Abstract
Spontaneous microcontractions and electrical field stimulation (EFS)-evoked contractions in isolated rat bladder strips from normal and from 6 weeks partial bladder outflow obstruction (pBOO) animals were studied to identify the potential site of action for the β3-adrenoceptor (AR) agonist mirabegron in detrusor overactivity in rats. For this, effects of the β-AR agonist isoprenaline and mirabegron were tested in presence or absence of selective antagonists for β-AR subtypes, namely CGP-20712A for β1-AR, ICI-118,551 for β2-AR, and L-748,337 for β3-AR. In detrusor strips from both normal and obstructed animals, EFS-induced contractions were weakly affected by isoprenaline and even less so by mirabegron. In contrast, microcontraction activity was more potently reduced by isoprenaline (pIC50 7.3; Emax ±85 %), whereas mirabegron showed a small effect. In pBOO strips, concentration response curves for isoprenaline and mirabegron at inhibition of EFS and spontaneous microcontractions were similar to those in normal strips. Isoprenaline-induced inhibition of microcontractions and EFS was antagonized by the β1-AR antagonist, but not by the β2- and β3-AR antagonists. In the context of β3-AR-mediated bladder functions for mirabegron in other experiments, the current data question a role for effects at spontaneous microcontractions, or neurogenic detrusor stimulation in the mode of action for mirabegron in vivo, since functional bladder effects for mirabegron are reported to occur at much lower concentrations.
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References
Andersson KE (2003) Storage and voiding symptoms: pathophysiologic aspects. Urology 62(Suppl 2):3–10
Baker JG (2005) The selectivity of β-adrenoceptor antagonists at the human β1, β2, and β3 adrenoceptors. Br J Pharmacol 144:317–322
Baker JG, Hall IP, Hill SJ (2003) Agonist actions of “β-blockers” provide evidence for two agonist activation sites or conformations of the human β1 adrenoceptor. Mol Pharmacol 63:1312–1321
Drake MJ, Harvey IJ, Gillespie JI (2003) Autonomous activity in the isolated Guinea pig bladder. Exp Physiol 88:19–30
Eastham J, Stephenson C, Gillespie JI (2015). The expression of β3 adrenoceptor and muscarinic type 3 receptor immuno-reactivity in the major pelvic ganglion of the rat and consequences for the mode of action of mirabegron.
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
Gillespie JI, Palea S, Guilloteau V, Guerard M, Lluel P, Korstanje C (2012) Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the β(3)-adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction. BJU Int 110:E132–E142
Gillespie JI, Rouget C, Palea S, Granato C, Birder L, Korstanje C (2015). The characteristics of intrinsic complex microcontractile activity in isolated strips of the rat bladder. Naunyn-Schmiedeberg’s Arch Pharmacol. doi:10.1007/s00210-015-1131-4
Granato C, Korstanje C, Guilloteau V, Rouget C, Palea S, Gillespie JI (2015). Prostaglandin E2 excitatory effects on rat urinary bladder: a comparison between the β-adrenoceptors modulation of non-voiding activity in vivo and micro-contractile activity in vitro. Naunyn-Schmiedeberg’s Arch Pharmacol. doi:10.1007/s00210-015-1139-9
Gunst SJ, Stropp JQ, Flavahan NA (1989) Muscarinic receptor reserve and β-adrenergic sensitivity in tracheal smooth muscle. J Appl Physiol 67:1294–1298
Hatanaka T, Ukai M, Watanabe M, Someya A, Ohtake A, Suzuki M, Ueshima K, Sato S, Sasamata M (2013) In vitro and in vivo pharmacological profile of the selective β3 adrenoceptor agonist mirabegron in rats. Naunyn Schmiedeberg's Arch Pharmacol 386:247–253
Levin RM, Haugaard N, Mogavero L, Leggett RE, Das A (1999) Biochemical evaluation of obstructive bladder dysfunction in men secondary to BPH: a preliminary report. Urology 53:446–450
Lluel P, Duquenne C, Martin D (1998) Experimental bladder instability following bladder outlet obstruction in the female rat. J Urol 160:2253–2257
MacKay D (1978) How should values of pA2 and affinity constants for pharmacological competitive antagonists be estimated? J Pharm Pharmacol 30:312–313
Mallem MY, Toumaniantz G, Serpillon S, Gautier F, Gogny M, Desfontis JC, Gauthier C (2004) Impairment of the low-affinity state beta1-adrenoceptor-induced relaxation in spontaneously hypertensive rats. Br J Pharmacol 143:599–605
Michel MC, Sand C (2009) Effect of pre-contraction on β-adrenoceptor-mediated relaxation of rat urinary bladder. World J Urol 27:711–715
Michel MC, Ochodnicky P, Summers RJ (2010) Tissue functions mediated by beta3-adrenoceptors -findings and challenges. Naunyn-Schmiedeberg's Arch Pharmacol 382:103--108
Naline E, Trifilieff A, Fairhurst RA, Advenier C, Molimard M (2007) Effect of indacaterol, a novel long-acting β2-agonist, on isolated human bronchi. Eur Respir J 29:575–581
Pinna C, Sanvito P, Puglisi L (2006) Altered neurogenic and mechanical responses to acetylcholine, ATP and substance P in detrusor from rats with outlet obstruction. Life Sci 79:1301–1306
Rouget C, Rekik M, Camparo P, Botto H, Rischmann P, Lluel P, Palea S, Westfall TD (2014) Modulation of nerve-evoked contractions by β3-adrenoceptor agonism in human and rat isolated urinary bladder. Pharmacol Res 80:14–20
Ruffolo Jr RR (1982) Review: important concepts of receptor theory. J Auton Pharmacol 2:277–295
Sacco E, Bientinesi R (2012) Mirabegron: a review of recent data and its prospects in the management of overactive bladder. Ther Adv Urol 6:315–324
Sadananda P, Drake MJ, Paton JFR, Pickering AE (2013) A functional analysis of the influence of β3-adrenoceptors on the rat micturition cycle. J Pharmacol Exp Ther 347:506–515
Sibley GNA (1997) Developments in our understanding of detrusor instability. Br J Urol 80(Suppl 1):54–61
Takasu T, Ukai M, Sato S, Matsui T, Nagase I, Maruyama T, Sasamata M, Miyata K, Uchida H, Yamaguchi O (2007) Effect of (R)-2-(2-aminothiazol-4-yl)-4′-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther 321:642–647
Takeda M, Obara K, Mizusawa T, Tomita Y, Arai K, Tsutsui T, Hatano A, Takahashi K, Nomura S (1999) Evidenxe for beta3-adrenoceptor subtypes in relaxation of the human urinary bladder detrusor: analysis by molecular biological and pharmacological methods. J Pharmacol Exp Ther 288:1367--1373
Van Wieringen JP, Michel-Reher MB, Hatanaka T, Ueshima K, Michel MC (2013) The new radioligand [3H]-L 748,337 differentially labels human and rat β3-adrenoceptors. Eur J Pharmacol 720:124–130
Watanabe H, Yamamoto TY (1979) Autonomic innervations of the muscles in the wall of the bladder and proximal urethra of male rats. J Anat 128:873–886
Woods M, Carson N, Norton NW, Sheldon JH, Argentieri TM (2001). Efficacy of the β3-adrenoceptor agonist CL-316243 at experimental bladder hyperreflexia and detrusor instability in the rat. J Urol 166: 1142-1147.
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Gillespie, J..., Rouget, C., Palea, S. et al. Beta adrenergic modulation of spontaneous microcontractions and electrical field-stimulated contractions in isolated strips of rat urinary bladder from normal animals and animals with partial bladder outflow obstruction. Naunyn-Schmiedeberg's Arch Pharmacol 388, 719–726 (2015). https://doi.org/10.1007/s00210-015-1136-z
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DOI: https://doi.org/10.1007/s00210-015-1136-z