Yilmaz M Sertac, Coskun Cenk, Yalcin Murat, Savci Vahide
Faculty of Medicine, Department of Pharmacology, Uludag University, Bursa, Turkey.
Naunyn Schmiedebergs Arch Pharmacol. 2008 Sep;378(3):293-301. doi: 10.1007/s00210-008-0300-0. Epub 2008 May 27.
In the present study, we aimed to determine whether cytidine-5'-diphosphatecholine (CDP-choline or citicoline) can improve the outcome of short-term myocardial ischemia-reperfusion injury in rats. Ischemia was produced in anesthetized rats by ligature of the left anterior descending coronary artery for 7 min followed by a reperfusion period of 7 min. Reperfusion-induced ventricular tachycardia (VT), ventricular fibrillation (VF), survival rate, and changes in arterial pressure were evaluated. Saline (1 ml/kg), CDP-choline (100, 250,and 500 mg/kg), or lidocaine (5 mg/kg) was intravenously injected in the middle of the ischemic period. Intracerebroventricular (i.c.v.) mecamylamine (50 microg) or atropine sulfate (10 microg) pretreatments were made 10 min before the coronary occlusion period. Pretreatment with intravenous (i.v.) atropine methylnitrate (2 and 5 mg/kg; i.v.) or bilateral vagotomy was performed 5 min before the induction of ischemia. An in vivo microdialysis study was performed in the nucleus ambiguus area (NA); choline and acetylcholine levels were measured in extracellular fluids. In control rats, VT, VF, and lethality were observed in 85%, 60% and 50% of the animals, respectively. Intravenous CDP-choline produced a short-term increase in blood pressure and reduced the incidence of VT, VF, and lethality dose-dependently when injected in the middle of the ischemic period. CDP-choline at doses of 250 and 500 mg/kg completely prevented death. Intracerebroventricular atropine sulfate pretreatment completely abolished the protective effect of CDP-choline, while mecamylamine pretreatment had no effect on the drug. CDP-choline increased the levels of extracellular choline and acetylcholine in the NA area. Bilateral vagotomy completely abolished the protective effect of CDP-choline in the reperfusion period. Moreover, the intravenous pretreatment with atropine methylnitrate produced dose-dependent blockade in the reduction of VT, VF, and mortality rates induced by CDP-choline. Neither of these pretreatments except mecamylamine affected the pressor effect of CDP-choline. Intracerebroventricular mecamylamine attenuated the increase in blood pressure induced by CDP-choline. In conclusion, intravenously injected CDP-choline prevents cardiac arrhythmias and death induced by short-term myocardial ischemia-reperfusion injury. Activation of central muscarinic receptors and vagal pathways mediates the protective effect of CDP-choline. The protective effect of CDP-choline is not related to its pressor effect.
在本研究中，我们旨在确定胞苷-5'-二磷酸胆碱（CDP-胆碱或胞磷胆碱）是否能改善大鼠短期心肌缺血-再灌注损伤的结局。通过结扎左冠状动脉前降支7分钟，随后再灌注7分钟，在麻醉大鼠中制造缺血。评估再灌注诱导的室性心动过速（VT）、室颤（VF）、存活率以及动脉压变化。在缺血期中间静脉注射生理盐水（1 ml/kg）、CDP-胆碱（100、250和500 mg/kg）或利多卡因（5 mg/kg）。在冠状动脉闭塞期前10分钟进行脑室内（i.c.v.）注射美加明（50 μg）或硫酸阿托品（10 μg）预处理。在缺血诱导前5分钟进行静脉注射硝酸甲基阿托品（2和5 mg/kg；静脉注射）或双侧迷走神经切断术预处理。在疑核区（NA）进行体内微透析研究；测量细胞外液中胆碱和乙酰胆碱水平。在对照大鼠中，分别有85%、60%和50%的动物出现VT、VF和死亡。在缺血期中间静脉注射CDP-胆碱可使血压短期内升高，并剂量依赖性地降低VT、VF和死亡率。250和500 mg/kg剂量的CDP-胆碱完全预防了死亡。脑室内注射硫酸阿托品预处理完全消除了CDP-胆碱的保护作用，而美加明预处理对该药物无效。CDP-胆碱增加了NA区细胞外胆碱和乙酰胆碱水平。双侧迷走神经切断术完全消除了CDP-胆碱在再灌注期的保护作用。此外，静脉注射硝酸甲基阿托品预处理对CDP-胆碱诱导的VT、VF和死亡率降低产生剂量依赖性阻断作用。除美加明外，这些预处理均未影响CDP-胆碱的升压作用。脑室内注射美加明减弱了CDP-胆碱诱导的血压升高。总之，静脉注射CDP-胆碱可预防短期心肌缺血-再灌注损伤诱导的心律失常和死亡。中枢毒蕈碱受体和迷走神经通路的激活介导了CDP-胆碱的保护作用。CDP-胆碱的保护作用与其升压作用无关。
