Biochemical studies: failure of tissue adenosine triphosphate levels to predict recovery of contractile function after controlled reperfusion

Abstract

This study tests the hypotheses that postischemic adenosine triphosphate levels are unreliable predictors of functional recovery, myocardial adenosine triphosphate concentration of less than 2 mumol/gm does not indicate irreversible damage, mitochondrial adenosine triphosphate generating capacity can be nearly normal despite low levels of tissue adenosine triphosphate and 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 mumol/gm by either global ischemia (37 degrees 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 less than 0.05 of control) despite adenosine triphosphate concentration greater than 2 mumol/gm. Transmural mitochondrial State 3 respiration averaged 83% of control values despite adenosine triphosphate levels of 1 mumol/gm in hearts undergoing 45 minutes of 37 degrees C global ischemia and 2 additional hours of aortic clamping with multidose glutamate-enriched blood cardioplegia. AICAR increased adenosine triphosphate to 2 mumol/gm (p less than 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 less than 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 less than 2 mumol/gm do not indicate irreversible ischemic injury. Low postischemic levels may be repleted partially by adenine nucleotide precursor supplementation (AICAR).(ABSTRACT TRUNCATED AT 400 WORDS)