Background. The large number of experimental studies showing that adenosine 'turns on' the protein kinase C (PKC)-mediated pathway that accounts for the cardioprotection conferred by ischemic preconditioning contrasts with the scarcity of clinical data documenting the preconditioning-like protective effect of adenosine during cardiac operations on humans. Methods. Forty-five patients undergoing coronary artery bypass were randomized to receive, after the onset of cardiopulmonary bypass, a 5-minute infusion of adenosine (140 μg · kg-1 · min-1) followed by 10 minutes of washout before cardioplegic arrest (n = 23) or an equivalent period (15 minutes) of prearrest drug-free bypass (controls, n = 22). Outcome measurements included troponin I release over the first 48 postoperative hours and activity of ecto-5'-nucleotidase, an admitted reporter of PKC activation, as assessed on right atrial biopsies taken before bypass and at the end of the preconditioning protocol (or after 15 minutes of bypass in control patients). Results. Aortic cross-clamping times were not different between the two groups. Likewise, prebypass values of ecto-5'-nucleotidase (nanomoles/mg protein per minute) were similar in control (3.14 ± 1.02) and adenosinetreated (2.66 ± 1.08) patients. They subsequently remained unchanged in control patients (3.87 ± 1.65) whereas they significantly increased after adenosine preconditioning (4.47 ± 1.96, p < 0.001 versus base line values), However, peak postoperative values of troponin I (μg/L) were not significantly different between control (4.8 ± 2.8) and adenosine-preconditioned patients (5.9 ±6.6) nor were the areas under the curve. There were no adverse effects related to adenosine. Conclusions. Adenosine, given at a clinically safe dose, can turn on the PKC-mediated signaling pathway in volved in preconditioning but this biochemical event does not translate into reduced cell necrosis after coronary artery surgery, suggesting that a preconditioning-like protocol may not be the best suited for exploiting the otherwise well-documented cardioprotective effetcs of adenosine. (C) 2000 by The Society of Thoracic Surgeons.