To investigate whether adenosine receptor blockade alters the response to serial coronary occlusions in the rabbit heart, we measured changes in segment length with ultrasonic dimension gauges placed in the field of a coronary branch. The coronary branch was subjected to four 5-minute occlusions, each separated by 10 minutes of reperfusion. In control hearts, the percentage of segment shortening fell from 15.7% to 9.3% after release of the first occlusion with no further deterioration after each of the subsequent three occlusions. In hearts in which adenosine receptors were blocked with PD 115,199, a potent blocker of both A1 and A2 receptors, segment shortening again recovered to about two thirds of the preischemic value during the reperfusion period after the first occlusion. Each subsequent occlusion, however, resulted in a further deterioration of function to the extent that shortening was less than 20% of the preischemic value during reperfusion after the fourth occlusion. Therefore the first occlusion of a series of four occlusions, while mildly stunning the heart, also preconditions the myocardium against further stunning by subsequent occlusions. Because that protection was when adenosine receptors were blocked, adenosine must play an important role in the mediation of this protective effect.