Objective: We tested the hypothesis that exercise induces myocardial preconditioning in dogs. Methods: We instrumented dogs with a snare on the anterior descending coronary artery and catheters in the root of the aorta, left ventricular cavity and coronary sinus. After recovering from surgery the dogs were trained to stay in the laboratory and run on a treadmill. Subsequently, they were randomly allocated to five groups: (1) non-preconditioned dogs: under anesthesia, the anterior descending coronary artery was occluded during 1 h and then reperfused during 4.5 h. (2) Early preconditioned dogs: procedure similar to group 1 but the dogs performed exercise on a treadmill for five periods of 5 min each before the coronary occlusion. (3) Late preconditioned dogs: procedure similar to group 2 but 24 h were allowed to elapse between the preconditioning exercise and the coronary occlusion. (4) Early preconditioned dogs plus 5-hydroxydecanoate: procedure similar to group 2 but 5-hydroxydecanoate was administered prior to exercise. (5) Non-preconditioned dogs with 5-hydroxydecanoate: procedure similar to group 1 but 5-hydroxydecanoate was administered at a time equivalent to that in group 4. Results: Exercise did not induce myocardial ischemia and the hemodynamics during the experiments did not differ between groups. Exercise immediately before the coronary occlusion decreased the infarct size (percent of the risk region) by 78% (P,0.05), an effect that was abolished with 5-hydroxydecanoate. Exercise 24 h prior to coronary occlusion decreased infarct size by 46% (P,0.05 vs. non-preconditioned dogs, P,0.05 vs. early preconditioned dogs). 5-Hydroxydecanoate by itself did not modify infarct size. These effects could not be explained by changes in collateral flow to the ischemic region. Conclusions: Exercise prior to a coronary occlusion induces early and late preconditioning of the infarct size. The early effect is mediated through mitochondrial ATP-sensitive potassium channels. 

The loss of cardioprotection induced by the NADPH oxidase inhibitor suggests that ROS generated by this enzyme are important mediators of the preconditioning response, which presumably involves NADPH oxidase-induced RyR2 S-glutathionylation.

We examined, in conscious dogs, the effects of beta-adrenergic stimulation on measurements of left circumflex coronary arterial diameter and blood flow and on calculations of late diastolic coronary resistance (LDCR) and left circumflex coronary internal cross-sectional area (CSA). Isoproterenol (0.1 microgram/kg) initially decreased mean arterial pressure by 25 +/- 2% (mean +/- SEM), and LDCR by 62 +/- 4%, and increased heart rate by 82 +/- 10%, left ventricular (LV) dP/dt by 79 +/- 12%, and mean coronary blood flow by 85 +/- 5%, while CSA rose slightly. The peak effects on CSA (24 +/- 2%) occurred later, along with decreases in mean arterial pressure (7.4 +/- 1.0%) and LDCR (25 +/-5.3%) and increases in coronary blood flow (14 +/- 2%), LV dP/dt (12 +/- 3%), and heart rate (24 +/- 4%). Pirbuterol (1.0 microgram/kg) induced changes that were qualitatively similar to those induced by isoproterenol. Prenalterol (20 micrograms/kg), a cardioselective beta 1-adrenergic receptor agonist, did not affect mean arterial pressure, but increased heart rate by 40 +/- 5%, LV dP/dt by 72 +/- 10%, mean coronary blood flow by 34 +/- 11%, and CSA by 26 +/- 3%, and decreased LDCR by 29 +/- 5+. Isoproterenol and pirbuterol, but not prenalterol, increased coronary sinus O2 content and decreased A-VO2 difference. After beta 1-adrenergic receptor blockade with atenolol (1 mg/kg), prenalterol no longer induced significant effects, whereas isoproterenol and pirbuterol decreased mean arterial pressure similarly to what was observed prior to blockade, but did not increase LV dP/dt, and induced attenuated increases in mean coronary blood flow, CSA, and decreases in LDCR. Thus, in the intact, conscious animal, large coronary arteries are regulated by beta-adrenergic mechanisms. Surprisingly, a major fraction of large coronary arterial dilation appeared to be either directly or indirectly due to beta 1-adrenergic receptor mechanisms, although beta 2-adrenergic effects were also significant.

We previously showed that exercise induces myocardial preconditioning in dogs and that early preconditioning is mediated through mitochondrial adenosine triphosphate-sensitive potassium channels. We decided to study if late preconditioning by exercise is also mediated through these channels. Forty-eight dogs, surgically instrumented and trained to run daily, were randomly assigned to 4 groups: (1) Nonpreconditioned dogs: under anesthesia, the coronary artery was occluded during 1 hour and then reperfused during 4.5 hours. (2) Late preconditioned dogs: similar to group 1, but the dogs run on the treadmill for 5 periods of 5 minutes each, 24 hours before the coronary occlusion. (3) Late preconditioned dogs plus 5-hydroxydecanoate (5HD): similar to group 2, but 5HD was administered before the coronary occlusion. (4) Nonpreconditioned dogs plus 5HD: similar to group 1, but 5HD was administered before the coronary occlusion. Infarct size (percent of the risk region) decreased by effect of exercise by 56% (P < 0.05), and this effect was abolished with 5HD. 5HD by itself did not modify infarct size. Exercise did not induce myocardial ischemia, and the hemodynamics during ischemia-reperfusion period did not differ among groups. These effects were independent of changes in collateral flow to the ischemic region. We concluded that late cardiac preconditioning by exercise is mediated through mitochondrial adenosine triphosphate-sensitive potassium channels.

SUMMARY In order to assess the effects of increasing myocardial metabolic demand on the large epicardial coronary arteries, we measured left circumflex coronary artery diameter (ultrasonic transit time technique) and blood flow in conscious dogs with chronically implanted transducers. Myocardia] oxygen consumption was increased by pacing-induced tachycardia and aortic constriction, and monitored by multiplying left circumflex coronary arterial blood flow by coronary arterio-venous oxygen content difference. Increase of heart rate by 90 beats/mi n caused myocardia] oxygen consumption to increase by 34 ± 4.3% (1 SEM); coronary blood flow at constant arterial pressure to increase by 32 ± 6.8%; and coronary diameter to increase by 0.07 ± 0.01 mm, P < 0.01. Aortic constriction, producing a 53 ± 5.1% increase of left ventricular systolic pressure, caused myocardial oxygen consumption to increase by 49 ± 7.2%, coronary blood flow to increase by 50 ± 6.0%, and coronary diameter to increase 0.13 ± 0.03 mm, P < 0.01. The increases in coronary artery diameter were gradual, not immediate, in onset and not altered by /9-adrenergic blockade. Thus, increased myocardial metabolic demand dilates large epicardial coronary arteries, but with a slower response time than the rapid dilation of the smaller resistance vessels. Cirv Res 49: 594-599, 1981 IT IS widely recognized that coronary arteriolar vessels are exquisitely sensitive to changes in myocardial metabolic demands (Berne and Rubio, 1979). It is not known whether large coronary vessels also are regulated by changes in myocardial metabolic demands. This topic has not been examined adequately due to lack of appropriate techniques, despite considerable clinical interest in view of the critical role played by large coronary vessels in the ischemic heart. The goal of the present investigation was to determine for the first time, using direct and continuous measurements, the effects of increasing myocardial metabolic demands, caused by increasing either cardiac frequency or afterload, on large and small coronary vessels in conscious dogs. Conscious dogs were studied in order to eliminate the potentially confusing effects of anesthetics and recent surgical manipulation on coronary vasoactivity (Vatner and Braunwald, 1975). MethodsMongrel dogs (n = 20) were anesthetized with pentobarbital Na, 30 mg/kg. Transducers were implanted through a thoracotomy in the 5th left intercostal space. Two miniature 7-MHz ultrasonic