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Effects of amitriptyline, a tricyclic antidepressant, on smooth muscle reactivity in isolated rat trachea

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Abstract

Purpose

This study was designed to investigate the action of amitriptyline, a tricyclic antidepressant, on airway smooth muscle reactivity and its underlying mechanisms.

Methods

In isolated rat trachea, isometric force was recorded to examine the effects of amitriptyline on the contractile response to acetylcholine (ACh), electrical field stimulation (EFS), calyculin A (a myosin light chain phosphatase inhibitor), and sphingosylphosphorylcholine (SPC; a Rhokinase activator). In addition, inositol monophosphate (IP1) accumulation was measured to examine its effects on inositol 1, 4, 5-trisphosphate (IP3) production during stimulation with ACh.

Results

Amitriptyline inhibited the contractile responses to ACh, EFS, calyculin A, and SPC, with the concentrations of amitriptyline (mean ± SD) required to exert 50% inhibition (IC50) being 4.3 ± 1.3 μM, 3.2 ± 1.6 μM, 256.4 ± 106.4 μM, and 98.2 ± 21.8 μM, respectively. In addition, amitriptyline (10 μM) eliminated the ACh (10 μM)-induced IP1 accumulation.

Conclusion

The results suggest that amitriptyline does not influence tracheal smooth muscle reactivity at clinical concentrations (<1 μM), but attenuates the reactivity at supraclinical concentrations (≥1 μM). The attenuated response to ACh brought about by amitriptyline is presumably due, at least in part, to the inhibition of phosphatidylinositol (PI) metabolism. The ability of amitriptyline to inhibit the calyculin Ainduced contraction suggests that amitriptyline also inhibits the Ca2+-calmodulin-myosin light chain pathway independently of the inhibition of PI metabolism. Finally, the difference between the IC50 values for SPC-induced contraction and those for calyculin A-induced contraction suggests that amitriptyline may also inhibit the Rho-kinase pathway.

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References

  1. Tremont-Lukats IW, Challapalli V, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetics to relieve neuropathic pain: a systematic review and meta-analysis. Anesth Analg. 2005;101:1738–1749.

    Article  PubMed  CAS  Google Scholar 

  2. Haderer A, Gerner P, Kao G, Srinivasa V, Wang GK. Cutaneous analgesia after transdermal application of amitriptyline versus lidocaine in rats. Anesth Analg. 2003;96:1707–1710.

    Article  PubMed  CAS  Google Scholar 

  3. Sawynok J, Esser MJ, Reid AR. Antidepressants as analgesics: an overview of central and peripheral mechanisms of action. J Psychiatry Neurosci. 2001;26:21–29.

    PubMed  CAS  Google Scholar 

  4. Sawynok J, Reid AR, Liu XJ, Parkinson FE. Amitriptyline enhances extracellular tissue levels of adenosine in the rat hindpaw and inhibits adenosine uptake. Eur J Pharmacol. 2005;518:116–122.

    Article  PubMed  CAS  Google Scholar 

  5. Meares RA, Mills JE, Horvath TB, Atkinson JM, Pun LQ, Rand MJ. Amitriptyline and asthma. Med J Aust. 1971;2:25–28.

    PubMed  CAS  Google Scholar 

  6. Wilson RC. Antiasthmatic effect of amitriptyline. Can Med Assoc J. 1974;111:212.

    PubMed  CAS  Google Scholar 

  7. Proskocil BJ, Fryer AD. Beta2-agonist and anticholinergic drugs in the treatment of lung disease. Proc Am Thorac Soc. 2005;2:305–310.

    Article  PubMed  CAS  Google Scholar 

  8. Brown E, Kendoll DA, Nahorski SR. Inositolphospholipid hydrolysis in rat cerebral cortical slices: I. Receptor characterization. J Neurochem. 1984;42:1379–1387.

    Article  PubMed  CAS  Google Scholar 

  9. Toda N, Hatano Y. Contractile responses of canine tracheal muscle during exposure to fentanyl and morphine. Anesthesiology. 1980;53:93–100.

    Article  PubMed  CAS  Google Scholar 

  10. Itabashi S, Aikawa T, Sekizawa K, Ohrui T, Sasaki H, Takishima T. Pre- and postjunctional muscarinic receptor subtypes in dog airways. Eur J Pharmacol. 1991;204:235–241.

    Article  PubMed  CAS  Google Scholar 

  11. Yu M, Wang Z, Robinson NE. Prejunctional α2-adrenoceptors inhibit acetylcholine release from cholinergic nerves in equine airways. Am J Physiol. 1 1993;265:L565–L570.

    CAS  Google Scholar 

  12. Szarek JL, Spurlock B. Antagonism of cholinergic nerve-mediated contractions by the sensory nerve inhibitory system in rat bronchi. J Appl Physiol. 1996;81:260–265.

    PubMed  CAS  Google Scholar 

  13. Lindén A, Ullman A, Skoogh BE, Löfdahl CG. The nonadrenergic, non-cholinergic response counteracts changes in guinea-pig airway tone with and without sympathetic activation. Br J Pharmacol. 1992;106:616–622.

    PubMed  Google Scholar 

  14. Burdyga T, Mitchell RW, Ragozzino J, Ford LE. Force and myosin light chain phosphorylation in dog airway smooth muscle activated in different ways. Respir Physiol Neurobiol. 2003;137:141–149.

    Article  PubMed  CAS  Google Scholar 

  15. Nakao F, Kobayashi S, Mogami K, Mizukami Y, Shirao S, Miwa S, Todoroki-Ikeda N, Ito M, Matsuzaki M. Involvement of Src family protein tyrosine kinases in Ca2+ sensitization of coronary artery contraction mediated by a sphingosylphosphorylcholine-Rho-kinase pathway. Circ Res. 2002;91:953–960.

    Article  PubMed  CAS  Google Scholar 

  16. James AN, Ryan JP, Parkman HP. Effects of clonidine and tricyclic antidepressants on gastric smooth muscle contractility. Neurogastroenterol Motil. 2004;16:143–153.

    Article  PubMed  CAS  Google Scholar 

  17. Huang Y, Lau CW. Inhibitory effect of amitriptyline on contraction of the rat isolated trachea. Pharmacology. 1997;54:312–318.

    Article  PubMed  CAS  Google Scholar 

  18. Vila JM, Medina P, Segarra G, Lluch P, Pallardo F, Flor B, Lluch S. Relaxant effects of antidepressants on human isolated mesenteric arteries. Br J Clin Pharmacol. 1999;48:223–229.

    Article  PubMed  CAS  Google Scholar 

  19. Medina P, Segarra G, Ballester R, Chuan P, Domenech C, Vila JM, Lluch S. Effects of antidepressants in adrenergic neurotransmission of human vas deferens. Urology. 2000;55:592–597.

    Article  PubMed  CAS  Google Scholar 

  20. Auguet M, Clostre F, DeFeudis FV. Effects of antidepressants on receptor-activated and Ca2+-activated contractions of rabbit isolated aorta. Gen Pharmacol. 1986;17:607–610.

    PubMed  CAS  Google Scholar 

  21. Kachur JF, Allbee WE, Gaginella TS. Antihistaminic and antimuscarinic effects of amitriptyline on guinea pig ileal electrolyte transport and muscle contractility in vitro. J Pharmacol Exp Ther. 1988;245:455–459.

    PubMed  CAS  Google Scholar 

  22. Lucchelli A, Santagostino-Barbone MG, D’Agostino G, Masoero E, Tonini M. The interaction of antidepressant drugs with enteric 5-HT7 receptors. Naunyn Schmiedebergs Arch Pharmacol. 2000;362:284–289.

    Article  PubMed  CAS  Google Scholar 

  23. Thirstrup S. Control of airway smooth muscle tone: II-pharmacology of relaxation. Respir Med. 2000;94:519–528.

    Article  PubMed  CAS  Google Scholar 

  24. Thirstrup S. Control of airway smooth muscle tone. I—electrophysiology and contractile mediators. Respir Med. 2000;94:328–336.

    Article  PubMed  CAS  Google Scholar 

  25. Proskocil BJ, Fryer AD. Beta2-agonist and anticholinergic drugs in the treatment of lung disease. Proc Am Thorac Soc. 2005;2:305–310.

    Article  PubMed  CAS  Google Scholar 

  26. Wood M, Wood AJJ. Drugs and anesthesia: pharmacology for anesthesiologists. 2nd ed. Baltimore: Williams & Wilkins; 1990. p. 443–444.

    Google Scholar 

  27. Iizuka K, Dobashi K, Yoshii A, Horie T, Suzuki H, Nakazawa T, Mori M. Receptor-dependent G protein-mediated Ca2+ sensitization in canine airway smooth muscle. Cell Calcium. 1997;22:21–30.

    Article  PubMed  CAS  Google Scholar 

  28. Iizuka K, Yoshii A, Samizo K, Tsukagoshi H, Ishizuka T, Dobashi K, Nakazawa T, Mori M. A major role for the rho-associated coiled coil forming protein kinase in G-protein-mediated Ca2+ sensitization through inhibition of myosin phosphatase in rabbit trachea. Br J Pharmacol. 1999;128:925–933.

    Article  PubMed  CAS  Google Scholar 

  29. Yoshii A, Iizuka K, Dobashi K, Horie T, Harada T, Nakazawa T, Mori M. Relaxation of contracted rabbit tracheal and human bronchial smooth muscle by Y-27632 through inhibition of Ca2+ sensitization. Am J Respir Cell Mol Biol. 1999;20:1190–1200.

    PubMed  CAS  Google Scholar 

  30. Iizuka K, Shimizu Y, Tsukagoshi H, Yoshii A, Harada T, Dobashi K, Murozono T, Nakazawa T, Mori M. Evaluation of Y-27632, a rho-kinase inhibitor, as a bronchodilator in guinea pigs. Eur J Pharmacol. 2000;406:273–279.

    Article  PubMed  CAS  Google Scholar 

  31. Thomas GD, Snetkov VA, Patel R, Leach RM, Aaronson PI, Ward JP. Sphingosylphosphorylcholine-induced vasoconstriction of pulmonary artery: activation of non-store-operated Ca2+ entry. Cardiovasc Res. 2005;68:56–64.

    Article  PubMed  CAS  Google Scholar 

  32. Shirao S, Kashiwagi S, Sato M, Miwa S, Nakao F, Kurokawa T, Todoroki-Ikeda N, Mogami K, Mizukami Y, Kuriyama S, Haze K, Suzuki M, Kobayashi S. Sphingosylphosphorylcholine is a novel messenger for Rho-kinase-mediated Ca2+ sensitization in the bovine cerebral artery: unimportant role for protein kinase C. Circ Res. 2002;91:112–119.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Anesthesiology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan

    Shoji Matsunaga, Osamu Shibata, Kenji Nishioka, Atsushi Tsuda, Tetsuji Makita & Koji Sumikawa

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  1. Shoji Matsunaga
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  2. Osamu Shibata
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  3. Kenji Nishioka
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  4. Atsushi Tsuda
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  6. Koji Sumikawa
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Matsunaga, S., Shibata, O., Nishioka, K. et al. Effects of amitriptyline, a tricyclic antidepressant, on smooth muscle reactivity in isolated rat trachea. J Anesth 23, 385–391 (2009). https://doi.org/10.1007/s00540-009-0781-0

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  • DOI: https://doi.org/10.1007/s00540-009-0781-0

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