Studies of controlled reperfusion after ischemia. II. Biochemical studies: Failure of tissue adenosine triphosphate levels to predict recovery of contractile function after controlled reperfusion

This study tests the hypotheses that (1) postischemic adenosine triphosphate levels are unreliable predictors of functional recovery, (2) myocardial adenosine triphosphate concentration of less than 2 μmol/gm does not indicate irreversible damage, (3) mitochondrial adenosine triphosphate generating capacity can be nearly normal despite low levels of tissue adenosine triphosphate and (4) the failure to replenish adenosine triphosphate after ischemia is due to depletion of the adenosine nucleotide pool, which can be replenished partially by exogenous precursors (e.g., 5-amino-4-imidazolecarboxamide ribotide [AICAR]). Myocardial adenosine triphosphate was depleted to less than 2 μmol/gm by either global ischemia (37°C aortic clamping) or regional ischemia (acute coronary occlusion). Reperfusion was either with normal blood or with substrate-enriched blood cardioplegic solution during total vented bypass. Tissue adenosine triphosphate content and mitochondrial adenosine triphosphate generating capacity were measured, and functional recovery was determined by right heart bypass function curves or regional segmental shortening (ultrasonic crystals). Hearts undergoing 15 minutes of global ischemia and normal blood reperfusion had impaired functional recovery (stroke work index = 58 ± 5%; p < 0.05 of control) despite adenosine triphosphate concentration >2 μmol/gm. Transmural mitochondrial State 3 respiration averaged 83% of control values despite adenosine triphosphate levels of 1 μmol/gm in hearts undergoing 45 minutes of 37°C global ischemia and 2 additional hours of aortic clamping with multidose glutamate-enriched blood cardioplegia. AICAR increased adenosine triphosphate to 2 μmol/gm (p < 0.05), but functional recovery was nearly complete (stroke work index = 94 ± 2% of control) and was comparable with and without AICAR. Hearts undergoing 4 hours of regional ischemia recovered 31 ± 5% systolic shortening after controlled reperfusion despite tissue adenosine triphosphate <0.5 mmol/gm (15% of control), and they retained 63% adenosine triphosphate generating capacity. Postischemic adenosine triphosphate levels correlate poorly with functional recovery, and adenosine triphosphate levels <2 μmol/gm do not indicate irreversible ischemic injury. Low postischemic levels may be repleted partially by adenosine nucleotide precursor supplementation (AICAR). The production of adenosine triphosphate can be relatively normal despite low levels of tissue adenosine triphosphate, and measurement of mitochondrial adenosine triphosphate generation and/or cardiac O₂ utilization rates may be better indices of potential recovery than are tissue adenosine triphosphate values.