A previous study has shown that endogenous
adenosine trapping during
ischemia (by blocking
adenine nucleoside transport and inhibiting
adenosine breakdown) prevents
myocardial stunning. In this study, we tested the hypothesis that delay of administration of inhibitors until reperfusion would similarly prevent
myocardial stunning in the absence of entrapped
adenosine. In both studies, a selective
nucleoside transport blocker, p-nitrobenzyl-
thioinosine, was used in combination with a potent
adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine, to entrap
adenosine (preischemic treatment) or
inosine (postischemic treatment) in an in vivo canine model of reversible global
ischemia. Twenty-five anesthetized adult dogs were instrumented (by sonomicrometry) to monitor left ventricular performance from the relationship between
stroke work and end-diastolic length as a sensitive and load-independent index of contractility. Hearts of animals supported by
cardiopulmonary bypass were subjected to 30 minutes of normothermic global
ischemia and 60 minutes of reperfusion.
Saline solution containing the pharmacologic agents were infused into the bypass circuit before
ischemia (group 1) or during reperfusion (group 2). Control group (group 3) received saline before and after
ischemia. Myocardial biopsy specimens were obtained before, during, and after
ischemia, and levels of
adenine nucleotides,
nucleosides, oxypurines, and the oxidized form of
nicotinamide-adenine dinucleotide were determined. Left ventricular contractility fully recovered within 30 minutes of reperfusion in the groups treated with erythro-9-(2-hydroxy-3-nonyl)adenine and p-nitrobenzyl-
thioinosine (p < 0.05 versus control group). Myocardial
adenosine triphosphate was depleted by 50% in all groups at the end of
ischemia.
Adenosine triphosphate recovered during reperfusion only in the group that was treated with inhibitors before
ischemia (group 1). At the end of
ischemia,
adenosine levels were low (< 10% of total
nucleosides) in the control group (group 3) and in the group treated only after
ischemia (group 2). A high level of
adenosine (> 90% of total
nucleosides) was present in group 1. We infer that selective pharmacologic blockade of
nucleoside transport, only after ischemic injury, accelerated functional recovery during reperfusion, even without trapping of endogenous
adenosine during
ischemia and without
adenosine triphosphate recovery during reperfusion. Recovery of myocardial
adenosine triphosphate required preischemic treatment and
adenosine entrapment during
ischemia and reperfusion. Therefore,
nucleoside trapping may be used to prevent reperfusion-mediated injury after reversible ischemic injury.