Lack of adenosine causes myocardial refractoriness

This study sought to investigate the myocardial mechanisms causing refractoriness to ischemic preconditioning in pigs.

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.

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.

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).

Myocardial refractoriness may be caused by the inability to produce adenosine endogenously. In refractory myocardium, application of CHA reinduces cardioprotection.