Abstract
β-Adrenoceptors mediate urinary bladder relaxation, and gender, age and hypertension have been linked to bladder dysfunction. Therefore, we have studied whether any of these factors affects the ability of β-adrenoceptor agonists to relax rat bladder detrusor muscle in vitro. For this purpose we have compared male and female Wistar rats, young and old male Wistar rats, and male normotensive and spontaneously hypertensive rats (SHR). Comparisons were done using KCl-precontracted bladder strips (length about 15–20 mm) and the endogenous agonist noradrenaline, the synthetic non-subtype-selective agonist isoprenaline, and the prototypical β3-adrenoceptor agonists BRL 37,344 and CGP 12,177. While all agonists yielded numerically weaker relaxation in female as compared to male rats (for example for noradrenaline Emax 40±4% vs 53±6% relaxation, pEC50 5.41±0.13 vs 5.60±0.14), this difference reached statistical significance only for the weak partial agonist CGP 12,177. Responses to all agonists were attenuated in old as compared to young rats, largely due to a reduced maximum effect, although the difference did not reach statistical significance for isoprenaline. The maximum relaxation responses to noradrenaline and isoprenaline were significantly lower in SHR than in normotensive rats, but both strains exhibited similar responses to the partial agonist BRL 37,344. We conclude that factors associated with bladder dysfunction, such as gender, age and hypertension, can be associated with impaired β-adrenoceptor-mediated bladder relaxation. However, these alterations are not always consistent across various agonists, and the extent of the differences can be small. Therefore, we propose that β-adrenoceptor dysfunction may contribute to the pathophysiology of such conditions, but is unlikely to be the only or even the major factor in this regard. We speculate that β-adrenoceptor agonists may be effective in the treatment of bladder dysfunction under all of these conditions.
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References
Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, Van KP, Victor A, Wein A (2002) The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 21:167–178
Afiatpour P, Latifpour J, Takahashi W, Yono M, Foster HE, Jr., Ikeda K, Pouresmail M, Weiss RM (2003) Developmental changes in the functional, biochemical and molecular properties of rat bladder endothelin receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 367:462–472
Andersson KE, Arner A (2004) Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev 84:935–986
Baker JG (2005) The selectivity of β-adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors. Br J Pharmacol 144:317–322
Brodde OE, Michel MC (1992) Adrenergic receptors and their signal transduction mechanisms in hypertension. J Hypertens Suppl 10:S133–S145
Brodde OE, Zerkowski HR, Schranz D, Broede-Sitz A, Michel-Reher M, Schafer-Beisenbusch E, Piotrowski JA, Oelert H (1995) Age-dependent changes in the β-adrenoceptor-G-protein(s)-adenylyl cyclase system in human right atrium. J Cardiovasc Pharmacol 26:20–26
Clemow DB, McCarty R, Steers WD, Tuttle JB (1997) Efferent and afferent neuronal hypertrophy associated with micturition pathways in spontaneously hypertensive rats. Neurourol Urodyn 16:293–303
Curran PK, Fishman PH (1996) Endogenous β3- but not β1-adrenergic receptors are resistant to agonist-mediated regulation in human SK-N-MC neurotumor cells. Cell Signal 8:355–364
Derweesh IH, Wheeler MA, Weiss RM (2000) Alterations in G-proteins and β-adrenergic responsive adenylyl cyclase in rat urinary bladder during aging. J Pharmacol Exp Ther 294:969–974
Engstrom T, Bratholm P, Vilhardt H, Christensen NJ (1997) Effect of pregnancy on rat myometrial beta 2-adrenoceptor mRNA and isoproterenol-induced relaxation of isolated uterine strips. J Endocrinol 153:393–399
Feldman RD (1990) Defective venous beta-adrenergic response in borderline hypertensive subjects is corrected by a low sodium diet. J Clin Invest 85:647–652
Fraeyman N, Van de Velde E, Van Ermen A, Bazan A, Vanderheyden P, Van EJ, Vandekerckhove J (2000) Effect of maturation and aging on beta-adrenergic signal transduction in rat kidney and liver. Biochem Pharmacol 60:1787–1795
Frazier EP, Matthy MJ, Peters SL, Michel M (2005) Does cyclic AMP mediate rat urinary bladder relaxation by isoproterenol? J Pharmacol Exp Ther 313:260–267
Fujimura T, Tamura K, Tsutsumi T, Yamamoto T, Nakamura K, Koibuchi Y, Kobayashi M, Yamaguchi O (1999) Expression and possible functional role of the β3-adrenoceptor in human and rat detrusor muscle. J Urol 161:680–685
Goepel M, Hoffmann JA, Piro M, Rubben H, Michel MC (2002) Prevalence and physician awareness of symptoms of urinary bladder dysfunction. Eur Urol 41:234–239
Hoffmann C, Leitz MR, Oberdorf-Maass S, Lohse MJ, Klotz KN (2004) Comparative pharmacology of human β-adrenergic receptor subtypes-characterization of stably transfected receptors in CHO cells. Naunyn-Schmiedeberg’s Arch Pharmacol 369:151–159
Joseph SS, Colledge WH, Kaumann AJ (2004a) Aspartate138 is required for the high-affinity ligand binding site but not for the low-affinity binding site of the β1-adrenoceptor. Naunyn-Schmiedeberg′s Arch Pharmacol 370:223–226
Joseph SS, Lynham JA, Colledge WH, Kaumann AJ (2004b) Binding of (-)-[3H]-CGP12177 at two sites in recombinant human β1-adrenoceptors and interaction with β-blockers. Naunyn-Schmiedeberg’s Arch Pharmacol 369:525–532
Kahonen M, Tolvanen JP, Sallinen K, Wu X, Porsti I (1998) Influence of gender on control of arterial tone in experimental hypertension. Am J Physiol 275:H15–H22
Kolta MG, Wallace LJ, Gerald MC (1984) Age-related changes in sensitivity of rat urinary bladder to autonomic agents. Mech Aging Dev 27:183–188
Kories C, Czyborra C, Fetscher C, Schneider T, Krege S, Michel MC (2003) Gender comparison of muscarinic receptor expression and function in rat and human urinary bladder: differential regulation of M2 and M3 receptors? Naunyn-Schmiedeberg’s Arch Pharmacol 367:524–531
Kubota Y, Nakahara T, Yunoki M, Mitani A, Maruko T, Sakamoto K, Ishii K (2002) Inhibitory mechanism of BRL37344 on muscarinic receptor-mediated contractions of the rat urinary bladder smooth muscle. Naunyn-Schmiedeberg’s Arch Pharmacol 366:198–203
Latifpour J, Kondo S, O′Hollaren B, Morita T, Weiss RM (1990) Autonomic receptors in urinary tract: sex and age differences. J Pharmacol Exp Ther 253:661–667
Leblais V, Pourageaud F, Ivorra MD, Marthan R, Muller B (2005) Comparison of the α-adrenoceptor-mediated effects of β3-adrenoceptor ligands in rat pulmonary artery. Naunyn-Schmiedeberg’s Arch Pharmacol 371:535–539
Li G, Zheng XH, Li K, Li ZH, Luo XD, Liu YL, Wang P (2003) Age-dependent alternations in β-adrenoceptor function in human detrusor and possible mechanism. Zhonghua Wai Ke Za Zhi 41:526–529
Lluel P, Palea S, Barras M, Grandadam F, Heudes D, Bruneval P, Corman B, Martin DJ (2000) Functional and morphological modifications of the urinary bladder in aging female rats. Am J Physiol Regul Integr Comp Physiol 278:R964–R972
Lluel P, Deplanne V, Heudes D, Bruneval P, Palea S (2003) Age-related changes in urethrovesical coordination in male rats: relationship with bladder instability? Am J Physiol Regul Integr Comp Physiol 284:R1287–R1295
Longhurst PA, Levendusky M (1999) Pharmacological characterization of β-adrenoceptors mediating relaxation of the rat urinary bladder in vitro. Br J Pharmacol 127:1744–1750
Mallem Y, Serpillon S, Gautier F, Gogny M, Gauthier C, Desfontis JC (2002) Alteration in relaxation of atypical beta-adrenergic but not beta-3 receptors in arterial hypertension in the rat. Arch Mal Coeur Vaiss 95:647–650
Matsubara S, Okada H, Shirakawa T, Gotoh A, Kuno T, Kamidono S (2002) Estrogen levels influence beta-3-adrenoceptor-mediated relaxation of the female rat detrusor muscle. Urology 59:621–625
Michel MC, Vrydag W (2006) α1-, α2- and β-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 147(Suppl 2):S88–S119
Michel MC, Heemann U, Schumacher H, Mehlburger L, Goepel M (2004) Association of hypertension with symptoms of benign prostatic hyperplasia. J Urol 172:1390–1393
Milsom I, Abrams P, Cardozo L, Roberts RG, Thuroff J, Wein AJ (2001) How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 87:760–766
Morita T, Masuda H, Tosaka A, Ishizaka K, Tsujii T, Kondo S (1998) Sex differences in function and distribution of beta-adrenoceptors in rabbit urinary bladder. J Urol 159:555–558
Nantel F, Bonin H, Emorine LJ, Zilberfarb V, Strosberg AD, Bouvier M, Marullo S (1993) The human β3-adrenergic receptor is resistant to short term agonist-promoted desensitization. Mol Pharmacol 43:548–555
Naslund T, Silberstein DJ, Merrell WJ, Nadeau JH, Wood AJ (1990) Low sodium intake corrects abnormality in beta-receptor-mediated arterial vasodilation in patients with hypertension: correlation with beta-receptor function in vitro. Clin Pharmacol Ther 48:87–95
Nishimoto T, Latifpour J, Wheeler MA, Yoshida M, Weiss RM (1995) Age-dependent alterations in beta-adrenergic responsiveness of rat detrusor smooth muscle. J Urol 153:1701–1705
Ordway GA, Esbenshade TA, Kolta MG, Gerald MC, Wallace LJ (1986) Effect of age on cholinergic muscarinic responsiveness and receptors in the rat urinary bladder. J Urol 136:492–496
Pagala MK, Tetsoti L, Nagpal D, Wise GJ (2001) Aging effects on contractility of longitudinal and circular detrusor and trigone of rat bladder. J Urol 166:721–727
Persson K, Pandita RK, Spitsbergen JM, Steers WD, Tuttle JB, Andersson KE (1998) Spinal and peripheral mechanisms contributing to hyperactive voiding in spontaneously hypertensive rats. Am J Physiol 275:R1366–R1373
Rajasekaran M, Wilkes N, Kuntz S, Albo E (2005) Rho-kinase inhibition suppresses bladder hyperactivity in spontaneously hypertensive rats. Neurourol Urodyn 24:295–300
Schneider T, Hein P, Bai J, Michel MC (2005a) A role for muscarinic receptors or rho-kinase in hypertension associated rat bladder dysfunction? J Urol 173:2178–2181
Schneider T, Hein P, Michel-Reher MB, Michel MC (2005b) Effects of ageing on muscarinic receptor subtypes and function in rat urinary bladder. Naunyn-Schmiedeberg’s Arch Pharmacol 372:71–78
Seguchi H, Nishimura J, Zhou Y, Niiro N, Kumazawa J, Kanaide H (1998) Expression of β3-adrenoceptors in rat detrusor smooth muscle. J Urol 159:2197–2201
Spitsbergen JM, Clemow DB, McCarty R, Steers WD, Tuttle JB (1998) Neurally mediated hyperactive voiding in spontaneously hypertensive rats. Brain Res 790:151–159
Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, Hunt TL, Wein AJ (2003) Prevalence and burden of overactive bladder in the United States. World J Urol 20:327–336
Tsujimoto G, Lee CH, Hoffman BB (1986) Age-related decrease in beta adrenergic receptor-mediated vascular smooth muscle relaxation. J Pharmacol Exp Ther 239:411–415
Wallukat G (2002) The beta-adrenergic receptors. Herz 27:683–690
Watters JM (2005) Insulin responses to glucose and isoproterenol decrease with age. Can J Surg 48:110–116
Woods M, Carson N, Norton NW, Sheldon JH, Argentieri TM (2001) Efficacy of the β3-adrenergic receptor agonist CL-316243 on experimental bladder hyperreflexia and detrusor instability in the rat. J Urol 166:1142–1147
Yamazaki Y, Takeda H, Akahane M, Igawa Y, Nishizawa O, Ajisawa Y (1998) Species differences in the distribution of β-adrenoceptor subtypes in bladder smooth muscle. Br J Pharmacol 124:593–599
Acknowledgements
This work was supported in part by a grant from the Deutsche Forschungsgemeinschaft (Mi 294/7-1). TS was recipient of a training fellowship from the intramural grant program of the University of Essen Medical School (IFORES).
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Frazier, E.P., Schneider, T. & Michel, M.C. Effects of gender, age and hypertension on β-adrenergic receptor function in rat urinary bladder. Naunyn-Schmied Arch Pharmacol 373, 300–309 (2006). https://doi.org/10.1007/s00210-006-0077-y
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DOI: https://doi.org/10.1007/s00210-006-0077-y