Classic preconditioning decreases the harmful accumulation of nitric oxideduring ischemia and reperfusion in rat hearts

Background-The role of NO in the mechanism of preconditioning is not unders tood. Therefore, we studied the effect of preconditioning and subsequent is chemia/reperfusion on myocardial NO content in the presence of an NO syntha se (NOS) inhibitor. Methods and Results-Isolated working rat hearts were subjected to precondit ioning protocols of 3 intermittent periods of rapid pacing or no-flow ische mia of 5 minutes' duration each followed by a test 30 minutes of global no- flow ischemia and 15 minutes of reperfusion, Test ischemia/reperfusion resu lted in a deterioration of myocardial function and a considerable increase in cardiac NO content as assessed by electron spin resonance. Preconditioni ng improved postischemic myocardial function and markedly decreased test is chemia/reperfusion-induced NO accumulation. In the presence of 4.6 mu mol/L N-G-nitro-L-arginine (LNA), basal cardiac NO content decreased significant ly, although test ischemia/reperfusion-induced functional deterioration and NO accumulation were not affected in nonpreconditioned hearts. However, th e protective effects of preconditioning on both test ischemia/reperfusion-i nduced functional depression and NO accumulation were abolished, When 4.6 m u mol/L LNA was administered after preconditioning, it failed to block the effect of preconditioning. In the presence of 46 mu mol/L LNA, ischemia/rep erfusion-induced NO accumulation was significantly decreased and postischem ic myocardial function was improved in nonpreconditioned hearts. Conclusions-Our results show that (1) although NO synthesis by the heart is necessary to trigger classic preconditioning, preconditioning in turn atte nuates the accumulation of NO during ischemia/reperfusion, and (2) blockade of ischemia/reperfusion-induced accumulation of cardiac NO by precondition ing or by an appropriate concentration of NOS inhibitor alleviates ischemia /reperfusion injury as demonstrated by enhanced postischemic function.