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NEUROPHARMACOLOGY
The Oxford Continence Group, Department of Pharmacology, University of Oxford, Oxford, United Kingdom
Received June 2, 2006; accepted August 28, 2006.
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Abstract |
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,
,methyleneATP. The isolated mouse whole bladder has proved a viable, robust model in which to demonstrate the pharmacological characteristic of the bladder and adds to the repertoire of in vitro tools for investigating potential therapeutic agents.
). The muscle bundles are not arranged in a definite pattern but form an interlacing network in which bundles freely criss-crosses one another (Dixon and Gosling, 1987). It is this unique characteristic arrangement that underlies the mechanics of bladder function conferring the detrusor smooth muscle the ability to simultaneously contract in a multidimensional fashion allowing the bladder transition between detrusor stretching (isovolumetric) that occurs during continence and contraction required for urine expulsion (Damaser, 1999).
Clinically, bladder function is evaluated through biomechanical characteristics such as pressure, volume, and urine flow rate (Damaser, 1999). For any in vitro model to be clinically relevant, it is imperative that these factors be taken into consideration during model development. Much of the knowledge of urinary bladder function comes from in vitro muscle strips studies, which have a functional utility limited by the fact that strip contraction can only be recorded in one plane; results do not reflect the potentially complex interactions that underlie the pressure-volume relationship of the intact bladder (Levin et al., 1983; Levin et al., 2000). The isolated mouse whole bladder, although technically challenging, offers more physiological relevance since it contains all the elements, including intramural ganglia and measurement of function is possible in terms of volume-pressure relationships. In addition, the availability of transgenic and gene knockout animals (Bishop, 1999) makes a mouse model very attractive for biomedical research.
In this study, we have employed the whole bladder to investigate the underlying cause of overactive bladder secondary to chronic inflammatory conditions such as hemorrhagic cystitis or interstitial cystitis. One of the contributing factors to these conditions is a functional change in the primary afferents brought about by the sensitization of both mechanosensitive and C-fibers afferents by potent inflammatory mediators such as bradykinin (Marceau et al., 1980; Maggi et al., 1989).
Evidence has linked the activity of bradykinin to efferent purinergic neurotransmission in rat isolated muscle strips (Acevedo et al., 1990; Patra and Westfall, 1996). The goals of this study were to validate the isolated mouse bladder model, to elicit neuronal hyperactivity with bradykinin (as the noxious stimulus), and to shed light on any functional relationship between bradykinin and P2X receptor subtypes in this preparation. An account of the findings has been presented previously to Urological Research Society annual meeting (Fabiyi and Brading, 2005).
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Materials and Methods |
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Muscle strips were prepared with the aid of dissecting microscope, the bladder was pinned down at the apex of the dome, connective tissue was then removed, and the bladder was split open along the ventral surface to expose the urothelium, which was then carefully peeled off from the muscle layer and discarded. The tissue was cut longitudinally into strips of approximately 5 x 1 mm. Each strip was then mounted vertically in a 0.2 ml-capacity, a superfusion organ bath between two recessed platinum electrodes through which electrical field stimulation (EFS) was delivered (for description of apparatus, see Brading and Sibley, 1982). The strips were constantly superfused with Krebs' solution (37°C) at a rate of 1 ml/min. A stretch equivalent to 1g force was applied, and tissues were equilibrated for at least 60 min before starting a procedure. Drugs were delivered by substituting drug containing solutions of the desired concentration for Krebs' solutions. Electrical field stimulation was delivered by a Grass S48 stimulator (Grass Instruments, Quincy, MA) at parameters of 0.05-ms pulse width (PW), 3-s train duration (TD), and 50 V at varying frequency. Isometric tension generated by the strips was measured using isometric force displacement transducers, Pioden Dynamometer UFI transducers (Pioden Controls Ltd., Canterbury, Kent, UK), or AD Instruments MLT050/D force transducers, amplified (Harvard Transducer/Amplifier; Harvard Apparatus Ltd., Edenbridge, Kent, UK) and analyzed using MacLab Data Acquisition system (AD Instruments, Sydney, Australia) or AD Instruments OCTAL Bridge Amplifier connected to Power Lab/8SP (AD Instruments) and Chart version 3.6 software (Macintosh) or Chart version 5 (PC).
Dose-response curves for carbachol (CCh; 0.1 µM –0.3 mM) were constructed by subjecting the preparations to a sequence of successive 20-s applications of increasing doses of drugs with intervening washout periods of at least 20 min. Frequency response curves were constructed in the absence and presence of either atropine (1 µM) or a cocktail of atropine and ,,methyleneATP (10 µM). Responses were also obtained in the presence of tetrodotoxin (TTX) to ensure that contractions were solely due to selective stimulation of intramural nerves and not direct smooth muscle stimulation.
For the isolated whole-bladder experiments, the ureters were ligated, and the bladder was excised at the distal urethral level. Any superfluous tissues were removed around the urethra and bladder neck. Using a silk ligature, the proximal end of the urethra was tied around a stainless steel pipe (4–5 mm long, 0.25-mm internal diameter) that was inserted into P-10 (0.28-mm internal diameter) tubing to provide a water-tight seal and prevent leakage from the bladder once filled. The pipe was sealed to the base of stainless steel J-tube (55 mm long, 0.58-mm diameter) that was clamped in place. Through the J-tube, the bladder was suspended in a 20-ml jacketed organ bath containing oxygenated Krebs' solution at 37°C and connected to a syringe pump (Harvard Apparatus Ltd.) and pressure transducer for measurement of intravesical pressure. Data were acquired and analyzed using MacLab Data Acquisition system (AD Instruments) or AD Instruments OCTAL Bridge Amplifier connected to Power Lab/8SP (AD Instruments) and Chart version 3.6 software (Macintosh) or Chart version 5 (PC).
Bladders were slowly filled with saline (0.1–0.15 ml) at the rate of 0.8 ml/h and allowed to equilibrate for 1 h. Before commencement of experiments, bladders were tested for viability by exposing them to 3 µM carbachol and, as soon as the maximal response was reached, washed for 5 min by overflow to prevent desensitization. EFS was applied through platinum plates, one on each side of the bladder. Stimulus parameters were 0.2-ms PW; 3-, 30-, or 35-s TD; 20-Hz frequency; and 50-V voltage. Intravesical pressure was measured, which reflects contraction of the detrusor. The bladder was exposed to drugs by exogenously applying the drug into the organ bath and intravesically as required. The duration of exposure of bladder to the drug depended on the protocol of the experiment as described in the legends.
Experiments were run in normal Krebs' solution with a maximal volume in the organ bath not exceeding 17 ml. Drugs were applied exogenously in the organ bath with a test volume not exceeding 0.5 ml to achieve the final concentration. Tetrodotoxin citrate from Alomone Laboratories (Jerusalem, Israel) was employed to establish the stimulation parameters at which intramural nerves were selectively stimulated. The cholinergic component was characterized by using a stable analog of acetylcholine, CCh, a nonselective muscarinic receptor antagonist, atropine, and a range of muscarinic selective antagonists including the M1-selective antagonist pirenzepine, the M2-selective antagonist AF-DX116, the M3-selective antagonist 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), and the M4-selective antagonist PD102807. The purinergic component was characterized with the aid of purinergic agonists that include ATP and the stable analog of ATP, ,,methyleneATP, which rapidly desensitized the receptors. For the characterization of bradykinin receptors, the antagonists used were desArg10 HOE 140 and HOE 140, which are selective B1 and B2 antagonists, respectively. Stock solutions were prepared in either distilled water or dimethyl sulfoxide (DMSO) and stored in aliquots at –30°C. All the above reagents were purchased from Sigma Chemical Co. (Poole, UK).
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), in which they found in a similar model that the peak contraction occurred at a volume range of between 0.1 and 0.12 ml. EFS parameters sensitive to TTX were determined as indicated in Fig. 2. From these results, parameters of 0.2-ms PW, 3-s TD, 50 V, and 20 Hz were used as standard EFS parameters in the subsequent studies. Responses were sensitive to TTX (0.3 µM).
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To establish whether the dual nature of neurotransmission seen in other mammalian bladders also applied to the mouse, the sequential effects of atropine and atropine plus ,,methyleneATP on the frequency response curves were determined, and the results compared with similar experiments on isolated muscle strips, as shown in Fig. 3. In both preparations, atropine (1 µM) inhibited the response by approximately 50%, and the additional presence of ,,methyleneATP (10 µM) greatly reduced the responses in the whole bladder and almost completely abolished them in the isolated strips. The responses produced in the presence of atropine and ,,methyleneATP appear not to differ from the response produced in the presence of TTX alone (Fig. 3). Further analysis shows that atropine insignificantly reduced responses at lower frequencies (1–5 Hz) but produced substantial reduction at frequency above 20 Hz, with maximal intravesical pressure reduction of 44% (Fig. 3a). In contrast, the desensitization of purinoceptors by ,,methyleneATP markedly reduced responses over all the frequency ranges tested with approximately 75% reduction in response observed at both 1 and 20 Hz (Fig. 3a).
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Differential Effects of Selective Muscarinic Receptor Antagonists on Mouse Whole Bladder. The purpose of these experiments was to characterize the muscarinic receptor subunits mediating direct bladder contraction and neuronally mediated bladder contraction by evaluating the effect of a range of selective antagonists (pirenzepine, AF-DX116, 4-DAMP, and PD102807) on bladder contraction to 3 µM carbachol and to electrical field stimulation (Fig. 4). The doses of pirenzepine (0.3 µM) and 4-DAMP (10 nM) tested were determined from the study of Giglio et al. (2001) on guinea pig urinary bladder strips. The dose for AF-DX116 (1 µM) was based on the work of Lagou et al. (2006). In the present study, exogenous application of carbachol elicited a robust contractile response of 29.7 ± 2.8 cm H2O. As expected, the vehicle (DMSO) had no effect (0.58 ± 5.7%); and 4-DAMP (10 nM), AF-DX116 (1 µM), and pirenzepine (0.3 µM) all significantly reduced the response by 75.7 ± 2.8, 51.09 ± 6.3, and 43.9 ± 3.8%, respectively (Fig. 4). PD102807 (1 µM) did not significantly affect the action of carbachol (6.2 ± 3.6%). Similar effects were seen on the contractile response to EFS (control, 21.6 ± 3.0 cm H2O). 4-DAMP (10 nM), pirenzepine (0.3 µM), and AF-DX116 (1 µM) all caused a significant reduction of 41.3 ± 6.7, 25.4 ± 11.2, and 21.5 ± 7.8%, respectively. PD102807 (1 µM) had no significant effect (Fig. 4).
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,,MethyleneATP-induced desensitization of P2X receptors was evoked by three consecutive additions of ,,methyleneATP at 0.01, 0.1, and 0.1 mM (Fig. 5a). The first application generated a transient increase in intravesical pressure reaching 25.1 ± 3.4 cm H2O, the second transiently increased pressure to 10.40 ± 3.40 cm H2O, and the third application only evoked a response of 1.3 ± 0.35 cm H2O, confirming almost complete desensitization of P2X receptors. Exogenous application of ATP (3 mM) before and after purinoceptor desensitization produced intravesical pressure of 15.8 ± 1.7 and 6.2 ± 1.0 cm H2O, respectively, suggesting that desensitization only partially inhibited the response to ATP (by approximately 60%; Fig. 5b).
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Interaction between Receptors. Experiments to examine the influence of bradykinin on either ATP- or CCh-induced bladder contractions showed that bradykinin did not significantly potentiate the effect of ATP (Fig. 9a), nor did it appreciably affect carbachol-induced contraction (Fig. 9b).
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These next set of experiments investigated whether atropine or ,,methyleneATP can modulate the effect of bradykinin. Treatment with atropine significantly reduced the response to EFS without affecting either the direct contractile effect of bradykinin on the bladder or the potentiation of the EFS response (Figs. 8 and 10a). In contrast, although treatment with ,,methyleneATP also reduced the bladder response to EFS, it also significantly enhanced the bradykinin-induced potentiation of EFS without affecting direct contractile effect of bradykinin (Figs. 8 and 10b).
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Discussion |
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; Brading and Williams, 1990). Validation experiments showed that external application of carbachol induced a dose-response curve that compares very well with that produced in isolated muscle strips. Five subtypes of muscarinic receptor have been identified molecularly and pharmacologically up to date and are denoted as M1 through M5 (Caulfield and Birdsall, 1998). In the human bladder, mRNA for all the receptor subtypes has been found (Sigala et al., 2002); however, only two of these subtypes, M2 and M3, are considered to have any physiological significance in micturition.
The selective muscarinic antagonists, apart from the M4-selective antagonist PD102807, tested at their optimal concentrations, reduced the contractile effects of CCh and EFS to a certain degree. However, the M3-selective antagonist 4-DAMP appeared to be the most effective. This finding supports the notion that M3 receptors are the main receptor subtype responsible for both direct (Hedge et al., 1997; Chess-Williams, 2002) and indirect (Chopping and Eglen, 2001a) bladder contractions. It has been proposed that the mechanism of action of the M2 receptor subunits is indirect through inhibition of -adrenoceptor-mediated relaxation to facilitate micturition (Hedge et al., 1997) and that the M1 receptor subtype facilitates the release of ACh in response to prolonged high-frequency nerve firing associated with voiding (Somogyi et al., 1994). Although the results of the current study are consistent with a prejunctional activity of these receptors by the virtue of their ability to modulate neuronally mediated bladder contractions, they also support some postjunctional activity since the antagonists appears to be more effective in antagonizing the contractile effect of CCh than EFS (Hedge et al., 1997). Our study also clearly shows that the M4 receptor subunit has no obvious functional role in the mouse bladder as demonstrated by the inability of its antagonist, PD102807, to modify the contractile effect of either CCh or EFS, an observation that is consistent with the findings of Choppin and Eglen (2001b).
The response to ATP suggests heterogeneous distribution of P2X receptors in the mouse bladder. This fact was substantiated by the failure of ,,methyleneATP-induced-P2X desensitization to completely abolish the contractile response to ATP. It has been shown that P2X receptor subtypes can be distinguished by ,,methyleneATP (for review, see Dunn et al., 2001). P2X1 and P2X3 receptors have high affinity for ,,methyleneATP and are desensitized rapidly; on the other hand, P2X2 and P2X2/3 receptor subtypes have low affinity for ,,methyleneATP and are slowly desensitized (for review, see Dunn et al., 2001). Thus, it is conceivable that ATP responses that are resistant to ,,methyleneATP-induced P2X desensitization were mediated by either the homomeric P2X2 or the heteromeric P2X2/3 receptor subtypes or both. This finding is particularly interesting in that it suggests a postjunctional activity for these receptors, contradicting the current view that their distribution, except for P2X1, is restricted to the intramural nerves (Cockayne et al., 2000, 2005; Vlaskovska et al., 2001; Rong et al., 2002). It is therefore possible that some of these receptors are expressed either on the urothelium or the detrusor muscle. Although it is necessary to further investigate the functional implication of these observations, it would be reasonable to speculate that if these receptors are located postjunctionally, their up-regulation could contribute to the pathogenesis of bladder dysfunction. In fact, in detrusor biopsy of patients with idiopathic detrusor instability, P2X2 mRNA was found to be significantly elevated, whereas other P2X receptor subtypes were significantly decreased. In addition, a purinergic component of nerve-mediated contractions could be found in specimens of unstable human bladders, although not in the normal controls (O'Reilly et al., 2002).
In contrast to the response to ATP, bradykinin produced a classic monophasic dose-response curve with a high potency (EC50, 90 nM). It also enhanced the response to neuronally mediated bladder contractions. These findings agree with previous evidence that bradykinin acts by sensitizing the primary afferent nerves either through release of sensory neuropeptides from nerve terminals (Marceau et al., 1980; Maggi et al., 1989) or by direct stimulation of bladder afferent nerves (Lecci et al., 1995). It is therefore reasonable to suggest that bradykinin potentiation of neuronally mediated bladder contraction seen in this model is due to the sensitization of intramural nerves and could thus mimic the pathophysiological process involved in chronic inflammation. A possible mechanism is that the activation of nociceptive nerves by bradykinin evokes the release of tachykinins from axon collaterals and in turn enhances the sensitivity of the smooth muscle to stimuli (Marceau et al., 1980).
As well as evoking excitatory responses, exogenous application of bradykinin also evoked tachyphylaxis following an initial rise in intravesical pressure. In the excitatory phase, bradykinin potentiated electrically evoked bladder contraction peaking after 5 min of continuous exposure. Previous studies have reported that the pharmacological effects of bradykinin can be attributed to two main receptors: B1 and B2 (Regoli and Barabe, 1980). The B1 receptor is thought to be stimulated by desArg9-Leu8-bradykinin, whereas the B2 receptor is stimulated by bradykinin. Bradykinin B2 receptors are constitutively expressed by various cell types (Bhoola et al., 1992), and it seems to be the predominant receptor mediating contractile responses under normal conditions (Meini et al., 2000). HOE 140 has been shown to selectively inhibit the action of bradykinin on B2 receptors in a noncompetitive manner (Wirth et al., 1991; Meini et al., 2000). On the other hand, the kinin B1 receptor is reported to be expressed de novo after inflammatory stimuli or tissue injury (Marceau et al., 1998; Belichard et al., 1999; Wotherspoon and Winter, 2000) and can be antagonized by desArg10 HOE 140, a selective B1 antagonist. Consistent with this, we found that HOE 140 (1 µM) almost completely suppressed bradykinin-induced contraction and considerably reduced bradykinin-induced potentiation of EFS-mediated bladder contraction, whereas desArg10HOE 140 (1 µM) had no significant antagonistic effect on either parameter. These findings would suggest that in the mouse whole bladder, the effects of bradykinin were mediated by the constitutively expressed B2 receptor, an observation that is in line with the proposal of Meini et al. (2000) in human and rat urinary bladder. The fact that HOE 140 also modulated direct contraction of the bladder means that B2 receptors are present on tissues other than the intramural nerves. It could be that they are also expressed in the muscle and urothelium as recently published by Chopra et al. (2005), who found B2 receptor mRNA to be constitutively expressed in the muscle and urothelium of normal rat bladders.
Because bradykinin had little effect on the bladder response to either ATP or carbachol, it is reasonable to postulate that bradykinin-induced potentiation of the response to EFS is through facilitation of parasympathetic neurotransmission. We therefore tested this hypothesis by examining the effect of bradykinin on the neurogenic response on the cholinergic and purinergic components for any differential effect. The sensitizing effect of bradykinin does not appear to be due to enhanced release of acetylcholine since atropine, although reducing the size of the response to EFS, failed to modify either the direct bradykinin-induced bladder contraction or the potentiation of intramural nerve stimulation. Similar observations were reported by Downie and Rouffignac (1981) and Nakahata et al. (1987) using rabbit detrusor strips. Therefore, it would seem that bradykinin sensitization of the neurogenic responses is mediated through purinergic transmission. Compatible with this notion, ,,methyleneATP, although it substantially reduced the size of the response to EFS, also markedly enhanced the bradykinin-induced potentiation of EFS without modifying the direct bradykinin-induced bladder contraction. Acevedo et al. (1990) and Patra and Westfall (1996), similarly observed the inhibitory effect of ,,methyleneATP on EFS in rat and guinea pig detrusor strips, respectively.
The bladder response to intramural nerve stimulation remaining after desensitization may indicate that the fraction of receptors resistant to ,,methyleneATP desensitization on the intramural nerves are likely to be responsible for the enhancement effect of bradykinin-induced potentiation of EFS. In addition, this subset of receptors may be identified as either the homomeric P2X2 or the heteromeric P2X2/3 receptors or both subtypes since P2X2 purinoceptor subtypes are known to have low affinity for ,,methyleneATP and slowly desensitize as indicated earlier (for review, see Dunn et al., 2001).
In conclusion, our results show that the mouse bladder behaves in a similar manner to other mammalian bladders, and the effects of bradykinin suggest that it possesses both pre- and postjunctional activity. Its prejunctional action is facilitated by the release of ATP from nerve terminals, and its postjunctional action is mediated by the B2 receptor. The mouse isolated whole-bladder set-up appears to be an effective functional assay to investigate the mechanisms underlying bladder pain and overactivity and therefore may serve as a powerful tool in the aid of developing therapeutic agents for the treatment of bladder dysfunction.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: EFS, electrical field stimulation; PW, pulse width; TD, train duration; CCh, carbachol; TTX, tetrodotoxin; pirenzepine, 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H pyrido[2,3-b] [1,4] benzodiacepin-6-one dihydrochloride; AF-DX116, 11–2[([(diethylamino) methyl]-1-piperidinyl)-acetyl]-5,11-dihydro-6Hpyrido(2,3b)(1,4)benzodiazepine-one; 4-DAMP, 4-diphenylacetoxy-N-methylpiperidine methobromide; PD102807, (3,6a,11,14-tetrahydro-9-methoxy-2-methyl-12H-isoquino[1,2-b]pyrrolo[3,2f][1,3]benzoxazine-1-carboxylic acid ethyl ester); p-F-HHSiD, para-fluoro hexahydrosiladifenidol; desArg10 HOE 140, H-D-Arf-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-OH; HOE 140, D-Arg0-Arg1-Pro2-Hyp3-Gly4-Thi5-Ser6-D-Tic7-Oic8-Arg9; DMSO, dimethyl sulfoxide; ANOVA, analysis of variance.
Address correspondence to: Adebola C. Fabiyi, Oxford Continence Group, University Department of Pharmacology, Mansfield Road, Oxford OX1 3QT, UK. E-mail: adebola.fabiyi{at}nds.ox.ac.uk
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