: Recently, we have shown that the selective opening of mitochondrial ATP-sensitive potassium channels with diazoxide significantly decreases myocardial injury. The purpose of this study was to determine the effects of diazoxide on apoptosis and the mechanisms modulating apoptosis and myocardial injury in a blood-perfused model of acute myocardial infarction. METHODS: Pigs (32 to 42 kg) undergoing total cardiopulmonary bypass underwent left anterior descending coronary artery occlusion for 30 minutes. The aorta was cross-clamped and magnesium-supplemented potassium cold-blood cardioplegia (DSA; n = 6) or magnesium-supplemented potassium cardioplegia containing 50 micromol/L diazoxide (DZX; n = 6) was administered, followed by 30 minutes of global ischemia and 120 minutes of reperfusion. Left ventricular tissue samples from DSA and DZX hearts were obtained after reperfusion. Apoptosis was determined by TUNEL, caspase-3 and PARP cleavage, and caspase-3 activity. Bax and bcl-2 levels were determined and tissue morphology was examined by light and transmission electron microscopy. RESULTS: Apoptosis, as estimated by TUNEL-positive nuclei/3,000 myocardial cells, was 120.3 +/- 48.8 in DSA hearts and was significantly decreased to 21.4 +/- 5.3 in DZX hearts (p < 0.05 vs control). Caspase-3 and poly-ADP-ribose polymerase cleavage and pro-apoptotic bax protein levels were significantly decreased with diazoxide (p < 0.05 vs DSA). Light and transmission electron microscopy indicated severe disruption of tissue with capillary dilatation, mitochondrial cristae damage, and evidence of increased presence of mitochondrial granules in DSA as compared with DZX hearts. CONCLUSIONS: The addition of diazoxide (50 micromol/L) to cardioplegia significantly decreases regional myocardial apoptosis and mitochondrial damage, and provides an additional modality for achieving myocardial protection.
BACKGROUND: Recently, we have shown that the selective opening of mitochondrial ATP-sensitive potassium channels with diazoxide significantly decreases myocardial injury. The purpose of this study was to determine the effects of diazoxide on apoptosis and the mechanisms modulating apoptosis and myocardial injury in a blood-perfused model of acute myocardial infarction. METHODS:Pigs (32 to 42 kg) undergoing total cardiopulmonary bypass underwent left anterior descending coronary artery occlusion for 30 minutes. The aorta was cross-clamped and magnesium-supplemented potassium cold-blood cardioplegia (DSA; n = 6) or magnesium-supplemented potassium cardioplegia containing 50 micromol/L diazoxide (DZX; n = 6) was administered, followed by 30 minutes of global ischemia and 120 minutes of reperfusion. Left ventricular tissue samples from DSA and DZX hearts were obtained after reperfusion. Apoptosis was determined by TUNEL, caspase-3 and PARP cleavage, and caspase-3 activity. Bax and bcl-2 levels were determined and tissue morphology was examined by light and transmission electron microscopy. RESULTS: Apoptosis, as estimated by TUNEL-positive nuclei/3,000 myocardial cells, was 120.3 +/- 48.8 in DSA hearts and was significantly decreased to 21.4 +/- 5.3 in DZX hearts (p < 0.05 vs control). Caspase-3 and poly-ADP-ribose polymerase cleavage and pro-apoptotic bax protein levels were significantly decreased with diazoxide (p < 0.05 vs DSA). Light and transmission electron microscopy indicated severe disruption of tissue with capillary dilatation, mitochondrial cristae damage, and evidence of increased presence of mitochondrial granules in DSA as compared with DZX hearts. CONCLUSIONS: The addition of diazoxide (50 micromol/L) to cardioplegia significantly decreases regional myocardial apoptosis and mitochondrial damage, and provides an additional modality for achieving myocardial protection.
Authors: F Monti; K Iwashiro; S Picard; A Criniti; S La Francesca; G Ruvolo; U Papalia; P P Campa; B Marino; P E Puddu Journal: J Thorac Cardiovasc Surg Date: 2000-04 Impact factor: 5.209
Authors: K D Garlid; P Paucek; V Yarov-Yarovoy; H N Murray; R B Darbenzio; A J D'Alonzo; N J Lodge; M A Smith; G J Grover Journal: Circ Res Date: 1997-12 Impact factor: 17.367
Authors: James D McCully; Yoshiya Toyoda; Hidetaka Wakiyama; Anthony J Rousou; Robert A Parker; Sidney Levitsky Journal: Ann Thorac Surg Date: 2006-07 Impact factor: 4.330
Authors: Raja B Singh; Sucheta P Dandekar; Vijayan Elimban; Suresh K Gupta; Naranjan S Dhalla Journal: Mol Cell Biochem Date: 2004-08 Impact factor: 3.396
Authors: James D McCully; Monoj K Bhasin; Christian Daly; Manuel C Guerrero; Simon Dillon; Towia A Liberman; Douglas B Cowan; John D Mably; Francis X McGowan; Sidney Levitsky Journal: Physiol Genomics Date: 2009-05-19 Impact factor: 3.107
Authors: James D McCully; Douglas B Cowan; Christina A Pacak; Ioannis K Toumpoulis; Haripriya Dayalan; Sidney Levitsky Journal: Am J Physiol Heart Circ Physiol Date: 2008-10-31 Impact factor: 4.733
Authors: Douglas B Cowan; Rouan Yao; Jerusha K Thedsanamoorthy; David Zurakowski; Pedro J Del Nido; James D McCully Journal: Sci Rep Date: 2017-12-12 Impact factor: 4.379
Authors: Erin E Tansey; Kevin F Kwaku; Peter E Hammer; Douglas B Cowan; Micheline Federman; Sidney Levitsky; James D McCully Journal: Ann Thorac Surg Date: 2006-10 Impact factor: 4.330
Authors: Douglas B Cowan; Rouan Yao; Vamsidhar Akurathi; Erin R Snay; Jerusha K Thedsanamoorthy; David Zurakowski; Maria Ericsson; Ingeborg Friehs; Yaotang Wu; Sidney Levitsky; Pedro J Del Nido; Alan B Packard; James D McCully Journal: PLoS One Date: 2016-08-08 Impact factor: 3.240