Advances in Clinical and Experimental Medicine
2018, vol. 27, nr 7, July, p. 893–897
Publication type: original article
Ivabradine inhibits carbachol-induced contractions of isolated rat urinary bladder
1 Department of Urology, University of Health Sciences, Trabzon Kanuni Training and Research Hospital, Turkey
2 Department of Urology, Akcaabat Hackali Baba State Hospital, Trabzon, Turkey
3 Department of Physiology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
4 Department of Urology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
Background. Overactive bladder (OAB), a symptom syndrome defined as urgency, is a common clinical condition, which sometimes cannot be satisfactorily treated with current medications in every subject; therefore, alternatives are needed.
Objectives. The aim of this in vitro study was to investigate the effects of ivabradine, a selective pacemaker If current inhibitor, on agonist-induced isometric contractions of the bladder smooth muscles.
Material and Methods. Urinary bladder strips were isolated from adult male Wistar rats and suspended in a tissue bath containing physiological solution. The strips were contracted by bath applications of carbachol (CCh, 1 μM). Ivabradine (30 μM, 60 μM or 90 μM) was added to the tissue bath either prior to or after the application of the agonist, and the resulting contractile activity was compared to the preceding contractile activity. The amplitude and area under force-time curves (AUFC) of the isometric contractions were evaluated.
Results. The addition of CCh caused a marked stimulation of contractile force in isolated urinary bladder strips, which was significantly inhibited by ivabradine, both in terms of peak amplitude (29% ±3%, 20% ±6% and 18% ±6% by 30 μM, 60 μM and 90 μM ivabradine, respectively) and AUFC (47% ±5.5%, 35% ±8% and 35% ±6% by 30 μM, 60 μM and 90 μM ivabradine, respectively; n = 7 for each). Pre-treatment with ivabradine (10 μM) significantly attenuated the contractile response to CCh (1 μM; mean peak amplitude from 1493 ±216 mg to 680 ±95 mg; p < 0.003; n = 7).
Conclusion. The results of this in vitro study demonstrated that ivabradine inhibits cholinergic agonistinduced bladder contractions, which means that in the future ivabradine may be used in OAB treatment.
urinary bladder, overactive bladder, ivabradine
- Fry CH, Meng E, Young JS. The physiological function of lower urinary tract smooth muscle. Auton Neurosci. 2010;154:3–13.
- Andersson KE, Arner A. Urinary bladder contraction and relaxation: Physiology and pathophysiology. Physiol Rev. 2004;84:935–986.
- Seth JH, Panicker JN, Fowler CJ. The neurological organization of micturition. Handb Clin Neurol. 2013;117:111–117.
- Sugaya K, Nishijima S, Miyazato M, Ogawa Y. Central nervous control of micturition and urine storage. J Smooth Muscle Res. 2005;41:117–132.
- Abrams P, Chapple CR, Jünemann KP, Sharpe S. Urinary urgency: A review of its assessment as the key symptom of the overactive bladder syndrome. World J Urol. 2012;30:385–392.
- Apoznański W, Polok M, Rysiakiewicz J, et al. An evaluation of the effectiveness of external urethral meatus incision in girls with an anterior deflected urinary stream and symptoms of detrusor overactivity. Adv Clin Exp Med. 2014;23:283–287.
- Verkerk AO, van Ginneken AC, Wilders R. Pacemaker activity of the human sinoatrial node: Role of the hyperpolarization-activated current, I(f). Int J Cardiol. 2009;132:318–336.
- Kolęda P, Pilecki W. Nature of interstitial cells of Cajal of the upper urinary tract. Adv Clin Exp Med. 2014;23:627–632.
- Siu CW, Lieu DK, Li RA. HCN-encoded pacemaker channels: From physiology and biophysics to bioengineering. J Membr Biol. 2006; 214:115–122.
- Sanders KM, Ward SM, Koh SD. Interstitial cells: Regulators of smooth muscle function. Physiol Rev. 2014;94:859–907.
- Takaki M, Suzuki H, Nakayama S. Recent advances in studies of spontaneous activity in smooth muscle: Ubiquitous pacemaker cells. Prog Biophys Mol Biol. 2012;102:129–135.
- Postea O, Biel M. Exploring HCN channels as novel drug targets. Nat Rev Drug Discov. 2011;10:903–914.
- Stamatiou K, Heretis I, Skoumbourdis E. Does ivabradine exhibit a role in the reduction of bladder overactivity? Int Urol Nephrol. 2008; 40:333–334.
- Johnston L, Woolsey S, Cunningham RM, et al. Morphological expression of kit positive interstitial cells of Cajal in human bladder. J Urol. 2010;184:370–377.
- Johnston L, Cunningham RM, Young JS, et al. Altered distribution of interstitial cells and innervation in the rat urinary bladder following spinal cord injury. J Cell Mol Med. 2012;16:1533–1543.
- Akino H. Spontaneous contractile activity of the detrusor muscle and its role in the pathogenesis of overactive bladder syndrome. Low Urin Tract Symptoms. 2012;4:42–47.
- Oh SJ, Ahn SC, Kim SJ, et al. Carbachol-induced sustained tonic contraction of rat detrusor muscle. BJU Int. 1999;84:343–349.
- Hidayat Santoso AG, Liang W. Bladder contractility is mediated by different K+ channels in the urothelium and detrusor smooth muscle. J Pharmacol Sci. 2011;115:127–134.
- Johnston L, Carson C, Lyons AD, Davidson RA, McCloskey KD. Cholinergic-induced Ca2+ signaling in interstitial cells of Cajal from the guinea pig bladder. Am J Physiol Renal Physiol. 2008;294:F645–655.
- Kim SO, Jeong HS, Jang S, et al. Spontaneous electrical activity of cultured interstitial cells of Cajal from mouse urinary bladder. Korean J Physiol Pharmacol. 2013;17:531–536.
- Nazarov IB, Schofield CJ, Terrar DA. Contributions of cardiac “funny” (f) channels and sarcoplasmic reticulum Ca2+ in regulating beating rate of mouse and guinea pig sinoatrial node. Physiol Rep. 2015;3(12): e12561. doi:10.14814/phy2.12561
- Kim SO, Oh BS, Chang IY, et al. Distribution of interstitial cells of Cajal and expression of nitric oxide synthase after experimental bladder outlet obstruction in a rat model of bladder overactivity. Neurourol Urodyn. 2011;30:1639–1645.
- Fry CH. Interstitial cells in the urinary tract, where are they and what do they do? BJU Int. 2014;114:434–435.
- Deng T, Zhang Q, Wang Q, Zhong X, Li L. Changes in hyperpolarization-activated cyclic nucleotide-gated channel expression and activity in bladder interstitial cells of Cajal from rats with detrusor overactivity. Int Urogynecol J. 2015;26:1139–1145.
- Colak MC, Parlakpinar H, Tasdemir S, et al. Therapeutic effects of ivabradine on hemodynamic parameters and cardiotoxicity induced by doxorubicin treatment in rat. Hum Exp Toxicol. 2012;31:945–954.
- Mathiaux F, Dulaurent S, Julia F, Gaulier JM. Case report of ivabradine intoxication. J Anal Toxicol. 2014;38:231–232.