BACKGROUND: Resuscitation fluids containing beta-hydroxybutyrate (BHB) have been shown to decrease cellular injury after hemorrhagic shock and resuscitation through an unknown mechanism. We tested whether this effect was related to BHB-induced metabolic modulations. METHODS: Male Sprague Dawley rats (n=30) were subjected to volume-controlled hemorrhage (27 mL/kg during 10 minutes followed by 75 minutes of shock during which another 8 mL/kg of blood was withdrawn). Experimental groups included the following: (1) sham, (2) no resuscitation (NR), (3) racemic lactated Ringer's (DL-LR) solution, (4) LR containing L-isomer only (L-LR), (5) ketone Ringer's solution with lactate substituted by BHB (KR), and (6) pyruvate Ringer's solution with lactate substituted by pyruvate (PR). The resuscitation fluids were infused during 45 minutes simultaneously with additional hemorrhage of 8 mL/kg. Hemodynamic and physiologic parameters and the plasma levels of BHB were serially measured. The animals were killed 2 hours after resuscitation, and tissues were frozen instantaneously for cellular adenylate extraction and adenosine triphosphate (ATP) and adenosine diphosphate analysis. Pulmonary apoptosis was studied using Western blotting, immunohistochemistry, and reverse transcriptase-polymerase chain reaction. Expression of enzymes involved in ketogenesis and ketolysis was analyzed by reverse transcriptase-polymerase chain reaction. RESULTS: NR and resuscitation with DL-LR increased the expression of apoptotic markers, whereas resuscitation with KR and PR significantly decreased the expression of apoptotic markers in rat lungs. Resuscitation with KR was followed by a profound increase in plasma BHB levels; however, the expression levels of ketolytic enzymes were essentially unaffected. KR infusion did not induce significant improvements in tissue ATP levels. CONCLUSIONS: Resuscitation with KR and PR protects against pulmonary apoptosis without improving tissue ATP content. Therefore, metabolic modulation is unlikely to be the major mechanism by which BHB exerts its protective effects during reperfusion.
BACKGROUND: Resuscitation fluids containing beta-hydroxybutyrate (BHB) have been shown to decrease cellular injury after hemorrhagic shock and resuscitation through an unknown mechanism. We tested whether this effect was related to BHB-induced metabolic modulations. METHODS: Male Sprague Dawley rats (n=30) were subjected to volume-controlled hemorrhage (27 mL/kg during 10 minutes followed by 75 minutes of shock during which another 8 mL/kg of blood was withdrawn). Experimental groups included the following: (1) sham, (2) no resuscitation (NR), (3) racemic lactated Ringer's (DL-LR) solution, (4) LR containing L-isomer only (L-LR), (5) ketone Ringer's solution with lactate substituted by BHB (KR), and (6) pyruvate Ringer's solution with lactate substituted by pyruvate (PR). The resuscitation fluids were infused during 45 minutes simultaneously with additional hemorrhage of 8 mL/kg. Hemodynamic and physiologic parameters and the plasma levels of BHB were serially measured. The animals were killed 2 hours after resuscitation, and tissues were frozen instantaneously for cellular adenylate extraction and adenosine triphosphate (ATP) and adenosine diphosphate analysis. Pulmonary apoptosis was studied using Western blotting, immunohistochemistry, and reverse transcriptase-polymerase chain reaction. Expression of enzymes involved in ketogenesis and ketolysis was analyzed by reverse transcriptase-polymerase chain reaction. RESULTS: NR and resuscitation with DL-LR increased the expression of apoptotic markers, whereas resuscitation with KR and PR significantly decreased the expression of apoptotic markers in rat lungs. Resuscitation with KR was followed by a profound increase in plasma BHB levels; however, the expression levels of ketolytic enzymes were essentially unaffected. KR infusion did not induce significant improvements in tissue ATP levels. CONCLUSIONS: Resuscitation with KR and PR protects against pulmonary apoptosis without improving tissue ATP content. Therefore, metabolic modulation is unlikely to be the major mechanism by which BHB exerts its protective effects during reperfusion.
Authors: Nancy E Witowski; Elizabeth R Lusczek; Charles E Determan; Daniel R Lexcen; Kristine E Mulier; Andrea Wolf; Beverly G Ostrowski; Greg J Beilman Journal: Mol Biosyst Date: 2016-04-26
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