NUCLEOSIDE TRAPPING DURING REPERFUSION PREVENTS VENTRICULAR DYSFUNCTION, STUNNING, IN ABSENCE OF ADENOSINE - POSSIBLE SEPARATION BETWEEN ISCHEMIC AND REPERFUSION INJURY

A previous study has shown that endogenous adenosine trapping during i schemia (by blocking adenine nucleoside transport and inhibiting adeno sine breakdown) prevents myocardial stunning. In this study, we tested the hypothesis that delay of administration of inhibitors until reper fusion would similarly prevent myocardial stunning in the absence of e ntrapped adenosine, In both studies, a selective nucleoside transport blocker, p-nitrobenzyl-thioinosine, was used in combination with a pot ent adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenin e, to entrap adenosine (preischemic treatment) or inosine (postischemi c treatment) in an in vivo canine model of reversible global ischemia. Twenty-five anesthetized adult dogs were instrumented (by sonomicrome try) to monitor left ventricular performance from the relationship bet ween stroke work and end-diastolic length as a sensitive and load-inde pendent index of contractility. Hearts of animals supported by cardiop ulmonary bypass were subjected to 30 minutes of normothermic global is chemia and 60 minutes of reperfusion. Saline solution containing the p harmacologic agents were infused into the bypass circuit before ischem ia (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 adeni ne nucleotides, nucleosides, oxypurines, and the oxidized form of nico tinamide-adenine dinucleotide were determined. Left ventricular contra ctility fully recovered within 30 minutes of reperfusion in the groups treated with erythro-9-(2-hydroxy-3-nonyl)adenine and p-nitrobenzyl-t hioinosine (p < 0.05 versus control group). Myocardial adenosine triph osphate was depleted by 50% in all groups at the end of ischemia. Aden osine 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 p resent in group 1. We infer that selective pharmacologic blockade of n ucleoside transport, only after ischemic injury, accelerated functiona l recovery during reperfusion, even without trapping of endogenous ade nosine during ischemia and without adenosine triphosphate recovery dur ing reperfusion. Recovery of myocardial adenosine triphosphate require d preischemic treatment and adenosine entrapment during ischemia and r eperfusion. Therefore, nucleoside trapping may be used to prevent repe rfusion-mediated injury after reversible ischemic injury.