The Achilles Heel in Melatonin: Asthma
Abstract
Asthma is a clinical syndrome characterized by chronic airway inflammation, airway responsiveness, and expiratory airflow limitation. Nocturnal symptoms and decreases in lung function are common aspects of the asthma clinical syndrome. Nocturnal symptoms also appear to be associated with asthma-related mortality.
In addition to its importance to the regulation of human circadian rhythms, an accumulating body of evidence also suggests that melatonin is also involved in the regulation of smooth muscle tone. For this reason, this study aimed to evaluate contraction and relaxation responses in tracheal smooth muscle rings obtained from rats treated with melatonin.
Following administration of melatonin (50mg/kg/day) at the same time every day for 6 weeks, in vitro organ bath experiments were performed with rat tracheal preparations exposed to contractile (acetycholine and serotonin) and relaxant (theophylline and papaverine) agents. Melatonin treatment strengthened contraction responses, but did not affect relaxation responses in rat tracheal preparations. We think that melatonin might play a role in the pathogenesis of nocturnal asthma.
Therefore, clinicians should be aware of the importance of melatonin to nocturnal exacerbation of asthma symptoms and alert asthmatic patients that use exogenous melatonin supplementation of its potential negative effects.
1. Burioka N, Fukuoka Y, Koyanagi S, Miyata M, Takata M, Chikumi H, et al. Asthma: chronopharmacotherapy and the molecular clock. Adv Drug Deliver Rev 2010;62(9-10):946-55.
2. Smolensky MH, Lemmer B, Reinberg AE.Chronobiology and chronotherapy of allergic and bronchial asthma. Adv Drug Deliver Rev 2007; 59(9-10):852-82.
3. Baibergenova A, Thabane L, Akhtar-Danesh N, Levine M, Gafni A. Patient characteristics associated with nocturnal emergency department visits for asthma. J Asthma 2006; 43(6):469-75.
4. Turner-Warwick M. Epidemiology of nocturnal asthma.Am J Med 1988; 85(suppl 1B): 6-8.
5. Tunstall RR, Shukla P, Grazul-Bilska A, Sun C, O’Rourke ST. MT2 receptors mediate the inhibitory effects of melatonin on nitric oxide-induced relaxation of porcine isolated coronary arteries. J Pharmacol Exp Ther 2011; 336(1):127-33.
6. Martins E Jr, Ligeiro de Oliveira AP, Fialho de Araujo AM, Tavares de Lima W, Cipolla-Neto J, Costa Rosa LF. Melatonin modulates allergic lung inflammation. J Pineal Res 2001; 31(4):363-9.
7. Weekley LB. Influence of melatonin on bovine pulmonary vascular and bronchial airway smooth muscle tone. Clin Auton Res 1995; 5(1):53-6.
8. Pang CS, Brown GM, Tang PL, Pang SF. G-protein linked melatonin binding sites in the chicken lung. Neurosci Lett 1993; 162(1-2):17-20.
9. Sutherland ER, Ellison MC, Kraft M, Martin RJ. Elevated serum melatonin is associated with the nocturnal worsening of asthma. J Allergy Clin Immunol 2003;112(3):513-7.
10. Van de Voorde J, Joos G. Regionally different influence of contractile agonists on isolated rat airway segments. Resp Physiol 1998; 112(2):185-94.
11. Ferraz E, Borges MC, Vianna EO. Influence of nocturnal asthma on chronotype. J Asthma 2008; 45 (10):911-5.
12. Bruderman I, Rahamimoff R. Alterations in tracheobronchial smooth muscle activity following melatonin. J Appl Physiol 1967; 23(6) 938-43.
13. Mercier FJ, Denjean A. Guinea-pig tracheal responsiveness in vitro following general anaesthesia with halothane. Eur Respir J 1996; 9(7):1451-5.
14. Harlow HJ, Weekley BL. Effect of melatonin on the force of spontaneous contractions of in vitro rat small and large intestine. J Pineal Res 1986; 3(3):2767-84.
15. Velarde E, Alonso- Gomez AL, Azpeleta C, Isoma E, Delgado MJ. Melatonin attenuates the acetylcholine- induced contraction in isolated intestine of a teleost fish. J Comp Physiol B 2009; 179(8):951-9.
16. Luchelli A, Santagostino-Barbone G, Tonini M.Investigation into the contractile response of melatonin in the guinea pig isolated proximal colon. The role of 5-HT4 and melatonin receptors. Br J Pharmacol 1997;121(8):1775-8.
17. Uchida K, Aoki T, Satoh H, Tajiri O. Effects of melatonin on muscle contractility and neuromuscular blockade produced by muscle relaxants. Masui 1997;46(2):205-12.
18. Barajas –Lopez C, Peres AL, Espinosa-Luna R, Reyes- Vazquez C, Prieto-Gomez B. Melatonin modulates cholinergic transmission by blocking nicotinic channels
in the guinea-pig submucous plexus. Eur J Pharmacol 1996, 312(3):319-25.
19. de Almeida-Paula LD, Costa-Lotufo LV, Silva Ferreira Z, Monteiro AE, Isoldi MC, Godinho RO, et al. Melatonin modulates rat myotube-acetylcholine receptors by inhibiting calmodulin. Eur J Pharmacol 2005; 525(1-3):24-31.
20. Guermonprez L, Ducrocq C, Gaudry-Talarmain YM.Inhibition of acetylcholine synthesis and tyrosine nitration induced by peroxynitirite are differentially prevented by antioxidants. Mol Pharmacol 2001;60(4):838-46.
21. Markus RP, Zago WM, Carneiro RCG. Melatonin modulation of presynaptic nicotinic acetylcholine receptors in the rat vas deferens. J Pharmacol Exp Ther 1996, 279(1):18-22.
22. Carneiro RC, Toffoleto O, Cipollo-Neto J, Markus RP.Modulation of sympathetic neurotransmission by melatonin. Eur J Pharmacol 1994; 257(1-2):73-7.
23. Gomez-Pinilla PJ, Gomez MF, Sward K, Hedlund P, Hellstrand P, Camello PJ, et al. Melatonin restores impaired contractility in aged guinea-pig urinary bladder. J Pineal Res 2008; 44(4):416-25.
24. Bai Y, Zhang M, Sanderson MJ. Contractility and Ca+2 signaling of smooth muscle cells in different generations of mouse airways. Am J Respir Cell Mol Biol 2007;36(1):122-30.
25. Kummer W, Wiegand S, Akinci S, Wessler I, Schinkel AH, Wess J. Role of acetylcholine and polyspecific cation transporters in serotonin-induced bronchoconstriction in the mouse. Respir Res 2006; 7: 65.
26. Yang Q, Scalbert E, Delagrange P, Vanhoutte PM, O’Rourke ST. Melatonin potentiates contractile responses to serotonin in isolated porcine coronary arteries. Am J Physiol Heart Circ Pyhsiol 2001; 280(1):H76-82.
27. Tamura EK, Silva CL, Markus RP. Melatonin inhibits endothelial nitric oxide production in vitro. J Pineal Res 2006; 41(3):267-84.
28. Tunstall RR, Shukla P, Grazul-Bilska A, Sun C, O’Rourke ST. MT2 receptors mediate the inhibitory effects of melatonin on nitric oxide-induced relaxation of porcine isolated coronary arteries. J Pharmacol Exp Ther 2011; 336(1):127-33.
29. Semercioz A, Onur R, Ayar A, Orhan I. The inhibitory role of melatonin on isolated guinea-pig urinary bladder: an endogenous hormone effects. BJU Int 2004;94(9):1373-6.
30. Reyes-Vazquez C, Naranjo-Rodriguez EB, Garcia- Segoviano JA, Trujillo-Santana JT, Prieto-Gomez B. Apamin blocks the direct relaxant effect of melatonin on rat ileal smooth muscle. J Pineal Res 1997; 22(1):1-8.
31. Kaneda T, Takeuchi Y, Matsui H, Shimizu K, Urakawa N, Nakajyo S. Inhibitory mechanisms of papaverine on carbachol-induced contraction in a bovine trachea. J Pharmacol Sci 2005; 98(3):275-82.
32. Ise S, Nishimura J, Hirano K, Hara N, Kanaide H.Theophylline attenuates Ca+2 sensivity and modulates BK channels in porcine tracheal smooth muscle. Brit J Pharmacol 2003; 140(5):939-47.
33. Evsyukova HV. The role of melatonin in pathogenesis of aspirin-sensivite asthma. Eur J Clin Invest 1999;29(6):563-7.
34. Gumral N, Calıskan S, Ozguner F, Kaleli S, Akkaya A, Yilmaz H, et al. Melatonin levels and enzymatic antioxidant defense system decrease in blood of patients with bronchial asthma. Toxicol Ind Health 2009;25(6):411-6.
35. Reiter RJ. Pineal gland interface between the photoperiodic environment and the endocrine system. Trends Endocrinol Metab 1991; 2(1):13-9.
36. Bojkowski CJ, Arendt J, Shih MC, Markey SP. Melatonin secretion in humans assessed by measuring its metabolite,6-sulphatoxymelatonin. Clin Chem 1987; 33(8):1343-48.
37. Ayar A, Kutlu S, Yılmaz B, Kelestimur H. Melatonin inhibits spontaneous and oxytocin-induced contractions of rat myometrium in vitro. Neuroendocrinol Lett 2001;22(3):199-207.
38. Onur R, Ozcan M, Tuygun U, Ozan T, Ayar A, Orhan I.Effects of combined use of trospium chloride and melatonin on in vitro contractility of rat urinary bladder. Urology 2010; 75(4):873-8.
39. Reiter RJ, Tan DX, Manchester LC, Qi W. Biochemical reactivity of melatonin with reactive oxgyen and nitrogen species: A review of the evidence. Cell Biochem Biophys 2001; 34(2):237-56.
40. Tan DX, Reiter RJ, Manchester LC, Yan MT, El-Sawi M, Sainz RM, et al. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2002; 2(2):181-97.
41. Girouard H, Chulak C, Lejossec M, Lamontagne D, de Champlain J. Vasorelaxant effects of the chronic treatment with melatonin on mesenteric and aorta of spontaneously hypertensive rats. J Hypertens 2001;19(8):1369-77.
42. Paulis L, Pechanova O, Zicha J, Barta A, Gardlik R, Celec P, et al. Melatonin interactions with blood pressure and vascular function during L-NAME-induced hypertension. J Pineal Res 2010; 48(2):102-8.
43. Wolfler A, Caluba HC, Abuja PM, Dohr G, Schauenstein K, Liebmann PM. Prooxidant activity of melatonin promotes fas-induced cell death in human leukemic Jurkat cells. FEBS Lett 2001; 502(3):127-31.
44. Yang Q, Scalbert E, Delagrange P, Vanhoutte PM, O’Rourke ST. Melatonin potentiates contractile responses to serotonin in isolated porcine coronary arteries. Am J Physiol Heart Circ Pyhsiol 2001; 280(1):H76-82.
Files | ||
Issue | Vol 11, No 3 (2012) | |
Section | Articles | |
Keywords | ||
Bronchial asthma Circadian rhythm Melatonin Trachea |
Rights and permissions | |
![]() |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |