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 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.
Abd-Elfattah
A S
AS
Department of Surgery, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0532.
Jessen
M E
ME
Wechsler
A S
AS
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000227:Adenine Nucleotides / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism*; D058892:Adenosine Deaminase Inhibitors; D000345:Affinity Labels / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D004285:Dogs; D005260:Female; D007288:Inosine / Q000378:metabolism*; D008297:Male; D017202:Myocardial Ischemia; D015425:Myocardial Reperfusion / Q000379:methods*; D017682:Myocardial Stunning / Q000503:physiopathology / Q000517:prevention & control*; D011688:Purinones / Q000378:metabolism; D011897:Random Allocation; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016277:Ventricular Function, Left / Q000187:drug effects
D000227:Adenine Nucleotides; D058892:Adenosine Deaminase Inhibitors; D000345:Affinity Labels; D011688:Purinones; D013868:Thioinosine; C010192:9-(2-hydroxy-3-nonyl)adenine; D007288:Inosine; C001789:4-nitrobenzylthioinosine; D000225:Adenine; D000241:Adenosine