Department of Pharmacology, Pharmacotherapy, University of Szeged, Albert Szent-Györgyi Medical Center, Szeged, Hungary.
Eur J Pharmacol. 2011 Sep 30;667(1-3):306-13. doi: 10.1016/j.ejphar.2011.06.010. Epub 2011 Jun 16.
This study has examined whether peroxynitrite (PN), generated during the preconditioning (PC) procedure or administered by brief intracoronary infusions, plays a trigger role in the anti-arrhythmic effects of preconditioning and peroxynitrite in anaesthetized dogs. To achieve this we infused the peroxynitrite scavenger uric acid (UA; 0.2 mg/kg/min, i.v.) over a 30 min period, just prior to a 25 min occlusion of the left anterior descending coronary artery, in preconditioned (UA+PC, n=8), peroxynitrite-treated (UA+PN, n=8) and in control (UAC; n=9) dogs. The effects were compared to those obtained from groups (PC, n=10; PN, n=10; C1, n=14) without uric acid administration. Severities of ischaemia (ST-segment elevation, inhomogeneity of electrical activation) and ventricular arrhythmias (VPBs, VT, VF), plasma nitrate/nitrite levels, as well as myocardial superoxide and nitrotyrosine productions were determined. Both preconditioning and the infusion of peroxynitrite increased nitrotyrosine formation which was abolished by the simultaneous administration of urate. Despite this, the protective effects of preconditioning (i.e. reductions in arrhythmias, superoxide and nitrotyrosine productions, as well as the increase in nitric oxide availability), occurring during the prolonged period of occlusion and reperfusion were still present. In contrast, urate completely abolished the protection resulted from peroxynitrite administration. This effect is most probably due to the fact that urate has already scavenged peroxynitrite during the infusion. Interestingly, urate itself, given prior to ischaemia and reperfusion, was also protective. We conclude that peroxynitrite in nanomolar concentrations can induce an anti-arrhythmic effect but peroxynitrite, generated during the preconditioning stimulus, is not necessary for the preconditioning-induced anti-arrhythmic protection.
这项研究探讨了过氧亚硝酸盐（PN），在预处理（PC）过程中产生或通过短暂的冠状动脉内输注，是否在预处理和过氧亚硝酸盐的抗心律失常作用中发挥触发作用。为了实现这一目标，我们在预处理（UA+PC，n=8）、过氧亚硝酸盐处理（UA+PN，n=8）和对照（UAC，n=9）狗中，在左前降支冠状动脉闭塞 25 分钟前，输注过氧亚硝酸盐清除剂尿酸（UA；0.2mg/kg/min，静脉内）30 分钟。将这些作用与未给予尿酸的各组（PC，n=10；PN，n=10；C1，n=14）的作用进行了比较。还测定了缺血严重程度（ST 段抬高、电激活不均一性）和室性心律失常（VPB、VT、VF）、血浆硝酸盐/亚硝酸盐水平以及心肌超氧化物和硝基酪氨酸产生。预处理和过氧亚硝酸盐输注均增加了硝基酪氨酸的形成，而尿酸的同时给予则消除了这种形成。尽管如此，预处理的保护作用（即在延长的闭塞和再灌注期间，心律失常、超氧化物和硝基酪氨酸产生的减少，以及一氧化氮可用性的增加）仍然存在。相比之下，尿酸完全消除了过氧亚硝酸盐给药产生的保护作用。这种效应很可能是由于尿酸在输注过程中已经清除了过氧亚硝酸盐。有趣的是，尿酸本身在缺血和再灌注之前给予也具有保护作用。我们得出结论，纳米摩尔浓度的过氧亚硝酸盐可以诱导抗心律失常作用，但预处理刺激过程中产生的过氧亚硝酸盐对于预处理诱导的抗心律失常保护不是必需的。
