Contractile behaviour of the urinary bladder and its sympathetic inhibition during storage phases are not well understood. Here, we explore muscularis mucosae (MM) as a predominant mucosal contractile element and the capability of sympathetic nerves to relax detrusor smooth muscle (DSM) or MM. Distribution of α-smooth muscle actin (α-SMA)-immunoreactive cells was compared in pig, human, guinea pig, rat and mouse bladders by immunohistochemistry, while contractility of the bladder mucosa was compared in these species by isometric tension recordings. In pig, human and guinea pig bladders, DSM and MM located in the lamina propria expressed α-SMA immunoreactivity, while both rat and mouse bladders lacked a MM. Consistent with this presence or absence of MM, bladder mucosa of pig, human and guinea pig but not rat and mouse developed spontaneous phasic contractions (SPCs). Distribution of tyrosine hydroxylase (TH)-immunoreactive sympathetic nerve fibres was compared in pig DSM, MM, trigone and urethra, as were their sympathetic nerve-evoked contractile/relaxing responses examined. In pig DSM or MM, where TH-immunoreactive sympathetic fibres exclusively projected to the vasculature, sympathetic relaxations were difficult to demonstrate. In contrast, sympathetic contractions were invariably evoked in pig trigone and urethra where the smooth muscle cells receive TH-immunoreactive sympathetic innervations. Thus, SPCs of bladder mucosa appear to predominantly arise from the MM displaying species differences. Despite the currently accepted concept of sympathetic nerve-mediated DSM relaxation during the storage phase, it is unlikely that neurally released noradrenaline acts on β-adrenoceptors to relax either DSM or MM due to the anatomical lack of sympathetic innervation.
This is a preview of subscription content, log in to check access.
The authors wish to thank Dr. Richard Lang (Monash University) for his critical reading of the manuscript and are also grateful to Drs Akito Yamaguchi and Shinji Kono (Harasanshin Hospital) for providing human bladder specimens.
The present study was partly supported by Grant-in-Aid for Young Scientists (B) (No. 16K19361) from Japan Society for Promotion of the Science (JSPS) to R.M. and Grant-in-Aid for Scientific Research (C) (No. 17K11187) from JSPS to H.H.
Compliance with ethical statements
Conflict of interest
The authors declare that there is no conflict of interest.
The experimental protocols used in the present study were approved by the animal experimentation ethics committee at Nagoya City University Graduate School of Medical Sciences (No. H-28M-07) and the Ethics Committees of the Graduate School of Medical Sciences, Kyushu University and Harasanshin Hospital (No. 28-54). All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments.
All subjects gave written informed consent.
Alm P, Elmér M (1975) Adrenergic and cholinergic innervation of the rat urinary bladder. Acta Physiol Scand 94:36–45PubMedGoogle Scholar
Andersson KE, Mattiasson A, Sjögren C (1983) Electrically induced relaxation of the noradrenaline contracted isolated urethra from rabbit and man. J Urol 129:210–214PubMedGoogle Scholar
Andersson KE, Boedtkjer DB, Forman A (2017) The link between vascular dysfunction, bladder ischemia, and aging bladder dysfunction. Ther Adv Urol 9:11–27PubMedGoogle Scholar
Andersson KE, Choudhury N, Cornu JN, Huang M, Korstanje C, Siddiqui E, Van Kerrebroeck P (2018) The efficacy of mirabegron in the treatment of urgency and the potential utility of combination therapy. Ther Adv Urol 10:243–256PubMedPubMedCentralGoogle Scholar
Brading AF (2006) Spontaneous activity of lower urinary tract smooth muscles: correlation between ion channels and tissue function. J Physiol 570:13–22PubMedPubMedCentralGoogle Scholar
De Groat WC, Saum WR (1972) Sympathetic inhibition of the urinary bladder and of pelvic ganglionic transmission in the cat. J Physiol 220:297–314PubMedPubMedCentralGoogle Scholar
De Groat WC, Theobald RJ (1976) Reflex activation of sympathetic pathways to vesical smooth muscle and parasympathetic ganglia by electrical stimulation of vesical afferents. J Physiol 259:223–237PubMedPubMedCentralGoogle Scholar
Gabella G, Uvelius B (1990) Urinary bladder of rat: fine structure of normal and hypertrophic musculature. Cell Tissue Res 262:67–79PubMedGoogle Scholar
Gevaert T, Vanstreels E, Daelemans D, Franken J, Van Der Aa F, Roskams T, De Ridder D (2014) Identification of different phenotypes of interstitial cells in the upper and deep lamina propria of the human bladder dome. J Urol 19:1555–1563Google Scholar
Gosling JA, Dixon JS, Jen PY (1999) The distribution of noradrenergic nerves in the human lower urinary tract. A review Eur Urol 36(Suppl 1):23–30PubMedGoogle Scholar
Gosling JA, Dixon JS, Lendon RG (1977) The autonomic innervation of the human male and female bladder neck and proximal urethra. J Urol 118:302–305PubMedGoogle Scholar
Heppner TJ, Hennig GW, Nelson MT, Vizzard MA (2017) Rhythmic calcium events in the lamina propria network of the urinary bladder of rat pups. Front Syst Neurosci 11(87):1–16Google Scholar
Heppner TJ, Layne JJ, Pearson JM, Sarkissian H, Nelson MT (2011) Unique properties of muscularis mucosae smooth muscle in guinea pig urinary bladder. Am J Phys Regul Integr Comp Phys 301:R351–3R62Google Scholar
Heppner TJ, Tykocki NR, Hill-Eubanks D, Nelson MT (2016) Transient contractions of urinary bladder smooth muscle are drivers of afferent nerve activity during filling. J Gen Physiol 147:323–335PubMedPubMedCentralGoogle Scholar
Ikeda Y, Fry C, Hayashi F, Stolz D, Griffiths D, Kanai A (2007) Role of gap junctions in spontaneous activity of the rat bladder. Am J Physiol Ren Physiol 293:F1018–F1025Google Scholar
Isogai A, Lee K, Mitsui R, Hashitani H (2016) Functional coupling of TRPV4 channels and BK channels in regulating spontaneous contractions of the guinea pig urinary bladder. Pflugers Arch 468:1573–1585PubMedGoogle Scholar
Klarskov P (1987) Non-cholinergic, non-adrenergic nerve-mediated relaxation of pig and human detrusor muscle in vitro. Br J Urol 59:414–419PubMedGoogle Scholar
Klarskov P, Gerstenberg TC, Ramirez D, Hald T (1983) Non-cholinergic, non-adrenergic nerve mediated relaxation of trigone, bladder neck and urethral smooth muscle in vitro. J Urol 129:848–850PubMedGoogle Scholar
Kushida N, Fry CH (2016) On the origin of spontaneous activity in the bladder. BJU Int 17:982–992Google Scholar
Larsen JJ, Nordling J, Christensen B (1978) Sympathetic innervation of the urinary bladder and urethral muscle in the pig. Acta Physiol Scand 104:485–490PubMedGoogle Scholar
Lee K, Isogai A, Antoh M, Kajioka S, Eto M, Hashitani H (2018) Role of K+ channels in regulating spontaneous activity in the muscularis mucosae of guinea pig bladder. Eur J Pharmacol 818:30–37PubMedGoogle Scholar
Lee K, Mitsui R, Kajioka S, Naito S, Hashitani H (2016) Role of PTHrP and sensory nerve peptides in regulating contractility of muscularis mucosae and detrusor smooth muscle in the guinea pig bladder. J Urol 196:1287–1294PubMedGoogle Scholar
McCarthy CJ, Zabbarova IV, Brumovsky PR, Roppolo JR, Gebhart GF, Kanai AJ (2009) Spontaneous contractions evoke afferent nerve firing in mouse bladders with detrusor overactivity. J Urol 181:1459–1466PubMedPubMedCentralGoogle Scholar
Mitsui R, Hashitani H (2013) Immunohistochemical characteristics of suburothelial microvasculature in the mouse bladder. Histochem Cell Biol 140:189–200PubMedGoogle Scholar
Moro C, Chess-Williams R (2012) Non-adrenergic, non-cholinergic, non-purinergic contractions of the urothelium/lamina propria of the pig bladder. Auton Autacoid Pharmacol 32:53–59PubMedGoogle Scholar
Moro C, Leeds C, Chess-Williams R (2012) Contractile activity of the bladder urothelium/lamina propria and its regulation by nitric oxide. Eur J Pharmacol 674:445–449PubMedGoogle Scholar
Moro C, Tajouri L, Chess-Williams R (2013) Adrenoceptor function and expression in bladder urothelium and lamina propria. Urology 81:211.e1-7PubMedGoogle Scholar
Moro C, Uchiyama J, Chess-Williams R (2011) Urothelial/lamina propria spontaneous activity and the role of M3 muscarinic receptors in mediating rate responses to stretch and carbachol. Urology 78:1442.e9–1442.15Google Scholar
Ro JY, Ayala AG, El-Naggar A (1987) Muscularis mucosa of urinary bladder. Importance for staging and treatment. Am J Surg Pathol 11:668–673PubMedGoogle Scholar
Robertson AS (1999) Behaviour of the human bladder during natural filling: the Newcastle experience of ambulatory monitoring and conventional artificial filling cystometry. Scand J Urol Nephrol Suppl 201:19–24PubMedGoogle Scholar
Sadananda P, Chess-Williams R, Burcher E (2008) Contractile properties of the pig bladder mucosa in response to neurokinin A: a role for myofibroblasts. Br J Pharmacol 153:1465–1473PubMedPubMedCentralGoogle Scholar
Shimizu Y, Mochizuki S, Mitsui R, Hashitani H (2014) Neurohumoral regulation of spontaneous constrictions in suburothelial venules of the rat urinary bladder. Vasc Pharmacol 60:84–94Google Scholar
Sibley GNA (1984) Comparison of spontaneous and nerve-mediated activity in bladder muscle from man, pig and rabbit. J Physiol 354:431–443PubMedPubMedCentralGoogle Scholar
Speakman MJ, Walmsley D, Brading AF (1988) An in vitro pharmacological study of the human trigone--a site of non-adrenergic, non-cholinergic neurotransmission. Br J Urol 61:304–309PubMedGoogle Scholar
Sui G, Fry CH, Montgomery B, Roberts M, Wu R, Wu C (2014) Purinergic and muscarinic modulation of ATP release from the urothelium and its paracrine actions. Am J Physiol Ren Physiol 306:F286–F298Google Scholar
Vahabi B, Drake MJ (2015) Physiological and pathophysiological implications of micromotion activity in urinary bladder function. Acta Physiol (Oxford) 213:360–370Google Scholar
Vahabi B, Sellers DJ, Bijos DA, Drake MJ (2013) Phasic contractions in urinary bladder from juvenile versus adult pigs. PLoS One 8:e58611PubMedPubMedCentralGoogle Scholar
Wakabayashi Y, Makiura Y, Tomoyoshi T, Kitahama K, Maeda T (1993) Immuno-electron microscopic study of tyrosine hydroxylase in the cat urinary bladder and proximal urethra. J Auton Nerv Syst 44:243–252PubMedGoogle Scholar