Role of glycolytic products in damage to ischemic myocardium. Dissociation of adenosine triphosphate levels and recovery of function of reperfused ischemic hearts.

Abstract

SUMMARY. The mechanism of irreversible damage to ischemic myocardium was investigated in the perfused rat heart. The time of transition from reversible to irreversible damage to contractile function was accelerated by accumulation of glycolytic products and increases in extracellular calcium. Both of these effects were largely independent of adenine nucleotide levels in the tissue. With zero coronary flow and 1.25 nut calcium the decrease in ability of the heart to recover ventricular function with reperfusion after 30 minutes of ischemia was directly correlated with accumulation of glycolytic products (as estimated by tissue lactate) during ischemia. The extent of lactate accumulation during ischemia was varied by preperfusing the hearts for 0, 10, or 15 minutes under anoxic, high coronary flow conditions to deplete tissue glycogen prior to ischemia, and by adding lactate back to the perfusate of these hearts during the ischemic period. Recovery of ventricular function was inversely related to tissue lactate during ischemia and varied from 28 to 92%, even though there was little or no change in tissue levels of residual adenosine triphosphate. Increasing extracellular calcium accelerated the time of onset of irreversible damage with little or no change in residual adenosine triphosphate levels. At any given calcium concentration, the time-dependent declines in the ability of the heart to recover ventricular function was also largely independent of adenosine triphosphate levels. These studies suggest a major role of anaerobic glycolytic products (lactate, hydrogen ion, or NADH) in ischemic damage to the heart that is unrelated to loss of tissue adenine nucleotides. With zero or low flow ischemia, this effect may result in irreversible damage to the myocardium before adenine nucleotides are reduced to critically low levels. (Circ Res 55: 816-824, 1984)

Redox Activation of Aldose Reductase in the Ischemic Heart

“…This is consistent with the observations of Ramasamy and colleagues (13)(14)(15) suggesting that inhibition of AR prevents tissue injury in ex vivo models of low-flow ischemia. The role of glycolysis during ischemia is, however, complex and although glycolysis is needed to generate ATP in the ischemic heart, accumulation of glycolytic products causes tissue injury (56). Indeed, the cardioprotective effects of early ischemic preconditioning are associated with a decrease in glycolysis (57), which may be a reflection of increased glucose utilization by activated AR.…”

Glucose for the Heart

“…Several studies have postulated a "toxic" effect of glycogen breakdown in ischemic heart that is due to an accumulation of protons and lactate and have suggested the beneficial consequences of depleting the glycogen stores before an ischemic episode. 79 Many other studies, however, have shown that protection of the heart against ischemic injury is related to glycogen availability. 73,81,[105][106][107][108][109] The absolute amount of glucose moieties arising from glycogen is not negligible at the onset of ischemia.…”

“…77 In severe ischemia, myocardial glucose extraction is inversely related to coronary flow, 78 until the degree of ischemia becomes so severe that glycolysis is inhibited by the accumulation of its products. 79 Once glycolysis is inhibited, glucose uptake progressively decreases, while protons, Na ϩ , and Ca 2ϩ continue to accumulate. [80][81][82] The decline of glucose uptake during prolonged severe ischemia may be attenuated by various interventions protecting the heart against ischemic injury, such as an increase of the extracellular glucose concentration or the addition of insulin.…”

Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3

“…Hypoxia may persist within the infarct and at its margins for days or weeks, exacerbating the injury (2)(3)(4). In response, the ischemic myocardium switches from respiration to glycolytic energy metabolism, with increased glucose consumption, lactic acid production, and lower intracellular pH (5)(6)(7). The extent of tissue loss to infarction is determined by the severity and duration of the ischemic period and is known to involve both necrotic and apoptotic cell death pathways (8)(9)(10).…”