Lack of adenosine causes myocardial refractoriness.

OBJECTIVES: This study sought to investigate the myocardial mechanisms causing refractoriness to ischemic preconditioning in pigs.
BACKGROUND: Ischemic preconditioning in the pig vanishes after 60 min and cannot be reinstated by a second cycle of brief coronary occlusions at this time point. Ischemic preconditioning has been shown to be mediated by adenosine A1-receptors. Because myocardial adenosine production during ischemia ceases as the number of repeated brief ischemic episodes increases, we hypothesized that this lack of adenosine may cause this myocardial refractoriness.
METHODS: In open chest pigs, ischemic preconditioning was achieved by repeated brief coronary occlusions. Myocardial adenosine content was assessed by high performance liquid chromatographic analysis of serial myocardial biopsy samples; infarct size (percent infarcted area of the area at risk) was determined using tetrazolium salts.
RESULTS: Ischemic preconditioning by two cycles of occlusion of the left anterior descending coronary artery (10 min) and reperfusion (30 min) decreased infarct size ([mean +/- SEM] 40.4+/-2.9%; control: 76.9+/-1.8%, p < 0.001). Prolonging the second reperfusion period to 60 min caused ischemic preconditioning to vanish (79.0+/-0.5%) and caused refractoriness to a second cycle of preconditioning (70.0+/-2.0%). Myocardial adenosine content increased only during the first coronary occlusion (baseline: 110.9+/-42.0 nmol/g dry weight; first coronary occlusion: 1,686.2+/-244.1, p < 0.001) but not during subsequent coronary occlusions. In refractory myocardium, intramyocardial microinfusion of the adenosine A1-receptor agonist N6-cyclohexyladenosine (CHA [0.3 mmol/liter]) again decreased infarct size (27.4+/-7.0%, p < 0.001 vs. control).
CONCLUSIONS: Myocardial refractoriness may be caused by the inability to produce adenosine endogenously. In refractory myocardium, application of CHA reinduces cardioprotection.