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CDP-choline prevents cardiac arrhythmias and lethality induced by short-term myocardial ischemia–reperfusion injury in the rat: involvement of central muscarinic cholinergic mechanisms

Naunyn-Schmiedeberg's Archives of Pharmacology volume 378, pages 293–301 (2008)Cite this article

Abstract

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 µg) or atropine sulfate (10 µg) 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.

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Acknowledgment

This study was supported by the grant from Scientific Research Foundation of Uludag University (2003/31). We are grateful to Cagatay Buyukuysal (Uludag University Faculty of Medicine, Department of Bioistatistic) for his valuable help with the statistical analysis. We would like to thank Dr. Daryl Henderson for his kind help in editing our manuscript.

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Affiliations

  1. Faculty of Medicine, Department of Pharmacology and Clinical Pharmacology, Uludag University, 16059, Gorukle, Bursa, Turkey

    M. Sertac Yilmaz, Cenk Coskun & Vahide Savci

  2. Faculty of Veterinary Medicine, Department of Physiology, Uludag University, Bursa, Turkey

    Murat Yalcin

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  1. M. Sertac Yilmaz
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  2. Cenk Coskun
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  3. Murat Yalcin
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  4. Vahide Savci
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Correspondence to Vahide Savci.

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Yilmaz, M.S., Coskun, C., Yalcin, M. et al. CDP-choline prevents cardiac arrhythmias and lethality induced by short-term myocardial ischemia–reperfusion injury in the rat: involvement of central muscarinic cholinergic mechanisms. Naunyn-Schmied Arch Pharmacol 378, 293–301 (2008). https://doi.org/10.1007/s00210-008-0300-0

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  • DOI: https://doi.org/10.1007/s00210-008-0300-0

Keywords

  • CDP-choline
  • Myocardial ischemia-reperfusion
  • Cholinergic
  • Muscarinic
  • Central
  • Vagal