Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Adibhatla RM, Hatcher JF (2005) Cytidine 5′-diphosphocholine (CDP-choline) in stroke and other CNS disorders. Neurochem Res 30:15–23

    Article  PubMed  CAS  Google Scholar 

  • Adibhatla RM, Hatcher JF, Dempsey RJ (2002) Citicoline: neuroprotective mechanisms in cerebral ischemia. J Neurochem 80:12–23

    Article  PubMed  CAS  Google Scholar 

  • Adibhatla RM, Hatcher JF, Larsen EC, Chen X, Sun D, Tsao FH (2006) CDP-choline significantly restores phosphatidylcholine levels by differentially affecting phospholipase A2 and CTP: phosphocholine cytidylyltransferase after stroke. J Biol Chem 81:6718–6725

    Article  CAS  Google Scholar 

  • Ando M, Katare RG, Kakinuma Y, Zhang D, Yamasaki F, Muramoto K, Sato T (2005) Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein. Circulation 112:164–170

    Article  PubMed  CAS  Google Scholar 

  • Bernik T, Friedman SG, Ochani M, DiRaimo R, Susarla S, Czura CJ, Tracey KJ (2002) Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion. J Vasc Surg 36:1231–1236

    Article  PubMed  Google Scholar 

  • Blusztajn JK, Wurtman RJ (1983) Choline and cholinergic neurons. Science 221:614–619

    Article  PubMed  CAS  Google Scholar 

  • Cansev M (2006) Uridine and cytidine in the brain: their transport and utilization. Brain Res Rev 52:389–397

    Article  PubMed  CAS  Google Scholar 

  • Cavun S, Savci V (2004) CDP-choline increases plasma ACTH and potentiates the stimulated release of GH, TSH and LH: the cholinergic involvement. Fundam Clin Pharmacol 18:513–523

    Article  PubMed  CAS  Google Scholar 

  • Cavun S, Savci V, Ulus IH (2004) Centrally injected CDP-choline increases plasma vasopressin levels by central cholinergic activation. Fundam Clin Pharmacol 18:71–77

    Article  PubMed  CAS  Google Scholar 

  • Cheng Z, Zhang H, Guo SZ, Wurster R, Gozal D (2004) Differential control over postganglionic neurons in rat cardiac ganglia by NA and DmnX neurons: anatomical evidence. Am J Physiol Regul Integr Comp Physiol 286:625–633

    Google Scholar 

  • De Jonge WJ, Van der Zanden EP, The FO, Bijlsma MF, Van Westerloo DJ, Bennink RJ, Berthoud HR, Uematsu S, Akira S, Van den Wijngaard RM, Boeckxstaens GE (2005) Stimulation of vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 6(8):844–851

    Article  PubMed  CAS  Google Scholar 

  • Dobelis P, Madl JE, Pfister JA, Manners GD, Walrond JP (1999) Effect of Delphinium alkaloids on neuromuscular transmission. J Pharm Exp Ther 291:538–546

    CAS  Google Scholar 

  • Jones JF (2001) Vagal control of the rat heart. Exp Physiol 86:797–801

    Article  PubMed  CAS  Google Scholar 

  • Kakinuma Y, Ando M, Kuwabara M, Katare RG, Okudela K, Kobayashi M, Sato T (2005) Acetylcholine from vagal stimulation protects cardiomyocytes against ischemia and hypoxia involving additive non-hypoxic induction of HIF-1alpha. FEBS Lett 579:2111–2118

    Article  PubMed  CAS  Google Scholar 

  • Kawashima K, Fuji T (2003) The lymphocytic cholinergic system and its contribution to the regulation of immune activity. Life Sci 74:675–696

    Article  PubMed  CAS  Google Scholar 

  • Lopez G-Coviella I, Agut J, Von Borstel R, Wurtman RJ (1987) Metabolism of cytidine (5′)-diphosphocholine (CDP-choline) following oral and intravenous administration to the human and the rat. Neurochem Int 11:293–297

    Article  CAS  PubMed  Google Scholar 

  • Lopez G-Coviella I, Agut J, Savcı V, Ortiz AJ, Wurtman RJ (1995) Evidence that 5′-cytidinediphosphocholine can affect brain phospholipid composition by increasing choline and cytidine plasma levels. J Neurochem 65:889–894

    Article  Google Scholar 

  • Mioni C, Bazzani C, Giuliani G, Altavilla D, Leone S, Ferrari A, Minutoli L, Bitto A, Marini H, Zaffe D, Boticelli AR, Iannone A, Tomasi A, Bigiani A, Bertolini A, Squadrito F, Guarini S (2005) Activation of an efferent cholinergic pathway produces strong protection against myocardial ischemia–reperfusion injury in rats. Crit Care Med 33:2621–2628

    Article  PubMed  CAS  Google Scholar 

  • Newman MB, Arendash GW, Shytle RD, Bickford PC, Tighe T, Sanberg PR (2002) Nicotine’s oxidative and antioxidant properties in CNS. Life Sci 71:2807–2820

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates. Academic Press, New York

    Google Scholar 

  • Savci V, Cavun S, Goktalay G, Ulus IH (2002) Cardiovascular effects of intracerebroventricularly injected CDP-choline in normotensive and hypotensive animals: the involvement of cholinergic system. Naunyn-Schmiedeberg’s Arch Pharmacol 365:388–398

    Article  CAS  Google Scholar 

  • Savci V, Goktalay G, Cansev M, Cavun S, Yilmaz MS, Ulus IH (2003) Intravenously injected CDP-choline increases blood pressure and reverses hypotension in haemorrhagic shock: effect is mediated by central cholinergic activation. Eur J Pharmacol 468:129–139

    Article  PubMed  CAS  Google Scholar 

  • Secades JJ, Lorenzo JL (2006) Citicoline: pharmacological and clinical review, 2006 update. Methods Find Exp Clin Pharmacol 28(Suppl B):1–56

    PubMed  CAS  Google Scholar 

  • Stegelmeier BL, Hall JO, Gardner DR, Panter KE (2003) The toxicity and kinetics of larkspur alkaloid, methyllycaconitine, in mice. J Anim Sci 81:1237–1241

    PubMed  CAS  Google Scholar 

  • Vanoli E, De Ferrai GM, Stramba-Badiale M, Hull SS, Foreman RD, Schwartz PJ (1991) Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res 68:1471–1481

    PubMed  CAS  Google Scholar 

  • Walker MJ, Curtis MJ, Hearse DJ, Campbell RW, Janse MJ, Yellon DM, Cobbe SM, Coker SJ, Harness JB, Harron DW (1988) The Lambeth Conventions: guidelines for the study of arrhythmias in ischaemia, infarction and reperfusion. Cardiovasc Res 22:447–455

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Su DM, Wang RH, Liu Y, Wang H (2005) Antinociceptive effects of choline against acute and inflammatory pain. Neuroscience 131:49–56

    Article  CAS  Google Scholar 

  • Weiss GB (1995) Metabolism and actions of CDP-choline as an endogenous compound and administered exogenously as citicoline. Life Sci 56:637–660

    Article  PubMed  CAS  Google Scholar 

  • Wurtman RJ, Regan M, Ulus IH, Yu L (2000) Effect of oral CDP-choline on plasma choline and uridine levels in humans. Biochem Pharmacol 60:989–992

    Article  PubMed  CAS  Google Scholar 

  • Yang B, Lin H, Xu C, Liu Y, Wang H, Han H, Wang Z (2005) Choline produces cytoprotective effects against ischemic myocardial injuries: Evidence for the role of cardiac M3 subtype muscarinic acetylcholine receptors. Cell Physiol Biochem 16:163–174

    Article  PubMed  CAS  Google Scholar 

  • Yilmaz MS, Yalcin M, Savci V (2006) Cytidine 5′-diphosphocholine restores blood flow of superior mesenteric and renal arteries and prolongs survival time in haemorrhaged anaesthetised rats. Clin Exp Pharmacol Physiol 33:415–420

    Article  PubMed  CAS  Google Scholar 

  • Zuanetti G, De Ferrai GM, Priori SG, Schwartz PJ (1987) Protective effect of vagal stimulation on reperfusion arrhythmias in cats. Circ Res 61:429–435

    PubMed  CAS  Google Scholar 

Download references

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.

Author information

Authors and 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

Authors
  1. M. Sertac Yilmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cenk Coskun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Murat Yalcin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vahide Savci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vahide Savci.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

Keywords

Search

Navigation