Injury in Isolated Perfused Rabbit Hearts

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 enddiastolic 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 I n the evolution of cell death induced by ischemia, a number of biochemical and structural alterations occur sequentially. Despite intense study, the molecular factors responsible for irreversible injury have not yet been fully elucidated. One element contributing to the irreversibility of injury is the development of focal deficits or breaks in the sarcolemma of the ischemic myocytes.' Once these have developed, myocytes become osmotically fragile, lose low molecular weight molecules, and accumulate extracellular electrolytes such as Na+ and Ca`+.1,2 Recent reports have suggested that ischemic contracture could be an important factor in the development of irreversible injury.3-5 In isolated myocytes, the rate of development of osmotic fragility, which temporally precedes breakdown of the sarcolemmal membrane, closely follows the rate of development of ischemic contracture.34 In the intact heart, development of ischemic contracture has been associated with massive cell disReceived August 6, 1992; accepted December 29, 1993. From the Cardiovascular Division, Washington University School of Medicine, St Louis, Mo. Correspondence to Steven R. Bergmann, MD, PhD, Cardiovascular Division, Washington University School of Medicine, Box 8086, 660 South Euclid Ave, St Louis, MO 63110. it would be tempting to conclude that BDM protected ischemic myocardium by preventing ischemic contracture, administration of BDM was also associated with reduced depletion ofATP 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. (Circ Res. 1994;74:817-828.)