The Dependence of Urinary Bladder Responses on Extracellular Calcium Varies Between Muscarinic, Histamine, 5-HT (Serotonin), Neurokinin, Prostaglandin, and Angiotensin Receptor Activation (original) (raw)
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Multiple sources of calcium for contraction of the human urinary bladder muscle
British Journal of Pharmacology, 1989
1 KC1, carbachol, neurokinin A and endothelin produced concentration-dependent contractions of mucosa-free muscle strips from the dome of the human urinary bladder. The maximal response to carbachol or neurokinin A exceeded that to KCI, while the maximal response to endothelin approached that to KCI. 2 Nifedipine (1 gM) abolished the response to KCI, reduced the response to carbachol or neurokinin A but had no effect on the response to endothelin. Bay K 8644 (1 gM) markedly potentiated the response to KCl but had little or no effect on the response produced by the other stimulants. 3 Superfusion of the strips with a nominally calcium (Ca)-free medium containing EDTA (1 mM) for 30min markedly reduced the response to carbachol, neurokinin A and endothelin, although a small response was still evident at high concentrations. Likewise, after a prolonged (60min) superfusion of the strips with a high K (80mM) Ca-free medium plus EDTA (1 mM) these three agonists still produced a small contractile response. 4 The nifedipine (1 gM) resistant response to carbachol, neurokinin A or endothelin was markedly depressed by LaCl3 (1 mM). In contrast, the nifedipine-(1 gM) resistant response to carbachol was not modified by NiCl2 (0.1 mM) or co-conotoxin (0.1 Mm). 5 Caffeine produced divergent effects depending upon the temperature of incubation: a relaxation at 370C-and a concentration-dependent (2.5-20mM) contraction at 250C. The latter was markedly inhibited by procaine (3mM) but unaffected by nifedipine (1 gM). 6 After a prolonged (60 min) superfusion with a high K, Ca-free medium containing EDTA the response to carbachol (100 Mm) was abolished by previous exposure to procaine (3mM). Conversely, the response to endothelin (1 MM) was unaffected by procaine. The response to endothelin in these experimental conditions was also resistant to LaCl3 (1 mM). 7 These findings indicate that multiple sources of Ca age mobilized for contraction of the human bladder muscle by different stimulants. Dihydropyridine-and voltage-sensitive Ca channels provide the major if not the sole source of Ca for the response to KCI, play some role in the response to muscarinic (carbachol) or NK-2 tachykinin receptor stimulation but are not involved in the response to endothelin. Carbachol, neurokinin A and endothelin all mobilize a Ca pool (either extracellular or located at membrane level) which is LaCl3-sensitive but nifedipine-resistant. Neither T-nor N-type channels appear to be involved in the response to carbachol. In addition, these agents mobilize a tightly bound Ca pool independently from membrane depolarization. This latter pool is probably a procaine-sensitive intracellular source of activator Ca mobilized by caffeine and carbachol. The failure of procaine to prevent the response to endothelin in high K, Ca-free medium raises the possibility that this peptide mobilizes an intracellular source of activator Ca, distinct from the caffeine-and carbachol-sensitive pool. Introduction Much evidence indicates that smooth muscles have lized for contraction (Somlyo & Somlyo, 1968; multiple sources of calcium ions (Ca) which are uti
Calcium Regulation of Urinary Bladder Function
The Journal of Urology, 1997
Purpose: To investigate the effect of independently inhibiting calcium influx from extracellular sources and calcium release from intracellular stores on the ability of the urinary bladder to generate pressure and empty.
Receptor Operated Intracellular Calcium Stores in the Smooth Muscle of the Guinea Pig Bladder
Journal of Urology, 1985
Study of the in vitro behavior of strips of guinea pig bladder and taenia coli demonstrated that: 1. Both bladder and taenia temporarily retain their ability to contract in Ca-free solutions, but the magnitude of this response decays with time. 2. Carbachol is capable of producing contraction in Ca-free solution for a longer period of time than K depolarisation. 3. Once lost, the ability of carbachol (but not K) to contract the tissues in Ca-free solution can be temporarily restored by a brief application of high Ca. 4. The size of the carbachol contraction in Ca-free solution is reduced in Na-free solution, suggesting that membrane-bound Ca may not play a major role in this response. 5. In depolarised bladder exposed to nifedipine 2xl0-7 M, carbachol can only elicit 1 large contraction, suggesting depletion of an intracellular source. 6. It is concluded that whereas the response of the bladder to depolarisation depends primarily on extracellular Ca, the response to carbachol may also involve release of stored Ca and that the bladder, like other smooth muscles, appears to contain agonist-releasable intracellular Ca stores. Although it is widely recognized that most mammalian detrusor muscle is heavily invested with homogeneously distributed muscarinic and region-specific adrenergic receptors, 1-3 little is known about how these receptors make free intracellular calcium available to the contractile apparatus of the bladder muscle. Indeed, these mechanisms are currently under much investigation in other smooth muscles and have been the subject of extensive reviews. 4 • 5 It is generally accepted that smooth muscle contraction occurs because of an increase in free cytoplasmic Ca. 6 • 7 Since depolarisation also results in smooth muscle contraction, it was initially felt that agonists produced contraction by depolarising the cell membrane, leading to Ca entry through voltage-sensitive Ca channels. It was then noted, however, that depolarised smooth muscles could contract further in response to agonists, 8 • 9 suggesting that there might also be voltage-independent mechanisms for activating contraction. These observations were further supported by the findings that some other smooth muscles could contract without any changes in membrane potential, 10 and still others, such as the rabbit superior mesenteric artery, could hyperpolarise during contraction.11 Further studies in Ca-free solution then revealed that the contractile response to agonists was lost only gradually, and with great differences among various smooth muscles with respect to speeds of loss and response to different agonists. These studies led to the concept of an intracellular source of Ca for contraction in addition to that provided by the extracellular medium. Such intracellular stores have been most extensively studied in vascular smooth muscle. 12-14 Recently the intracellular store of the guinea pig taenia coli has been characterized and discussed as one of several possible sources of Ca for the activation of the contractile apparatus of this tissue. 15 • 16 The following experiments were undertaken to investigate whether a similar store might be present in the smooth muscle of the guinea pig bladder. MATERIALS AND METHODS Male albino guinea pigs weighing 200 to 400 gm. were stunned and bled and the bladder and taenia coli removed and placed
Involvement of calcium regulating ion channels in contractility of human isolated urinary bladder
General physiology and biophysics, 2018
This study specified the role of several key calcium-operating ion channels in contraction/ relaxation of human detrusor muscle as possible target for overactive bladder (OAB) treatment. Detrusor samples, obtained from 18 males (average age 61.5 ± 5.9 years), were investigated by organ tissue bath method with following agents: diltiazem for L-type voltage-gated calcium channels; 3-fluropyridine-4-carboxylic acid (FPCA) for Orai-STIM channels; SKF 96365-hydrochloride for transient receptor potential (TRP) channels, T-type channels and Orai-STIM channels; 2-aminoethoxydiphenyl borate (2-APB) for inositol-triphosphate receptors (IP 3 Rs) and Orai-STIM channels. Oxybutynin and mirabegron were tested under the same conditions as controls. Mirabegron, 2-APB and FPCA exhibited the best suppressive effect on carbachol-induced detrusor contractility. As expressed by area under the contractile curve (AUCC), 2-APB, FPCA and mirabegron have similar AUCC: 1.79, 1.73, 1.73. The highest AUCC was 3.64 for diltiazem+SKF, followed by 3.21 for diltiazem, 3.16 for SKF and 2.94 for oxybutynin. The lowest median amplitude and contraction variability is for 2-APB followed by mirabegron and FPCA. There were significant differences between: 2-APB/FPCA vs.: ditiazem, diltiazem+SKF and SKF. Summary of results suggested the principal role of IP 3 Rs, Orai-STIM coupling and large-conductance calcium-activated potassium channels in detrusor contraction and pointed on Orai-STIM channels as possible targets for OAB pharmacotherapy.
Contractile Activity of the Bladder Urothelium and Lamina Propria
2012
The normal function of the urinary bladder is to store and void urine in a controlled manner. During the filling stage the bladder exhibits spontaneous non-voiding contractions yet the mechanisms underlying these contractions are unclear. The internal lining of the bladder (urothelium/lamina propria) is an important regulator of bladder function by its involvement in sensory mechanisms and via releasing chemical mediators. In addition, the urothelium/lamina propria also exhibits spontaneous contractions which are mediated by unknown mechanisms. This activity may influence contractions of the bladder and play an important role in bladder function. The present study aimed to investigate the spontaneous contractions of the urothelium/lamina propria to identify receptors which modulate the activity.
Ca2+ mobilization in cultured human bladder smooth muscle cells in response to hypotonic stimuli
Experimental Physiology
The effects of hypotonic solutions on intracellular Ca2" were determined on primary cultures of human detrusor smooth muscle cells. In the presence of external Ca2 , changing from a solution containing 290 mosmol 1' to one containing 240 mosmol 1F1 (80 % normal tonicity) activated a rise in intracellular Ca2 . If the exposure to 240 mosmol 1-l was followed by exposure to 150 mosmol 1F (50 % normal tonicity) a further increase in Ca2' was noted. Exposure to hypotonic solutions which contained nominally zero Ca2+ also resulted in a rise in intracellular Ca2 , suggesting that mechanical perturbation of the surface membrane can mobilize Ca2' directly from intracellular stores. Stimulation of cells with a brief exposure to agonist (histamine, 5 /LM) in the nominal absence of external Ca21 produced a release of Ca2+ from intracellular stores. Under these conditions the response to a subsequent hypotonic stimulation was small or absent. These observations suggest that hypotonic stress induces a mobilization of Ca2+ from the same store as that activated by agonist. Detailed analysis of data from individual bladders revealed that there were significant differences between cells cultured from normal bladders and those from bladders with detrusor instability. On exposure to 240 mosmol 1F1 cells from unstable bladders gave larger responses than cells from normal bladders. However, exposure of cells from unstable bladders to a subsequent stimulus of 150 mosmol 1-' resulted in a smaller rise in Ca2+ than was observed with normal cells.
British Journal of Pharmacology, 2005
The functional effects of NS1608 ((N-(3-(trifluoromethyl)phenyl)-N 0-(2-hydroxy-5-chlorophenyl)urea), an opener of the large conductance, Ca 2 þ-activated K þ (BK Ca) channel, on the contractility of guinea-pig urinary bladder muscle are described. 2 NS1608 (0.3-30 mM) had no significant effect on the integrated myogenic activity (tension integral) or the electrically evoked twitches of detrusor muscle strips. Possible mechanisms for the discrepancy between the lack of functional effects of NS1608 per se on detrusor contractility and this drug's agonistic effect on BK Ca currents in isolated bladder myocytes are discussed. 3 4-Aminopyridine (1 mM), a blocker of voltage-gated K þ (K V) channels, increased the tension integral 2.7-fold, on average. NS1608 (30 mM) counteracted this effect. 4 Apamin (100 nM), a selective blocker of the small conductance, Ca 2 þ-activated K þ (SK Ca) channel, increased the tension integral 1.7-fold, on average. This effect was reversed by NS1608 (30 mM). 5 Ryanodine (10 mM), a modulator of the sarcoplasmic reticulum (SR) Ca 2 þ-release channel, increased the tension integral 1.9-fold, on average. This effect was reversed by NS1608 (30 mM). 6 Iberiotoxin (IbTX, 50 nM), a selective blocker of the BK Ca channel, caused additional increases in the tension integral of detrusor strips pretreated with apamin or ryanodine and prevented the inhibitory effects of NS1608 (30 mM) in detrusor contractility. 7 The present study shows that blockade of repolarizing currents carried by, respectively apaminand 4-aminopyridine-sensitive K þ channels unmasks an activation of BK Ca in guinea-pig urinary bladder smooth muscle strips.