The aim of this study was to differentiate
myocardial reperfusion injury from that of
ischemia. We assessed the role of the myocardial
adenosine 5'-triphosphate (
ATP) catabolites,
hypoxanthine and
xanthine, generated during
ischemia and the early phase of reperfusion, in
reperfusion injury by modulating
adenosine transport and metabolism with specific metabolic inhibitors. This was followed by intracoronary infusion of exogenous
hypoxanthine and
xanthine. Twenty-four dogs instrumented with minor-axis piezoelectric crystals and intraventricular pressure transducers were subjected to 30 minutes of normothermic global
myocardial ischemia and 60 minutes of reperfusion. In Group 1 (n = 7),
normal saline was infused into the
cardiopulmonary bypass reservior before
ischemia and before reperfusion.
Saline solution containing 25 microM p-nitrobenzylthioinosine (
NBMPR) and 100 microM erythro-9-(2-hydroxy-3-nonyl)adenine (
EHNA) was infused in Group 2 (n = 10) dogs. Group 3 (n = 7) dogs were treated exactly like those in Group 2 except, at the end of the ischemic period and immediately before releasing the cross-clamp, a
solution of
EHNA-
NBMPR containing 100 microM
hypoxanthine and 100 microM
xanthine was infused into the aortic root. Left ventricular performance and myocardial
adenine nucleotide pool intermediates were determined before and after
ischemia.
ATP was depleted by about 50% (p less than 0.05 vs. preischemia) in all groups after 30 minutes of
ischemia.
Inosine was the major
ATP catabolite (9.29 +/- 1.2 nmol/mg
protein) in Group 1, while
adenosine (9.91 +/- 0.7 nmol/mg
protein) was the major metabolite in
EHNA-
NBMPR-treated dogs (Groups 2 and 3).
Hypoxanthine levels were fivefold more in Group 1 compared with Groups 2 and 3 (p less than 0.05). Left ventricular performance in Group 1 decreased from 76.8 +/- 7.6 to 42.9 +/- 9.8 and 52.3 +/- 8.4 dynes/cm2 x 10(3) (p less than 0.05), while myocardial
ATP decreased from 30.9 +/- 2.2 to 17.2 +/- 1.0 and 16.5 +/- 1.0 nmol/mg
protein during 30 and 60 minutes of reperfusion, respectively (p less than 0.05 vs. preischemia). Ventricular function in Group 2 dogs completely recovered within 30 minutes of reperfusion, and myocardial
ATP recovered to the preischemic level at 60 minutes of reperfusion. In Group 3, left ventricular performance was depressed by 39% and 30% during 30 and 60 minutes of reperfusion (p less than 0.05), respectively, and myocardial
ATP did not recover during reperfusion despite a significant intramyocardial
adenosine accumulation.(ABSTRACT TRUNCATED AT 400 WORDS)