Characterization of the urinary bladder dysfunction in renovascular hypertensive rats†
Antonio C.S. Ramos-Filho
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorFabíola Z.T. Mónica
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorCarla F. Franco-Penteado
Hematology and Hemotherapy Center, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorJulio A. Rojas-Moscoso
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorFernando R. Báu
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorAndré A. Schenka
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorGilberto De Nucci
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorCorresponding Author
Edson Antunes Ph.D.
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), 13084-971 Campinas, SP, Brazil.Search for more papers by this authorAntonio C.S. Ramos-Filho
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorFabíola Z.T. Mónica
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorCarla F. Franco-Penteado
Hematology and Hemotherapy Center, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorJulio A. Rojas-Moscoso
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorFernando R. Báu
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorAndré A. Schenka
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorGilberto De Nucci
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Search for more papers by this authorCorresponding Author
Edson Antunes Ph.D.
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil
Department of Pharmacology, Faculty of Medical Sciences, University of Campinas (UNICAMP), 13084-971 Campinas, SP, Brazil.Search for more papers by this authorConflict of interest: none.
Abstract
Aims
Association between arterial hypertension and urinary bladder dysfunction has been reported in humans and spontaneously hypertensive rats. However, no study exists evaluating the bladder dysfunction in conditions of renovascular hypertension. The purpose of this study was to characterize the bladder dysfunction in two kidney-one clip (2K-1C) hypertensive rats.
Methods
A silver clip was placed around the renal artery of male Wistar rats. After 8 weeks, cystometric study, concentration–response curves to contractile and relaxant agents, frequency-dependent contractions, histomorphometry, muscarinic M2/M3 mRNA expression and cyclic AMP measurements were performed.
Results
2K-1C rats showed enhanced bladder volume, wall thickness and smooth muscle density. 2K-1C rats also exhibited increases in bladder capacity and non-void contractions, and decreases in the inter-contraction intervals. In isolated detrusor smooth muscle (DSM), contractions to carbachol and electrical-field stimulation (EFS) were significantly greater in 2K-1C rats. The Rho-kinase inhibitor Y27632 (10 µM) significantly reduced the carbachol-induced contractions in SHAM and 2K-1C rats, but DSM remained overactive in 2K-1C rats in presence of Y27632. Concentration-dependent contractions to the P2X receptor agonist α,β-methylene ATP, KCl and extracellular Ca2+ did not change between SHAM and 2K-1C groups. In 2K-1C rats, isoproterenol, metaproterenol and BRL 37-344 (non-selective, β2- and β3-selective adrenoceptor agonists, respectively) produced significantly lower relaxations and decreased cAMP levels, whereas relaxant responses to sodium nitroprusside and BAY 41-2272 remained unchanged. Muscarinic M3 mRNA expression receptors were higher in 2K-1C group.
Conclusions
Renovascular hypertensive rats exhibit bladder dysfunction that involves tissue remodeling and enhanced muscarinic M3-mediated contractions associated with reduced β-adrenoceptor-mediated signal transduction. Neurourol. Urodynam. 30:1392–1402, 2011. © 2011 Wiley-Liss, Inc.
REFERENCES
- 1 Abrams P, Andersson KE, Buccafusco JJ, et al. Muscarinic receptors: Their distribution and function in body systems, and the implications for treating overactive bladder. Br J Pharmacol 2006; 148: 565–78.
- 2 Michel MC, Barendrecht MM. Physiological and pathological regulation of the autonomic control of urinary bladder contractility. Pharmacol Ther 2008; 117: 297–312.
- 3 Michel MC, Heemann U, Schumacher H, et al. Association of hypertension with symptoms of benign prostatic hyperplasia. J Urol 2004; 172: 1390–3.
- 4 Persson K, Pandita RK, Spitsbergen JM, et al. Spinal and peripheral mechanisms contributing to hyperactive voiding in spontaneously hypertensive rats. Am J Physiol 1998; 275: R1366–73.
- 5 Spitsbergen JM, Clemow DB, McCarty R, et al. Neurally mediated hyperactive voiding in spontaneously hypertensive rats. Brain Res 1998; 790: 151–9.
- 6 Tong YC, Hung YC, Lin SN, et al. Comparisons of neurotransmitter concentrations in the synaptosomal preparation of the normotensive and hypertensive rat urinary bladder. Neurosci Lett 1996; 204: 141–3.
- 7
Clemow DB,
McCarty R,
Steers WD, et al.
Efferent and afferent neuronal hypertrophy associated with micturition pathways in spontaneously hypertensive rats.
Neurourol Urodyn
1997;
16:
293–303.
10.1002/(SICI)1520-6777(1997)16:4<293::AID-NAU5>3.0.CO;2-9 CAS PubMed Web of Science® Google Scholar
- 8 Ribeiro MO, Antunes E, Nucci G, et al. Chronic inhibition of nitric oxide synthesis: A new model of arterial hypertension. Hypertension 1992; 20: 298–303.
- 9 Mónica FZT, Reges R, Cohen D, et al. Long-term administration of BAY 41-2272 prevents bladder dysfunction in nitric oxide-deficient rats. Neurourol Urodyn 2010; DOI: 10.1002/nau.20992.
- 10 Mónica FZ, Bricola AA, Báu FR, et al. Long-term nitric oxide deficiency causes muscarinic supersensitivity and reduces β3-adrenoceptor-mediated relaxation, causing rat detrusor overactivity. Br J Pharmacol 2008; 153: 1659–68.
- 11 Berglund G, Andersson O, Wilhelmsen L. Prevalence of primary and secondary hypertension: Studies in a random population sample. Br Med J 1976; 2: 554–56.
- 12 Andersson KE, Arner A. Urinary bladder contraction and relaxation: Physiology and pathophysiology. Physiol Rev 2004; 84: 935–86.
- 13 Tanabe N, Ueno A, Tsujimoto G. Angiotensin I1 receptors in the rat urinary bladder smooth muscle: Type 1 subtype receptors mediate contractile responses. J Urol 1993; 150: 1056–9.
- 14 Saito M, Kondo A, Kato T, et al. Response of the human bladder to angiotensins: A comparison between neurogenic and control bladders. J Urol 1993; 149: 408–11.
- 15 Weaver-Osterholtz D, Reams G, Wu Z, et al. The urinary bladder angiotensin system: Response to infusions of angiotensin I and angiotensin-converting enzyme inhibitors. Am J Kidney Dis 1996; 28: 603–9.
- 16 Yamada S, Takeuchi C, Oyunzul L, et al. Bladder angiotensin-II receptors: Characterization and alteration in bladder outlet obstruction. Eur Urol 2009; 55: 482–9.
- 17 Moreno H, Jr., Metze K, Bento AC, et al. Chronic nitric oxide inhibition as a model of hypertensive heart muscle disease. Basic Res Cardiol 1996; 91: 248–55.
- 18 Lagaud GJ, Randriamboavonjy V, Roul G, et al. Mechanism of Ca2+ release and entry during contraction elicited by norepinephrine in rat resistance arteries. Am J Physiol 1999; 276: H300–H308.
- 19 Salt PJ. Inhibition of noradrenaline uptake2 in the isolated rat heart by steroids, clonidine and methoxylate phenethylamines. Eur J Pharmacol 1972; 20: 329–40.
- 20 Zimmermann H. ATP and acetylcholine, equal brethren. Neurochem Int 2008; 52: 634–48.
- 21 Bozkurt TE, Sahin-Erdemli I. M1 and M3 muscarinic receptors are involved in the release of urinary bladder-derived relaxant factor. Pharmacol Res 2009; 59: 300–5.
- 22 Burnstock G. Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 2007; 87: 659–797.
- 23 Wang P, Luthin GR, Ruggieri MR. Muscarinic acetylcholine receptor subtypes mediating urinary bladder contractility and coupling to GTP binding proteins. J Pharmacol Exp Ther 1995; 273: 959–66.
- 24 Matsui M, Motomura D, Karasawa H, et al. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci USA 2000; 97: 9579–84.
- 25 Igawa Y, Zhang X, Nishizawa O, et al. Cystometric findings in mice lacking muscarinic M2 or M3 receptors. J Urol 2004; 172: 2460–4.
- 26 Ehlert FJ, Griffin MT, Abe DM, et al. The M2 muscarinic receptor mediates contraction through indirect mechanisms in mouse urinary bladder. J Pharmacol Exp Ther 2005; 313: 368–78.
- 27 Khattab M, AL-Shabanah O, EL-Kashef H. Comparative study of the contractile activity evoked by ATP and diadenosine tetraphosphate in isolated rat urinary bladder. Pharmacol Res 2002; 45: 93–9.
- 28 Yoshimura N, Kaiho Y, Miyazato M, et al. Therapeutic receptor targets for lower urinary tract dysfunction. Naunyn Schmiedebergs Arch Pharmacol 2008; 377: 437–48.
- 29 Bayliss M, Wu C, Newgreen D, et al. A quantitative study of atropine-resistant contractile responses in human detrusor smooth muscle, from stable, unstable and obstructed bladders. J Urol 1999; 162: 1833–9.
- 30 Pinna C, Sanvito P, Puglisi L. Altered neurogenic and mechanical response to acetylcholine, ATP and substance P in detrusor from rat with outlet obstruction. Eur J Pharmacol 2006; 79: 1301–6.
- 31 Kennedy C, Tasker PN, Gallacher G, et al. Identification of atropine-and P2X1 receptor antagonist-resistant, neurogenic contractions of the urinary bladder. J Neurosci 2007; 27: 845–51.
- 32 Lee DL, Webb RC, Jin L. Hypertension and RhoA/Rho-kinase signaling in the vasculature: Highlights from the recent literature. Hypertension 2004; 44: 796–9.
- 33 Christ GJ, Andersson KE. Rho-kinase and effects of rho-kinase inhibition on the lower urinary tract. Neurourol Urodynam 2007; 26: 948–54.
- 34 Chitaley K, Webb RC. Nitric oxide induces dilation of rat aorta via inhibition of Rho-kinase signaling. Hypertension 2002; 39: 438–2.
- 35 Wibberley A, Chen Z, Hu E, et al. Expression and functional role of Rho-kinase in rat urinary bladder smooth muscle. Br J Pharmacol 2003; 138: 757–66.
- 36 Rajasekaran M, Wilkes N, Kuntz S, et al. Rho-kinase inhibition suppresses bladder hyperactivity in spontaneously hypertensive rats. Neurourol Urodyn 2005; 24: 295–300.
- 37 Schneider T, Hein P, Bai J, et al. A role for muscarinic receptors or Rho-kinase in hypertension associated rat bladder dysfunction? J Urol 2005; 172: 2178–81.
- 38 Morelli A, Filippi S, Sandner P, et al. Vardenafil modulates bladder contractility through cGMP-mediated inhibition of RhoA/Rho kinase signaling pathway in spontaneously hypertensive rats. J Sex Med 2009; 6: 1594–608.
- 39 Chang S, Hypolite JA, DiSanto ME, et al. Increased basal phosphorilation of detrusor smooth muscle myosin in alloxan-induced diabetic rabbit is mediated by upregulation of Rho-kinase β and CPI-17. Am J Renal Physiol 2006; 290: F650–6.
- 40 Nobe K, Yamazaki T, Tsumita N, et al. Glucose-dependent enhancement of diabetic bladder contraction is associated with a Rho kinase-regulated protein kinase C pathway. J Pharmacol Exp Ther 2009; 28: 940–50.
- 41 Rapp DE, Lyon MB, Bales GT, et al. A role for the P2X receptor in urinary tract physiology and in the pathophysiology of urinary dysfunction. Eur Urol 2005; 48: 303–8.
- 42 Rivera L, Brading AF. The role of Ca2+ influx and intracellular Ca2+ release in the muscarinic-mediated contraction of mammalian urinary bladder smooth muscle. BJU Int 2006; 98: 868–75.
- 43 Takeda H, Yamazaki Y, Akahane M, et al. Role of the β3-adrenoceptor in urine storage in the rat: Comparison between the selective β3-adrenoceptor agonist, CL316, 243, and various smooth muscle relaxants. J Pharmacol Exp Ther 2000; 293: 939–45.
- 44 Michel MC, Vrydag W. α1-, α2- and β-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 2006; 147: S88–S119.
- 45 Yamaguchi O, Chapple CR. β3-Adrenoceptors in urinary bladder. Neurourol Urodyn 2007; 26: 752–6.
- 46 Yamazaki Y, Takeda H, Akahane M, et al. Species different in the distribution of β-adrenoceptor subtypes in bladder smooth muscle. Br J Pharmacol 1998; 124: 593–9.
- 47 Takeda M, Obara K, Mizusawa T, et al. Evidence for β3-adrenoceptor subtypes in relaxation of the human urinary bladder detrusor: Analysis by molecular biological and pharmacological methods. J Pharmacol Exp Ther 1999; 288: 1367–73.
- 48 Ursino MG, Vasina V, Raschi E, et al. The β3-adrenoceptor as a therapeutic target: Current perspectives. Pharmacol Res 2009; 59: 221–334.
- 49 Uchida H, Shishido K, Nomiya M, et al. Involvement of cyclic AMP-dependent and -independent mechanisms in the relaxation of rat detrusor muscle via β-adrenoceptors. Eur J Pharmacol 2005; 518: 195–202.
- 50 Theobald RJ, Jr. Differing effects of NG-monomethyl L-arginine and 7-nitroindazole on detrusor activity. Neurourol Urodyn 2003; 22: 62–9.
- 51 Persson K, Pandita RK, Aszòdi A, et al. Functional characteristics of urinary tract smooth muscles in mice lacking cGMP protein kinase type I. Am J Physiol Regul Integr Comp Physiol 2000; 279: 1112–20.
- 52 Stasch JP, Becker EM, Alonso-Alija C, et al. NO-independent regulatory site on soluble guanylate cyclase. Nature 2001; 410: 212–5.
- 53 Báu FR, Mónica FZ, Priviero FB, et al. Evaluation of the relaxant effect of the nitric oxide-independent soluble guanylyl cyclase stimulator BAY 41-2272 in isolated detrusor smooth muscle. Eur J Pharmacol 2010; 637: 171–7.
- 54 Andersson KE, Hedlund H, Stahl M. Contractions induced by angiotensin I, angiotensin II, and bradykinin in isolated muscle from the human detrusor. Acta Phys Scand 1992; 145: 253–9.
- 55 Palmer LS, Lee C, Decker RS, et al. The effect of angiotensin converting enzyme inhibition and angiotensin II receptor antagonism on obstructed rat bladder. J Urol 1997; 158: 1100–4.
- 56 Buttyan R, Chen MW, Levin RM. Animal models of bladder outlet obstruction and molecular insights into the basis for the development of bladder dysfunction. Eur Urol 1997; 32: 32–9.
- 57 Cheng EY, Decker RS, Lee C. Role of angiotensin II in bladder smooth muscle growth and function. Adv Exp Med Biol 1999; 462: 183–91.
- 58 Phull H, Salkini M, Escobar C, et al. The role of angiotensin II in stress urinary incontinence: A rat model. Neurourol Urodyn 2007; 26: 81–8.
Citing Literature
