Influence of 2,3-butanedione monoxime on heart energy metabolism

The influence of 2,3-butanedione monoxime (BDM) on function and subcellular energy status in isolated perfused guinea pig hearts was examined during ischemia and reperfusion. For this purpose the mitochondrial and extramitochondrial contents of ATP, ADP, creatine phosphate (CrP) and creatine (Cr) were determined after fractionation of freeze-clamped heart tissue in non-aqueous solvents. Furthermore, the inhibitory action of this compound on isolated cardiac mitochondria and the actomyosin-ATPase was studied. BDM in the millimolar range inhibited both the actomyosin-ATPase in skinned-fibers (IC50 22 mM) and the electron transport chain in isolated mitochondria (IC50 28 mM). In normoxia at 35 degrees C the contractile function of isolated guinea pig hearts was completely inhibited and oxygen consumption was markedly reduced (-60%) by 30 mM BDM. The mitochondrial and extramitochondrial contents of adenine nucleotides (sum of ATP + ADP) and total creatine (sum of CrP + Cr) as well as the extramitochondrial ATP/ADP- and CrP/Cr-ratios were decreased. Similar changes, significantly more pronounced, however, were found after 30 min of warm (35 degrees C) ischemia. However, if hearts were exposed to BDM during cold ischemia, extramitochondrial ATP/ADP- and CrP/Cr-ratios were increased compared to BDM-free controls. If hearts were exposed to BDM during ischemia (at 35 degrees C) and were then reperfused BDM-free, ATP/ADP- and CrP/Cr-ratios were decreased. However, if hearts were exposed to BDM during cold ischemia and were then reperfused BDM-free, extramitochondrial ATP/ADP- and CrP/Cr-ratios were unchanged. These results confirm earlier studies on the tissue protective action of BDM but point to the importance of low temperature exposure to BDM for its beneficial effect.