diacetylmonoxime and Contracture

Protection of the ischemic myocardium by pretreatment with a high dose of 2,3-butanedione monoxime (BDM) is attributed to the enhancement of glycolytic ATP production rather than to the inhibition of contracture during mild ischemia. Our objective was to investigate whether the inhibition of contracture would protect the arrested heart during prolonged ischemia. Isolated perfused rat hearts were subjected to 30 min of low-flow ischemia followed by reperfusion. Ischemic hearts were treated with BDM (5 mmol/l) after beating stopped. BDM ameliorated the increase in intraventricular pressure after ischemia without significant changes in ATP levels and with a decreased accumulation of lactate. BDM treatment accelerated the recovery of function and high-energy phosphates with reduced myocardial Ca2+ overload. The results of this study suggested that inhibition of contracture can protect the heart from ischemia-reperfusion injury.

Topics: Adenosine Triphosphate; Animals; Calcium; Contracture; Diacetyl; Energy Metabolism; Heart; In Vitro Techniques; Lactic Acid; Male; Myocardial Ischemia; Myocardium; Phosphocreatine; Rats; Rats, Sprague-Dawley; Ventricular Function, Left

The role of contracture in the manifestation of calcium paradox-induced damage was examined using 2,3-butanedione monoxime (BDM) to inhibit myofibrillar activity. Calcium and sodium gain, loss of intracellular components, and changes in structure were monitored. If 30 mM BDM was added at the time of calcium repletion after 10 minutes of calcium-free perfusion, some protection was afforded, particularly at the early stages of calcium repletion. However, much greater protection was obtained if BDM was present during the final 2 minutes of calcium-free perfusion and throughout repletion. Sodium gain and loss of intracellular components were markedly attenuated, as was the incidence of severely contracted cells. Calcium gain, although significantly reduced during the period of repletion, was not abolished. After 10 minutes of repletion, a calcium content of 11.44 +/- 1.57 mumol/g dry wt was observed. This suggests that other noncontracture related routes of calcium entry are involved. If BDM is removed after 5 minutes of calcium repletion and perfusion is continued with BDM-free perfusate, there is a rapid gain of sodium, further gain of calcium, loss of intracellular components and the cells contract severely, tearing away from neighboring cells. It is evident, therefore, that returning calcium to hearts after a period of calcium-free perfusion under conditions that significantly reduce the typical calcium paradox-associated damage does not necessarily repair the underlying defect. These results support the hypothesis that contracture-induced sarcolemmal disruption may be responsible for the terminal manifestation of the calcium paradox.

Topics: Animals; Calcium; Contracture; Diacetyl; Female; Heart; Intracellular Membranes; Microscopy, Electron; Myocardium; Osmolar Concentration; Perfusion; Rats; Rats, Inbred Strains; Sodium