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It is well established that peroxynitrite (PN), formed endogenously by the reaction of nitric oxide (NO) and superoxide, largely contributes to the development of myocardial injury, resulting from ischaemia and reperfusion (I/R). However, more recent evidence suggests that PN in a lower (nanomolar/low micromolar) concentration range, may exert preconditioning (PC)-like protective effects. For example, we have shown in a previous study that PN administered in 100 nM concentration, markedly reduced the severity of ventricular arrhythmias that resulted from acute coronary artery occlusion and reperfusion in anaesthetized dogs (Kiss et al., 2008). This study, however, did not examine whether PN, generated during the brief periods of preconditioning I/R insults, plays also a trigger role in the PC-induced antiarrhythmic protection. Therefore, in the first series of experiments (Study I) we examined this by the use of uric acid (UA; 0.2 mg/kg/min, over 30 min), a relatively selective scavenger of PN, and the effects obtained in PC dogs were compared to those dogs that had been received PN exogenously, 25 min before the occlusion of the left anterior descending coronary artery (LAD). In these experiments the severity of ischaemia and of ventricular arrhythmias, changes in plasma nitrate/nitrite (NOx) levels, as well as myocardial superoxide and nitrotyrosine (NT) production (a marker of PN generation) were assessed. We have found that both the PC procedure (2x5 min occlusion/reperfusion) and the administration of PN resulted in a significant increase in NT formation, which was abolished or markedly attenuated in the presence of UA. This attenuation of PN formation in PC dogs, however, did not influence the PC-induced protection; i.e. the number and the incidence of ventricular arrhythmias during the prolonged occlusion remained to be suppressed, whereas the increase in NO bioavailability and the decrease in superoxide production were as the same as in the PC animals. In contrast, UA completely abrogated the protection that resulted from the administration of PN. Interestingly, UA itself also reduced the arrhythmias; an effect which might be associated with the antioxidant property of the compound. Our conclusion was that PN administration results in a PC-like protection against arrhythmias, but PN, generated during the PC procedure, is not necessary for triggering the PC-induced antiarrhythmic protection. The second series of experiments (Study II) aimed to examine whether the increased NO bioavailability that occurs in PC dogs, is the direct consequence of an enhanced nitric oxide synthase (NOS) activity or other NO producing mechanisms, such as the non-enzymatic NO formation, may also play a role. Therefore, we designed studies in which the time-course changes in NOS activity, NO bioavailability, as well as superoxide and NT productions were simultaneously examined in control dogs and in dogs subjected to PC. We have found that in control dogs subjected to a 25 min LAD occlusion, there was an initial increase in NOS activation that occurred around 5 min of the occlusion. Afterwards the enzyme activity continuously decreased up to the end of the occlusion period. These changes in NOS activity were almost parallel with the alterations in NO levels. In control dogs, there were also marked increases in tissue superoxide and NT concentrations, determined at the end of the 25 min of the occlusion. In contrast, in dogs subjected to PC the activation of NOS and the production of NO were significantly increased during the PC procedure, and these were maintained over the entire period of the subsequent prolonged ischaemic insult. Although the PC procedure increased the superoxide and NT levels, the generation of these oxidative stress products was markedly suppressed during the prolonged occlusion. We concluded from these results that PC preserves the NOS enzyme-dependent NO formation, and perhaps through this mechanism, it reduces the harmful consequences of the reperfusion-induced oxidative stress. We propose that this NOS-dependent increase in NO bioavailability during ischaemia plays a mandatory role in the antiarrhythmic effect of PC.

Further evidence for the role of nitric oxide in the antiarrhythmic effect of ischaemic preconditioning: the effect of peroxynitrite and changes in NOS-dependent NO production