Metabolic interventions capable of preventing ventricular dysfunction “stunning” or accelerating its functional recovery have potential clinical importance. Myocardial protection of the stunned myocardium has not been documented when drugs were administered only during postischemic reperfusion. The role ofATP depletion and release of purines in myocardial injury was assessed using the selective nucleoside transport blocker p-nitrobenzylthioinosine (NBMPR) in a combination with specific adenosine deaminase inhibitor erythro-9-[hydroxy-3-nonyl]adenine (EHNA) administered during reperfusion after reversible ischemic injury.Methods and Results
Sixteen anesthetized dogs were instrumented with minor axis sonocrystals and intraventricular Millar. Ventricular performance was determined, off bypass, from the slope of the relationship between stroke-work and end-diastolic length as a sensitive and load-independent index of contractility within physiological range. Hearts were subjected to 20 minutes' warm global ischemia and reperfused with warm blood treated with either saline (control group, n=8) or saline containing 100 μmol/L EHNA and 25, tmol/L NBMPR (EHNA/NBMPR-treated group, n=8). Myocardial biopsies were collected and analyzed for ATP and metabolites using high-performance liquid chromatography. Warm ischemia induced significant depletion of ATP (P<.05 versus preischemia) and accumulation of inosine at the end of ischemia (>90%o of total nucleosides) in both groups. Complete functional recovery was observed in the EHNA/NBMPR-treated group (P<.05 versus control group).Conclusions
Selective entrapment of adenine nucleosides during postischemic reperfusion attenuated ventricular dysfunction (stunning) after brief global ischemia. It is concluded that nucleoside transport plays an important role in myocardial stunning, and its blockade augmented myocardial protection against reperfusion injury. Selective entrapment of endogenous inosine, generated during ischemia, represents an attractive therapeutic approach to the alleviation of postischemic dysfunction mediated by reperfusion in a wide spectrum of ischemic syndromes, including percutaneous transluminal coronary angioplasty and coronary artery bypass graft surgery.