The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

A Novel Pathway Underlying the Inhibitory Effects of Melatonin on Isolated Rat Urinary Bladder Contraction

  • Han, June-Hyun (Department of Urology, KEPCO Medical Foundation, Han-il General Hospital) ;
  • Chang, In-Ho (Department of Urology, Chung-Ang University Hospital) ;
  • Myung, Soon-Chul (Department of Urology, Chung-Ang University Hospital) ;
  • Lee, Moo-Yeol (Department of Physiology, College of Medicine, Chung-Ang University) ;
  • Kim, Won-Yong (Department of Microbiology, College of Medicine, Chung-Ang University) ;
  • Lee, Seo-Yeon (Department of Urology, Kwandong University Myungji Hospital) ;
  • Lee, Shin-Young (Department of Urology, Seoul Medical Center) ;
  • Lee, Seung-Wook (Department of Urology, Hanyang University Guri Hospital) ;
  • Kim, Kyung-Do (Department of Urology, Chung-Ang University Hospital)
  • Received : 2011.11.01
  • Accepted : 2012.01.08
  • Published : 2012.02.29
Download PDF
⟨ Previous Next ⟩

Abstract

The aim of the present study was to elucidate the direct effects of melatonin on bladder activity and to determine the mechanisms responsible for the detrusor activity of melatonin in the isolated rat bladder. We evaluated the effects of melatonin on the contractions induced by phenylephrine (PE), acetylcholine (ACh), bethanechol (BCh), KCl, and electrical field stimulation (EFS) in 20 detrusor smooth muscle samples from Sprague-Dawley rats. To determine the mechanisms underlying the inhibitory responses to melatonin, melatonin-pretreated muscle strips were exposed to a calcium channel antagonist (verapamil), three potassium channel blockers [tetraethyl ammonium (TEA), 4-aminopyridine (4-AP), and glibenclamide], a direct voltage-dependent calcium channel opener (Bay K 8644), and a specific calcium/calmodulin-dependent kinase II (CaMKII) inhibitor (KN-93). Melatonin pretreatment ($10^{-8}{\sim}10^{-6}M$) decreased the contractile responses induced by PE ($10^{-9}{\sim}10^{-4}M$) and Ach ($10^{-9}{\sim}10^{-4}M$) in a dose-dependent manner. Melatonin ($10^{-7}M$) also blocked contraction induced by high KCl ($[KCl]_{ECF}$; 35 mM, 70 mM, 105 mM, and 140 mM) and EFS. Melatonin ($10^{-7}M$) potentiated the relaxation response of the strips by verapamil, but other potassium channel blockers did not change melatonin activity. Melatonin pretreatment significantly decreased contractile responses induced by Bay K 8644 ($10^{-11}{\sim}10^{-7}M$). KN-93 enhanced melatonin-induced relaxation. The present results suggest that melatonin can inhibit bladder smooth muscle contraction through a voltage-dependent, calcium-antagonistic mechanism and through the inhibition of the calmodulin/CaMKII system.

Keywords

References

  1. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, Van Kerrebroeck P, Victor A, Wein A. Standardisation Sub-Committee of the International Continence Society. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology. 2003;61:37-49. https://doi.org/10.1016/S0090-4295(02)02243-4
  2. Wein A, Lose GR, Fonda D. Nocturia in men, women and the elderly: a practical approach. BJU Int. 2002;90 Suppl 3:28-31.
  3. Homma Y, Yamaguchi T, Kondo Y, Horie S, Takahashi S, Kitamura T. Significance of nocturia in the International Prostate Symptom Score for benign prostatic hyperplasia. J Urol. 2002;167:172-176. https://doi.org/10.1016/S0022-5347(05)65406-7
  4. Appell RA, Sand PK. Nocturia: etiology, diagnosis, and treatment. Neurourol Urodyn. 2008;27:34-39. https://doi.org/10.1002/nau.20484
  5. Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995;346:541-544. https://doi.org/10.1016/S0140-6736(95)91382-3
  6. Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Zisapel N. Melatonin replacement therapy of elderly insomniacs. Sleep. 1995;18:598-603.
  7. Drake MJ, Mills IW, Noble JG. Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement. J Urol. 2004;171:1199-1202. https://doi.org/10.1097/01.ju.0000110442.47593.ea
  8. Sugaya K, Nishijima S, Miyazato M, Kadekawa K, Ogawa Y. Effects of melatonin and rilmazafone on nocturia in the elderly. J Int Med Res. 2007;35:685-691. https://doi.org/10.1177/147323000703500513
  9. Matsuta Y, Yusup A, Tanase K, Ishida H, Akino H, Yokoyama O. Melatonin increases bladder capacity via GABAergic system and decreases urine volume in rats. J Urol. 2010;184:386-391. https://doi.org/10.1016/j.juro.2010.03.002
  10. Semercioz A, Onur R, Ayar A, Orhan I. The inhibitory role of melatonin on isolated guinea-pig urinary bladder: an endogenous hormone effect. BJU Int. 2004;94:1373-1376. https://doi.org/10.1111/j.1464-410X.2004.05175.x
  11. Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJ, Zisapel N, Cardinali DP. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol. 2008;85:335-353. https://doi.org/10.1016/j.pneurobio.2008.04.001
  12. Ayar A, Kutlu S, Yilmaz B, Kelestimur H. Melatonin inhibits spontaneous and oxytocin-induced contractions of rat myometrium in vitro. Neuro Endocrinol Lett. 2001;22:199-207.
  13. Thor PJ, Krolczyk G, Gil K, Zurowski D, Nowak L. Melatonin and serotonin effects on gastrointestinal motility. J Physiol Pharmacol. 2007;58 Suppl 6:97-103.
  14. Abrams P, Andersson KE. Muscarinic receptor antagonists for overactive bladder. BJU Int. 2007;100:987-1006. https://doi.org/10.1111/j.1464-410X.2007.07205.x
  15. Drake MJ. Emerging drugs for treatment of overactive bladder and detrusor overactivity. Expert Opin Emerg Drugs. 2008;13:431-446. https://doi.org/10.1517/14728214.13.3.431
  16. Nowak JZ, Zawilska JB. Melatonin and its physiological and therapeutic properties. Pharm World Sci. 1998;20:18-27. https://doi.org/10.1023/A:1008688724058
  17. 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;75:873-877. https://doi.org/10.1016/j.urology.2009.08.086
  18. Pressman MR, Figueroa WG, Kendrick-Mohamed J, Greenspon LW, Peterson DD. Nocturia. A rarely recognized symptom of sleep apnea and other occult sleep disorders. Arch Intern Med. 1996;156:545-550. https://doi.org/10.1001/archinte.1996.00440050103011
  19. Salvatore S, Soligo M, Proietti F, Citterio S, Artibani W, Milani R. Overactive bladder syndrome: considerations in pharmacotherapy and new perspectives. Eur J Obstet Gynecol Reprod Biol. 2005;120:129-133. https://doi.org/10.1016/j.ejogrb.2004.10.014
  20. Coge F, Guenin SP, Fery I, Migaud M, Devavry S, Slugocki C, Legros C, Ouvry C, Cohen W, Renault N, Nosjean O, Malpaux B, Delagrange P, Boutin JA. The end of a myth: cloning and characterization of the ovine melatonin MT(2) receptor. Br J Pharmacol. 2009;158:1248-1262. https://doi.org/10.1111/j.1476-5381.2009.00453.x
  21. Ouyang H, Vogel HJ. Melatonin and serotonin interactions with calmodulin: NMR, spectroscopic and biochemical studies. Biochim Biophys Acta. 1998;1383:37-47. https://doi.org/10.1016/S0167-4838(97)00157-X
  22. Ozveren E, Korkmaz B, Buharalioglu CK, Tunctan B. Involvement of calcium/calmodulin-dependent protein kinase II to endotoxin-induced vascular hyporeactivity in rat superior mesenteric artery. Pharmacol Res. 2006;54:208-218. https://doi.org/10.1016/j.phrs.2006.05.001

Cited by

  1. Comparison of the Melatonin Receptor Agonist Ramelteon and the Non-Benzodiazepine Hypnotic Zolpidem for Nocturia vol.3, pp.8, 2013, https://doi.org/10.4236/oju.2013.38055
  2. Bladder Hyperactivity Induced by Oxidative Stress and Bladder Ischemia: A Review of Treatment Strategies with Antioxidants vol.22, pp.11, 2021, https://doi.org/10.3390/ijms22116014