The mechanical effects of
ischemic contracture may be important in the development of irreversible cellular damage as it increases mechanical stress on sarcolemmal membranes and restricts endocardial perfusion. To assess the relative importance of these mechanical effects compared with decreased energy supply in the development of irreversible injury, the effects of inhibiting
ischemic contracture with
2,3-butanedione monoxime (BDM), an agent that disrupts excitation-contraction coupling, were delineated in isovolumically contracting isolated rabbit hearts. Administration of 20 mmol/L BDM in 12 hearts subjected to 60 minutes of low-flow
ischemia prevented
ischemic contracture (left ventricular end-diastolic pressure [LVEDP], 12 +/- 3 compared with 48 +/- 14 mm Hg in 20 control hearts; P < .001), reduced membrane damage (
creatine kinase [CK] release, -54% compared with control hearts; P < .05), and enhanced functional recovery during reperfusion (left ventricular developed pressure [LVDP], 86 +/- 10% of baseline compared with 56 +/- 23% in control hearts; P < .01). These observations were not related to increased intracavitary pressure and its effects on flow distribution, since venting the left ventricle in additional hearts did not result in improved function during reperfusion. Although it would be tempting to conclude that BDM protected ischemic myocardium by preventing
ischemic contracture, administration of BDM was also associated with reduced depletion of
ATP during
ischemia, perhaps related to diminished energy demand. To distinguish between the relative importance of inhibiting
contracture from provision of adequate energy, the period of
ischemia was extended to 120 minutes. BDM still prevented
ischemic contracture (LVEDP, 10 +/- 6 mm Hg) and preserved
ATP stores, but it did not prevent membrane damage (CK release, 483 +/- 254 U/g dry weight) or contractile failure during reperfusion (LVDP, 68 +/- 7% of baseline). In contrast, increasing the rate of anaerobic glycolysis during
ischemia by doubling
glucose and
insulin in the presence of BDM markedly decreased membrane damage (CK release, 114 +/- 72 U/g dry weight; P < .05) and contractile failure during reperfusion (LVDP, 88 +/- 7% recovery of baseline; P < .01). These results suggest that insufficient energy production is primarily responsible for myocardial ischemic damage, whereas mechanical effects of
ischemic contracture appear to play only a minor role.