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Activation of peripheral opioid receptors has no effect on heart rate variability

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Abstract

Opioid receptors involved in regulating the motility of the gastrointestinal tract have been localized in both contractile and neuronal tissues. Trimebutine, a peripheral opioid receptor agonist, modulates gastrointestinal motor activity in both directions and also may act on cardiac tissue. This study investigated the effects of trimebutine in clinical doses on cardiac autonomic functions with heart rate variability. The effect of trimebutine on cardiac autonomic outflows was evaluated in 11 healthy subjects. Trimebutine (200 mg) or placebo was administered orally at random in a double-blind, cross-over manner. Continuous electrocardiography recordings were obtained before and after drug administration during three states: rest, controlled breathing, and a hand grip exercise. Heart rate variability analysis showed that there was no significant difference between subjects administered with placebo or trimebutine throughout rest, controlled breathing, or the hand grip exercise. We concluded that trimebutine, in clinical doses, has no significant effect on cardiac autonomic functions.

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References

  1. Boehm S, Kubista H (2002) Fine tuning of sympathetic transmitter release via ionotropic and metabotropic presynaptic receptors. Pharmacol Rev 54:43–99

    Article  PubMed  CAS  Google Scholar 

  2. Caffrey JL, Mateo Z, Napier LD, Gaugl JF, Barron B (1995) Intrinsic cardiac enkephalins inhibit vagal bradycardia in the dog. Am J Physiol 268:H848–H855

    PubMed  CAS  Google Scholar 

  3. Delvaux M, Wingate D (1997) Trimebutine: mechanism of action, effects on gastrointestinal function and clinical results. J Int Med Res 25:225–246

    PubMed  CAS  Google Scholar 

  4. Diop L, Pascaud X, Le Gallou B, Junien JL (1992) Travel stress alters the intestinal migrating myoelectric complex in rats: antagonist effect of trimebutine. Life Sci 50:263–271

    Article  PubMed  CAS  Google Scholar 

  5. Drolet B, Rousseau G, Daleau P, Cardinal R, Turgeon J (2000) Domperidone should not be considered a no-risk alternative to cisapride in the treatment of gastrointestinal motility disorders. Circulation 102:1883–1885

    PubMed  CAS  Google Scholar 

  6. Ellidokuz E, Kaya D (2003) The effect of metoclopramide on QT dynamicity: double-blind, placebo-controlled, cross-over study in healthy male volunteers. Aliment Pharmacol Ther 18:151–155

    Article  PubMed  CAS  Google Scholar 

  7. Hung CF, Chang WL, Liang HC, Su MJ (2000) Identification of opioid receptors in the sympathetic and parasympathetic nerves of guinea-pig atria. Fundam Clin Pharmacol 14:387–394

    Article  PubMed  CAS  Google Scholar 

  8. Igawa O, Kotake H, Hirai S, Hisatome I, Hasegawa J, Mashiba H (1989) Effects of trimebutine maleate on electrical activities of isolated mammalian cardiac preparations. J Pharm Pharmacol 41:311–315

    PubMed  CAS  Google Scholar 

  9. Jhee OH, Lee YS, Shaw LM, Jeon YC, Lee MH, Lee SH, Kang JS (2007) Pharmacokinetic and bioequivalence evaluation of two formulations of 100 mg trimebutine maleate (Recutin™ and Polybutin™) in healthy male volunteers using the LC–MS/MS method. Clin Chim Acta 375:69–75

    Article  PubMed  CAS  Google Scholar 

  10. Kamath MV, Fallen EL (1993) Power spectral analysis of heart ate variability: a noninvasive signature of cardiac autonomic function. Crit Rev Biomed Eng 21:245–311

    PubMed  CAS  Google Scholar 

  11. Kaya D, Ellidokuz E, Onrat E, Ellidokuz H, Celik A, Kilit C (2003) The effect of dopamine type-2 receptor blockade on autonomic modulation. Clin Auton Res 13:275–280

    Article  PubMed  Google Scholar 

  12. Lacheze C, Coelho AM, Fioramonti J, Bueno L (1998) Influence of trimebutine on inflammation- and stress-induced hyperalgesia to rectal distension in rats. J Pharm Pharmacol 50:921–928

    PubMed  CAS  Google Scholar 

  13. Mannelli M, Ianni L, Lazzeri C, Castellani W, Pupilli C, La Villa G, Barletta G, Serio M, Franchi F (1999) In vivo evidence that endogenous dopamine modulates sympathetic activity in man. Hypertension 34:398–402

    PubMed  CAS  Google Scholar 

  14. Morisawa T, Hasegawa J, Tanabe K, Watanabe A, Kitano M, Kishimoto Y (2000) Effects of trimebutine maleate on delayed rectifier K+ currents in guinea-pig ventricular myocytes. J Pharm Pharmacol 52:403–408

    Article  PubMed  CAS  Google Scholar 

  15. Nagasaki M, Komori S, Ohashi H (1993) Effect of trimebutine on voltage-activated calcium current in rabbit ileal smooth muscle cells. Br J Pharmacol 110:399–403

    PubMed  CAS  Google Scholar 

  16. Okano H, Saeki S, Inui A, Kawai Y, Ohno S, Morimoto S, Ohmoto A, Nakashima T, Miyamoto M, Okita M, et al (1993) Effect of trimebutine maleate on emptying of stomach and gallbladder and release of gut peptide following a solid meal in man. Dig Dis Sci 38:817–823

    Article  PubMed  CAS  Google Scholar 

  17. Pugsley MK, Saint DA, Hayes E, Kramer D, Walker MJA (1998) The sodium channel blocking properties of spiradoline, a κ-receptor agonist, are responsible for its antiarrhythmic action in the rat. J Cardiovasc Pharmacol 32:863–874

    Article  PubMed  CAS  Google Scholar 

  18. Pugsley MK, Saint DA, Penz WP, Walker MJA (1993) Electrophysiological and antiarrhythmic actions of the kappa agonist PD129290, and its R,R (+) enantiomer. PD 129289. Br J Pharmacol 110:1579–1585

    PubMed  CAS  Google Scholar 

  19. Roman FJ, Lanet S, Hamon J, Brunelle G, Maurin A, Champeroux P, Richard S, Alessandri N, Gola M (1999) Pharmacological properties of trimebutine and N-monodesmethyltrimebutine. J Pharmacol Exp Ther 289:1391–1397

    PubMed  CAS  Google Scholar 

  20. Schultz JE, Gross GJ (2001) Opioids and cardioprotection. Pharmacol Ther 89:123–137

    Article  PubMed  CAS  Google Scholar 

  21. Stendal C (1998) Practical guide to gastrointestinal function testing. Blackwell Scientific Publications Ltd, Milan

  22. Taniyama K, Sano I, Nakayama S, Matsuyama S, Tadeka K, Yoshihara C, Tanaca C (1991) Dual effect of trimebutine on contractility of the guinea pig ileum via the opioid receptors. Gastroenterology 101:1579–1587

    PubMed  CAS  Google Scholar 

  23. Task Force of the European Society of Cardiology, the North American Society of Pacing and Electrophysiology (1996) Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation 93:1043–1065

    Google Scholar 

  24. Ventura C, Spurgeon H, Lakatta EG, Guarnieri C, Capogrossi MC (1992) κ and δ opioid receptor stimulation affects cardiac myocyte function and Ca2+ release from an intracellular pool in myocytes and neurons. Circ Res 70:66–81

    PubMed  CAS  Google Scholar 

  25. Wang SH, Lin CY, Huang TY, Wu WS, Chen CC, Tsai SH (2001) QT interval effects of cisapride in the clinical setting. Int J Cardiol 80:179–183

    Article  PubMed  CAS  Google Scholar 

  26. Wong TM, Shan J (2001) Modulation of sympathetic actions on the heart by opioid receptor stimulation. J Biomed Sci 8:299–306

    Article  PubMed  CAS  Google Scholar 

  27. Wysowski DK, Bacsanyi J (1996) Cisapride and fatal arrhythmia. N Engl J Med 335:290–291

    Article  PubMed  CAS  Google Scholar 

  28. Xiao RP, Pepe S, Spurgeon HA, Capogrossi MC, Lakatta EG (1997) Opioid peptide receptor stimulation reverses β adrenergic effects in rat heart cells. Am J Physiol 272:H797–H805

    PubMed  CAS  Google Scholar 

  29. Zimlichman R, Gefel D, Eliahou H, Matas Z, Rosen B, Gass S, Ela C, Eilam Y, Vogel Z, Barg J (1996) Expression of opioid receptors during heart ontogeny in normotensive and hypertensive rats. Circulation 93:1020–1025

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Dept. of Internal Medicine and Gastroenterology, School of Medicine, Celal Bayar University, Manisa, Turkey

    Ender Ellidokuz MD, PhD

  2. Celal Bayar University Uygulama ve Arastirma Hastanesi, Gastroenteroloji Bilim Dali, 45020, Manisa, Turkey

    Ender Ellidokuz MD, PhD

  3. Dept. of Cardiology, Izmir Tepecik Education and Research Hospital, Izmir, Turkey

    Dayimi Kaya

  4. Dept. of Internal Medicine, School of Medicine, Afyonkarahisar Kocatepe University, Afyonkarahisar, Turkey

    İhsan Uslan

  5. Dept. of Gastroenterology, School of Medicine, Afyonkarahisar Kocatepe University, Afyonkarahisar, Turkey

    İhsan Uslan

  6. Dept. of Cardiology, School of Medicine, Afyonkarahisar Kocatepe University, Afyonkarahisar, Turkey

    Ataç Çelik

  7. Dept. of Cardiology, Kosuyolu Heart Education and Research Hospital, Istanbul, Turkey

    Ali Metin Esen & İrfan Barutça

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  1. Ender Ellidokuz MD, PhD
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  2. Dayimi Kaya
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Correspondence to Ender Ellidokuz MD, PhD.

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Ellidokuz, E., Kaya, D., Uslan, İ. et al. Activation of peripheral opioid receptors has no effect on heart rate variability. Clin Auton Res 18, 145–149 (2008). https://doi.org/10.1007/s10286-008-0469-9

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  • DOI: https://doi.org/10.1007/s10286-008-0469-9

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