(Circulation. 1995;91:2810-2818.)
© 1995 American Heart Association, Inc.
Articles |
Mechanisms of Ischemic Preconditioning in Rat Myocardium
Roles of Adenosine, Cellular Energy State, and Mitochondrial F1Fo-ATPase
From the Departments of Medical Biochemistry (K.V., P.R., I.E.H., A.A.-R.) and Internal Medicine (K.Y., K.P.), University of Oulu, Oulu, Finland.
Correspondence to Dr Ilmo Hassinen, Department of Medical Biochemistry, University of Oulu, Kajaanintie 52 A, FIN-90220 Oulu 22, Finland.
Background Adenosine has been proposed as one mediator for the preconditioning effect in the myocardium of some animals, but recent investigations have shown that this may not be the mechanism in the rat heart, although the effect itself is clearly demonstrable. The cellular energy state has been shown to be better in preconditioned hearts, and the role of ATP consumption has been discussed. The role of inhibition of mitochondrial F1Fo-ATPase as a mechanism for the preservation of ATP in preconditioned hearts remains controversial.
Methods and Results Three-minute global ischemia followed by 9 minutes of reperfusion was used to precondition Langendorff-perfused rat hearts, and control hearts were perfused under normoxic conditions for the same time. The duration of sustained ischemia in both groups of hearts was 21 minutes, after which the hearts were reperfused for 15 minutes to evaluate their mechanical and metabolic recovery. Separate experiments were performed for tissue metabolite determinations, mitochondrial ATPase activity measurements, and 31P nuclear magnetic resonance studies. The recovery of the rate-pressure product was better in the preconditioned group. Three-minute preconditioning ischemia caused inhibition of the mitochondrial ATPase that persisted throughout the 9-minute intervening reperfusion so that at the early stages of sustained ischemia the enzyme activity was still more inhibited in preconditioned hearts. ATP was better preserved in preconditioned hearts than in control hearts during sustained ischemia. The accumulation of adenosine and its degradation products during sustained ischemia was greater in the control group. More lactate and H+ ions accumulated in this group, indicating higher anaerobic glycolysis. Also, inhibition of mitochondrial ATPase by oligomycin slowed ATP depletion during ischemia.
Conclusions The results indicate that preconditioning causes inhibition of rat heart mitochondrial ATPase that persists during reperfusion so that the enzyme is inhibited from the very beginning of the sustained ischemia. This inhibition leads to sparing of high-energy phosphates and improves the time-averaged energy state during ischemia. Although a causal relationship is difficult to prove, this reversible inhibition may contribute to postischemic recovery of the heart.
Key Words: adenosine • myocardium • ischemia
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