INTERMITTENT AORTIC CROSS-CLAMPING PREVENTS CUMULATIVE ADENOSINE-TRIPHOSPHATE DEPLETION, VENTRICULAR-FIBRILLATION, AND DYSFUNCTION (STUNNING) - IS IT PRECONDITIONING

This study was designed to determine whether intermittent warm aortic crossclamping induces cumulative myocardial stunning or if the myocard ium becomes preconditioned after the first episode of ischemia in cani ne models in vivo. The role of adenosine triphosphate catabolism and s ubsequent release of purines on reperfusion-mediated postischemic vent ricular dysfunction and arrhythmias was assessed with the use of selec tive inhibitors of nucleoside transport, p-nitrobenzylthioinosine (NBM PR), and a specific adenosine deaminase inhibitor, erythro-9- [2-hydro xy-3-nonyl] adenine (EHNA). Thirty two anesthetized dogs were instrume nted to monitor left ventricular contractility, off bypass, by sonomic rometry. During cardiopulmonary bypass dogs were treated before ischem ia with either saline solution (control group, n = 8) or EHNA (100 mu mol/L) and NBMPR (25 mu mol/L) (EHNA/NBMPR group, n = 8). Hearts were subjected to either 60 minutes of global ischemia and 120 minutes of r eperfusion (n = 16) or 6 episodes of 10 minutes of global ischemia and 10 minutes of reperfusion, followed by 60 minutes of reperfusion (n = 16). Sixty minutes of sustained ischemia resulted in 80% loss of aden osine triphosphate and induced reperfusion-mediated ventricular fibril lation and severe left ventricular dysfunction in the control group. E HNA/NBMPR treatment augmented myocardial adenosine trapping during isc hemia, attenuated ventricular fibrillation, and enhanced left ventricu lar functional recovery, despite similar depletion of adenosine tripho sphate (80% loss). In the intermittent ischemia experiment, the first episode of 10 minutes of ischemia and reperfusion caused significant a denosine triphosphate depletion, ventricular fibrillation, and left ve ntricular stunning in both control and drug-treated groups. The preval ence of ventricular fibrillation was greater in the control group than in the drug-treated group after the first episode of ischemia (p < 0. 05). Adenosine was the major nucleoside accumulated in the myocardium at the end of 10 minutes of ischemia in the EHNA/NBMPR-treated group ( p < 0.05 versus control). Subsequent episodes of ischemia prevented ve ntricular fibrillation and did not cause cumulative left ventricular s tunning in either group. Left ventricular function fully recovered in the EHNA/NBMPR-treated group after intermittent ischemia, but remained stunned in the control group. Unlike sustained ischemia, intermittent ischemia and reperfusion preserved myocardial adenosine triphosphate, limited purine release, and prevented ventricular fibrillation and cu mulative stunning. These results suggest that intermittent ischemia an d reperfusion augmented the endogenous protective mechanism or mechani sms of ''preconditioning.'' Nucleoside trapping improved functional re covery after sustained or repetitive ischemia. It is concluded that ad enosine triphosphate preservation or blockade of nucleoside transport may play an important role in the activation of endogenous myocardial protective mechanisms that ''precondition'' against subsequent ischemi c stress.