Does preconditioning protect the coronary vasculature from subsequent ischemia/reperfusion injury?

BACKGROUND "Preconditioning" with brief episodes of coronary artery occlusion reduces infarct size caused by subsequent sustained ischemia. However, the effects of preconditioning on the coronary vasculature are poorly understood. We sought to determine whether preconditioning would attenuate "low reflow" (ie, the deterioration in resting myocardial perfusion) and blunt the loss in coronary vasodilator reserve after sustained occlusion/reperfusion in the anesthetized open-chest canine model. METHODS AND RESULTS Thirty-two dogs underwent 1 hour of sustained left anterior descending (LAD) coronary artery occlusion and 4 hours of reperfusion. Each dog was randomly assigned to the preconditioned group (four episodes of 5 minutes of LAD occlusion plus 5 minutes of reperfusion before sustained ischemia) or control group (no intervention). Submaximal vasodilator reserve was determined by measuring the increase in CBF in response to 0.01 mg acetylcholine (an endothelium-dependent dilator) and 0.05 mg nitroglycerin (an endothelium-independent dilator); low reflow was assessed by measurement of regional myocardial blood flow at 30 minutes and 4 hours after reflow; and infarct size was delineated by triphenyltetrazolium staining. In protocol 1 (n = 14), vasodilator reserve was measured at baseline and at 30 minutes and 4 hours after reflow. There was no change in the response to acetylcholine and nitroglycerin at 30 minutes after reperfusion compared with baseline. However, all dogs exhibited a loss in vasodilator reserve during the subsequent 3.5 hours of reflow, with no difference between control and preconditioned groups. That is, in control dogs, acetylcholine increased CBF from a baseline value of 10.1 +/- 1.3 mL/min to 18.0 +/- 2.6, 18.2 +/- 2.1, and 15.4 +/- 1.7 mL/min before occlusion, 30 minutes after reflow, and 4 hours after reperfusion, respectively (P < .05 for 30 minutes vs 4 hours after reperfusion). Similarly, in the preconditioned group, acetylcholine increased CFB from a baseline value of 12.0 +/- 2.9 mL/min to 19.6 +/- 3.8, 23.6 +/- 5.3, and 15.6 +/- 3.5 mL/min, respectively (P < .01 for 30 minutes vs 4 hours after reperfusion; P = NS between groups). In addition, all dogs exhibited low reflow, with no difference between control and preconditioned groups: subendocardial blood flow deteriorated between 30 minutes and 4 hours after reflow, from 0.91 +/- 0.20 to 0.40 +/- 0.03 mL min-1 x g-1 in control animals (P = .05 for 30 minutes vs 4 hours after reperfusion) and from 1.03 +/- 0.25 to 0.35 +/- 0.02 mL.min-1 x g-1 in the preconditioned group (P < .05 for 30 minutes vs 4 hours after reperfusion). However, all dogs in protocol 1 had small infarcts (3 +/- 1% and 2 +/- 1% of the risk region in control and preconditioned groups; P = NS), suggesting that control dogs may have been "preconditioned" by the vasodilators. An additional 18 dogs were entered into protocol 2, which was identical to protocol 1 except that acetylcholine and nitroglycerin were given only after reperfusion. In this case, we observed the expected reduction in infarct size in preconditioned dogs vs control dogs (2 +/- 1% vs 11 +/- 3% of the risk region; P < .01). However, the loss in vasodilator reserve was similar to that observed in protocol 1, with no difference between groups. Subendocardial blood flow at 30 minutes after reperfusion was higher in control animals than in preconditioned dogs (1.84 +/- 0.50 vs 0.74 +/- 0.08 mL.min-1 x g-1; P < .05), but subendocardial flow then deteriorated during the subsequent 3.5 hours to a similar value in both groups (0.55 +/- 0.11 and 0.50 +/- 0.06 mL.min-1 x g-1 in control and preconditioned dogs; P < .05 vs 30 minutes after reperfusion for both groups). CONCLUSIONS The protective effects of preconditioning do not extend to the coronary vasculature in this canine model: Preconditioning neither prevented the deterioration in resting myocardial perfusion nor blunted the loss in submaximal vasodilator reserve obs