INFLUENCE OF 2,3-BUTANEDIONE MONOXIME ON HEART ENERGY-METABOLISM

The influence of 2,3-butanedione monoxime (BDM) on function and subcel lular energy status in isolated perfused guinea pig hearts was examine d 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-clampe d heart tissue in non-aqueous solvents. Furthermore, the inhibitory ac tion of this compound on isolated cardiac mitochondria and the actomyo sin-ATPase was studied. BDM in the millimolar range inhibited both the actomyosin-ATPase in skinned-fibers (IC50 22 mM) and the electron tra nsport chain in isolated mitochondria (IC50 28 mM). In normoxia at 35 degrees C the contractile function of isolated guinea pig hearts was c ompletely inhibited and oxygen consumption was markedly reduced (-60 % ) by 30 mM BDM. The mitochondrial and extramitochondrial contents-of a denine 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, w ere found after 30 min of warm (35 degrees C) ischemia. However, if he arts were exposed to BDM during cold ischemia, extramitochondrial ATP/ ADP- and CrP/Cr-ratios were increased compared to BDM-free controls. I f hearts were exposed to BDM during ischemia (at 35 degrees C) and wer e 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-ratio s were unchanged. These results confirm earlier studies on the tissue protective action of BDM but point to the importance of low temperatur e exposure to BDM for its beneficial effect.