Delayed cardioprotective effects of exercise in dogs are aminoguanidine sensitive: possible involvement of nitric oxide

Dogs were subjected to exercise on a treadmill, using a protocol in which the speed and slope were increased every 3min, and which elevated both heart rate (to a mean of 198±14beatsċmin^-1) and mean arterial blood pressure (to 150±4mmHg). Then, 24 or 48h later, the dogs were anaesthetized with a mixture of α-chloralose and urethane and subjected to a 25min occlusion of the left anterior descending coronary artery. The control dogs (instrumented but not exercised) were subjected to the same procedure. In some dogs the nitric oxide synthase inhibitor aminoguanidine (50mgċkg^-1; intravenous) was administered 30min before occlusion. Baroreflex sensitivity (BRS) was determined by the rapid bolus injection of phenylephrine 60min before, and again 3min after, the onset of occlusion. Exercise markedly reduced the consequences of coronary artery occlusion 24h (but not 48h) later, without modifying myocardial tissue blood flow. In the exercised dogs there were reductions in arrhythmia severity [ventricular fibrillation (VF) during occlusion, 0%; survival from the combined ischaemia/reperfusion insult, 70%] compared with controls (VF during occlusion, 36%; survival, 9%). BRS was preserved during occlusion in the exercised dogs (before occlusion, 1.60±0.54msċmmHg^-1; 3min after occlusion, 1.37±0.4msċmmHg^-1), but not in controls (before occlusion, 1.28±0.29msċmmHg^-1; 3min after occlusion, 0.45±0.12msċmmHg^-1; P < 0.05), and other ischaemic changes (inhomogeneity of electrical activation and changes in the ST-segment, recorded over the ischaemic region) were also less marked in the exercised dogs. Exercise-induced cardioprotection was abolished by aminoguanidine (VF during occlusion, 25%; survival, 0%). The results show that even a single period of exercise affords delayed protection against ischaemia/reperfusion-induced VF and other ischaemic changes. Since this protection is abolished by aminoguanidine, and since (inducible) NO synthase activity was elevated 3-fold in left ventricular samples 24h after exercise, we suggest that this protection is mediated by nitric oxide.