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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)

Triphenyltetrazolium chloride has been used to detect irreversibly damaged tissue after regional ischemia and reperfusion. We used this staining technique in our studies of myocardial ischemia and reperfusion and found that a transmural triphenyltetrazolium chloride nonstaining pattern is not an accurate predictor of myocardial necrosis: functional recovery occurs despite nonstaining. Mongrel dogs (n = 91) were anesthetized and made ischemic by ligation of the left anterior descending coronary artery. Regional myocardial function was assessed by means of ultrasonic crystals. Following 2, 4, or 6 hours of ischemia, the ligature was removed, and each heart was reperfused either in the working state or during total bypass with either normal blood or substrate-enriched blood cardioplegic solution of differing composition. The hearts were then removed and incubated in triphenyltetrazolium chloride at 37° C for 20 to 40 minutes. The pattern of nonstaining in the area at risk varied from patchy subendocardial, to confluent subendocardial, to transmural and did not correlate with the recovery of regional contraction following ischemia. Mitochondrial ultrastructure was altered minimally in nonstained muscle, which regained contractile function after 6 hours of ischemia. Fifty-two of sixty-five hearts (80%) showing a transmural nonstaining pattern in the area of ultrasonic crystal placement recovered the capacity to shorten systolically immediately after controlled reperfusion during total vented bypass. These results show that the triphenyltetrazolium chloride staining method does not predict myocardial necrosis and that appropriate reperfusion following 2 to 6 hours of ischemia will result in recovery of myocardial shortening despite transmural nonstaining.