Urinary Bladder Contraction Research Articles

The effects of Glivec on the urinary bladder excitation of rats with suprasacral or sacral spinal cord transection

BackgroundTo investigate the effects of the c-kit blocker imatinib mesylate (Glivec) on the bladders of animals with suprasacral cord injury (SSCI) and sacral cord injury (SCI). Materials and methodsWe randomized 60 female Sprague-Dawley rats into control, sham, SSCI (T8/9 transection), and SCI (S1-3 transection) groups. Six weeks later, we evaluated the effects of stepwise Glivec administrations on urinary bladder contraction using cystometry and the detrusor strip stretch-test. We investigated spontaneous calcium transients of kit-positive interstitial cells of Cajal (ICCs) with the preloaded Ca2+ indicator fluo-3AM. The expression levels of c-kit and the number of ICCs in those bladders were determined using Western blot and fluorescence staining analyses, respectively. ResultsBladder capacity and compliance were decreased in SSCI bladders and increased in SCI bladders (P<0.05). The amplitude and frequency of spontaneous contractions of detrusor strips, the frequency and relative fluorescence intensity of the spontaneous Ca2+ waves, and c-kit expression in the bladder were significantly increased in the SSCI group and decreased in the SCI group compared with the control and sham groups (P<0.05). The dose-dependent effects of Glivec also confirmed consistent functional variations in bladder activity. ConclusionsThe expressions and effects of Glivec were enhanced in SSCI bladders and inhibited in SCI bladders, which may indicate potential roles of ICCs for the c-kit signaling pathway in the pathogenesis of SSCI and SCI bladder.

Fourier Transform Analysis of Rabbit Detrusor Autonomous Contractions Reveals Length Dependent Increases in Tone and Slow Wave Development at Long Lengths

Bladder wall muscle (detrusor) develops low amplitude rhythmic contractions. Low amplitude rhythmic contraction activity is increased in detrusor from patients with overactive bladder. In this in vitro study we used fast Fourier transforms to assess the length dependence of low amplitude rhythmic contraction components. Rabbit detrusor strips were placed in a muscle bath between 2 clips to adjust length and record isometric tension. Tissues stretched from 70% to 130% of a reference muscle length at 10% increments were allowed to develop low amplitude rhythmic contractions at each length for 20 minutes. Low amplitude rhythmic contraction data were analyzed using fast Fourier transforms and represented by a frequency rather than a time spectrum. Based on fast Fourier transform analysis summarized by signal peaks within specific frequency ranges, rabbit low amplitude rhythmic contraction waveforms were divided into 1 tonic and 2 phasic components, defined as A0 + A1F1 + A2F2, where A0 is a length dependent basal tonic component that increases linearly, A1F1 is a slow wave with a length dependent specific amplitude (A1) and a length independent constant frequency (F1) of approximately 11.2 Hz, and A2F2 is a fast wave with a length dependent amplitude (A2) and frequency (F2) of approximately 0.03 Hz. Fast Fourier transform analysis revealed that rabbit low amplitude rhythmic contractions consist of a basal tonic component plus 2 phasic components. The amplitude of all 3 components was length dependent. The frequency of the fast component was not length dependent and the slow component was absent at short muscle lengths, developing only at muscle lengths beyond that producing a maximum active contraction.

TRPM8 agonists modulate contraction of the pig urinary bladder

The transient receptor potential melastin-8 (TRPM8) channel is activated by the "cooling" compounds menthol and icilin. Pathophysiologically, it is implicated in the overactive bladder and bladder cooling reflex, but the activity of TRPM8 in normal bladder physiology is poorly understood. We investigated the distribution of TRPM8 channels and the effect of TRPM8 agonists on the contractile function of pig bladder (n = 35) strips and whole bladders. The distribution of TRPM8 was examined by immunohistochemistry. The effect of vesical or intravascular menthol (0.1-0.3 mmol/L) or icilin (50 μmol/L) on carbachol-induced isolated whole bladder contractions was monitored by recording vesical pressure. Strips of denuded detrusor or mucosa were mounted in organ baths to study the effect of TRPM8 agonists on the contractile responses to 10 μmol/L carbachol. TRPM8-like immunoreactivity was detected on pig urothelium. Intravascular menthol (0.3 mmol/L) and icilin (50 μmol/L) significantly decreased the magnitude of carbachol-induced whole bladder contraction, whereas vesical administration significantly increased the response. In detrusor and mucosal strips, both menthol (0.3 mmol/L) and icilin (50 μmol/L) inhibited carbachol-induced contractions. We conclude that the TRPM8 channel is expressed on the urothelium of pig bladder. In the whole organ, exposure of the urothelium to menthol or icilin increases the contractile response to carbachol. Where detrusor muscle is exposed directly to these compounds, the contractile response to carbachol is reduced.

Role of Serotonin Receptors in Regulation of Contractile Activity of Urinary Bladder in Rabbits

To evaluate the role of different serotonin (5-hydroxytryptamine [5-HT]) receptor subtypes on urinary bladder contraction, pharmacologic analysis of electromotor activity (EMA) variation was performed using a rabbit bladder model. Measurements of EMA were performed on 3 urinary bladder portions: top, body, and trigone. The experiments were performed on 24 Shinshilla rabbits of both sexes, 5-6 months old, and weighing 2.5-4.0 kg. The bladder was isolated. Noninvasive electrodes were superimposed on the surface of the top, body, and trigone of the bladder. Contact between the electrode tips and the bladder surface was achieved. The bladder EMA was measured using bipolar silver electrodes for extracellular recordings. The stimulation of the serotoninergic fibers and parasympathetic nerve resulted in increased bladder EMA frequency and amplitude (72% and 25%, respectively). The increase in bladder EMA was prevented by administration of selective inhibitors of serotonin receptor subtypes such as droperidol, spiperone, and sumatriptan. Exogenous serotonin administered to the rabbits after vagus nerve excitation increased the typical EMA of the bladder body smooth muscle. The serotoninergic system has been widely implicated in the control of urinary bladder function. In the present study, we have demonstrated that preganglionic fibers and ganglionic serotoninergic neurons, expressing the 5-HT3 and 5-HT4 receptors, and the effector smooth muscle cells, expressing 5-HT1 and 5-HT2 receptors, are actively involved in the regulation of the bladder contractile activity in rabbits.

Long-acting formulation of a new muscarinic receptor antagonist for the treatment of overactive bladder

A new muscarinic receptor antagonist, 5-hydroxymethyl tolterodine (5-HMT), was successfully encapsulated into PLGA microspheres. With an increase of PLGA concentration from 15% to 40%, encapsulation efficiency of 5-HMT increased from 55.39% to 76.32%, and the particle size of microsphere increased from 34.33 to 70.48 µm. Increasing the homogenisation speed from 850 to 2300 rpm, the particle size was reduced about 65%.The in vitro and in vivo studies in beagle dogs show that the release profile of 5-HMT-loaded microspheres (5-HMT MS) prepared with 503H is characterised by a low initial burst followed by slow release that lasted for 2 weeks. A Cmax of 1.617 ± 0.392 ng/mL was found on the sixth day. When evaluated for inhibition of the carbachol-induced contraction of rat urinary bladder, 5-HMT MS showed a much longer and more potent effect than tolterodine tablets. The mean urination time of the rats in the 5-HMT MS group was significantly decreased (p < 0.05 or p < 0.01) to less than 2 weeks.

Modulation of bladder afferent signals in normal and spinal cord‐injured rats by purinergic P2X3 and P2X2/3 receptors

To evaluate the role of bladder sensory purinergic P2X3 and P2X2/3 receptors on modulating the activity of lumbosacral neurones and urinary bladder contractions in vivo in normal or spinal cord-injured (SCI) rats with neurogenic bladder overactivity. SCI was induced in female rats by complete transection at T8-T9 and experiments were performed 4 weeks later, when bladder overactivity developed. Non-transected rats were used as controls (normal rats). Neural activity was recorded in the dorsal horn of the spinal cord and field potentials were acquired in response to intravesical pressure steps via a suprapubic catheter. Field potentials were recorded under control conditions, after stimulation of bladder mucosal purinergic receptors with intravesical ATP (1 mm), and after intravenous injection of the P2X3/P2X2/3 antagonist AF-353 (10 mg/kg and 20 mg/kg). Cystometry was performed in urethane-anaesthetised rats intravesically infused with saline. AF-353 (10 mg/kg) was systemically applied after baseline recordings; the rats also received a second dose of AF-353 (20 mg/kg). Changes in the frequency of voiding (VC) and non-voiding (NVC) contractions were evaluated. SCI rats had significantly higher frequencies for field potentials and NVC than NL rats. Intravesical ATP increased field potential frequency in control but not SCI rats, while systemic AF-353 significantly reduced this parameter in both groups. AF-353 also reduced the inter-contractile interval in control but not in SCI rats; however, the frequency of NVC in SCI rats was significantly reduced. The P2X3/P2X2/3 receptors on bladder afferent nerves positively regulate sensory activity and NVCs in overactive bladders.

1,4-Dioxane, a Suitable Scaffold for the Development of Novel M3 Muscarinic Receptor Antagonists

In this study the modulation of the pharmacological profile from agonist to antagonist was successfully obtained by replacing the methyl group in position 6 of the 1,4-dioxane scaffold of the potent M(2)/M(3) muscarinic agonist 1 with bulkier groups. In particular, the 6,6-diphenyl substitution provided the potent M(3) preferring antagonist (±)-17, which in in vivo study proved to be effective in reducing the volume-induced contractions of rat urinary bladder and was devoid of cardiovascular effects.

A Novel Pathway Underlying the Inhibitory Effects of Melatonin on Isolated Rat Urinary Bladder Contraction

The aim of the present study was to elucidate the direct effects of melatonin on bladder activity and to determine the mechanisms responsible for the detrusor activity of melatonin in the isolated rat bladder. We evaluated the effects of melatonin on the contractions induced by phenylephrine (PE), acetylcholine (ACh), bethanechol (BCh), KCl, and electrical field stimulation (EFS) in 20 detrusor smooth muscle samples from Sprague-Dawley rats. To determine the mechanisms underlying the inhibitory responses to melatonin, melatonin-pretreated muscle strips were exposed to a calcium channel antagonist (verapamil), three potassium channel blockers [tetraethyl ammonium (TEA), 4-aminopyridine (4-AP), and glibenclamide], a direct voltage-dependent calcium channel opener (Bay K 8644), and a specific calcium/calmodulin-dependent kinase II (CaMKII) inhibitor (KN-93). Melatonin pretreatment (10-8~10-6 M) decreased the contractile responses induced by PE (10-9~10-4 M) and Ach (10-9~10-4 M) in a dose-dependent manner. Melatonin (10-7 M) also blocked contraction induced by high KCl ([KCl]ECF; 35 mM, 70 mM, 105 mM, and 140 mM) and EFS. Melatonin (10-7 M) potentiated the relaxation response of the strips by verapamil, but other potassium channel blockers did not change melatonin activity. Melatonin pretreatment significantly decreased contractile responses induced by Bay K 8644 (10-11~10-7 M). KN-93 enhanced melatonin-induced relaxation. The present results suggest that melatonin can inhibit bladder smooth muscle contraction through a voltage-dependent, calcium-antagonistic mechanism and through the inhibition of the calmodulin/CaMKII system.

Pharmacological Effects of Imidafenacin (KRP-197/ONO-8025), a New Bladder Selective Anti-cholinergic Agent, in Rats

Imidafenacin (CAS 170105-16-5, KRP-197, ONO-8025) has been developed for the treatment of overactive bladder as a new anti-cholinergic with high affinities for muscarinic acetylcholine M3 and M1 receptors. The pharmacological profiles of imidafenacin on the urinary bladder function by determining carbamylcholine (CCh)-induced decrease in bladder capacity and distention-induced rhythmic bladder contraction in conscious rats were investigated. In addition, effects of imidafenacin on CCh-induced salivary secretion and performance in the Morris water maze task in rats were investigated to evaluate side effects, such as dry mouth and cognitive dysfunction in the central nervous system (CNS). Imidafenacin prevented the CCh-induced decrease in bladder capacity dose-dependently with an ID50 of 0.055 mg/kg. On the distention-induced rhythmic bladder contraction, imidafenacin, propiverine, tolterodine, oxybutynin and darifenacin showed inhibitory effects with ID30's of 0.17, 15, 3.0, 3.2 and 0.85 mg/kg, respectively. The rank order of inhibitory potency was: imidafenacin > darifenacin > tolterodine > or = oxybutynin > propiverine. Imidafenacin, propiverine, tolterodine, oxybutynin and darifenacin showed inhibitory effects on the CCh-stimulated salivary secretion with ID50's of 1.5, 14, 15, 4.4 and 1.2 mg/kg, respectively. The rank order of inhibitory potency was: darifenacin > or = imidafenacin > oxybutynin > propiverine > or = tolterodine. Imidafenacin at the doses of 1 and 10 mg/ kg did not affect the escape latencies in the Morris water maze task compared with those in vehicle controls. Oxybutynin at the dose of 100 mg/kg induced a significant increase in the escape latencies, but propiverine at the dose of 100 mg/kg did not induce significant changes. These results suggest that imidafenacin inhibits urinary bladder contraction to a greater extent than the salivary secretion (compared with the M3 receptor selective antagonist, darifenacin, and the non-selective antagonists, propiverine, tolterodine and oxybutynin) or the CNS functions, such as performance in the Morris water maze task (compared with oxybutynin). In conclusion, imidafenacin has organ selectivity for the bladder over the salivary gland, without influence on the central nervous system such as spatial learning and memory.

Detecting the Onset of Urinary Bladder Contractions Using an Implantable Pressure Sensor

This study investigates whether signals obtained from an implantable pressure sensor placed in the urinary bladder wall could be used to detect the onset of bladder contractions. The sensor assembly was custom made using a small piezoresistive sensor die. The die was mounted on ceramic substrate (8 mm × 8 mm) and encapsulated in silicone by a two-part moulding process. The final sensor was lens shaped with a diameter of 13.6 mm and height of 2.0 mm. Experiments were performed in six pigs that had one or more sensors placed in the bladder wall. An external reference sensor was used to simultaneously monitor intravesical pressure via a transurethral catheter. Bladder contractions were evoked by unilateral electrical stimulation of the pelvic nerve. Onset latency was computed using both signals. In addition, the correlation between wall pressure and intravesical pressure was calculated. On average, the onset latency was - 307 ms using the wall sensors compared to the intravesical pressure, i.e., the detection occurred earlier using the wall sensors than the intravesical sensor. In 91 of 114 recordings the correlation coefficient was above 0.90. In conclusion, the implantable sensor performs similar to the reference sensor when used to detect the onset of bladder contractions.

The Effects of the c-kit Blocker Glivec on the Contractile Response of Urinary Bladder

To investigate the effects of imatinib (Glivec) on the urinary bladder contraction and excitation induced by neurostimulation, therefore to clarify the relationships between the bladder interstitial cell of Cajal (ICC) and the neural signals. In invivo experiments, pelvic nerves of rats were stimulated by square-wave pulses. The contractile response was recorded before and 40 min after the administration of medications (atropine, Glivec, and ketotifen). In invitro experiments, the bladder contractile response induced by acetylcholine with or without Glivec was evaluated. The space relationship between ICC and neural fibers were observed with double-labeled fluorescence using primary antibodies (anti-c-kit and anti-vesicular acetylcholine transferase) and secondary fluorescent antibodies (Alexa 488 and Alexa 594; Molecular Probes, Eugene, OR). Atropine and Glivec could significantly inhibit the bladder contractile response induced by the electrical stimulation in a dose-dependent manner, while ketotifen did not obviously affect bladder contractile response. In invitro experiments, Glivec did not affect acetylcholine-induced bladder contractile response. The location of ICC in close proximity to cholinergic nerve fibers was confirmed by double-labeled fluorescence. Bladder ICC play an important role as intermediaries in the transmission of cholinergic signals from nerve to smooth muscle cells.

Characterization of bencycloquidium bromide, a novel muscarinic M 3 receptor antagonist in guinea pig airways

In this study we have investigated the antagonist affinity, efficacy and duration of action of bencycloquidium bromide (BCQB), a selective muscarinic M 3 receptor antagonist, as a possible clinical bronchodilator for the treatment of chronic obstructive pulmonary disease (COPD) and asthma. In competition studies, BCQB showed high affinity toward the M 3 receptor in Chinese hamster ovary (CHO) cells (M 3 p Ki = 8.21, M 2 p Ki = 7.21, and M 1 p Ki = 7.86); pA 2 = 8.85, 8.71 and 8.57 in methacholine-induced contraction of trachea, ileum and urinary bladder, 8.19 in methacholine-induced bradycardia of right atrium in vitro, respectively. In function studies, duration of inhibition of carbachol-induced tonic contraction, BCQB and ipratropium had a very similar onset and offset of action, but onset faster and offset slower than that of tiotropium. After treatment with intratracheally instilled or the inhalation route, BCQB protects against methacholine or antigen-induced bronchoconstriction in a dose-dependent manner in the normal and sensitized guinea pigs in vivo. BCQB and ipratropium-induced inhibitory activity was short lasting, as it declined quickly when compared to tiotropium. These results suggest that BCQB bind muscarinic M 3 receptors with high affinity. On this basis we speculate that a putative BCQB-based therapy for COPD might require more than once-a-day administration to be as effective as the currently employed once-daily therapy with tiotropium. Nevertheless, Inhalable M 3-selective compounds may spare M 2-cardiac receptors and reduce the risks of cardiovascular events associated with the long-term treatment of these agents.

Involvement of Bradykinin in Trypsin-Induced Urinary Bladder Contraction in Cyclophosphamide-Treated Rats

Protease-activated receptor-2 (PAR-2) is activated by serine proteases, such as trypsin and mast cell tryptase. Previous studies have demonstrated that both trypsin and PAR-2 activating peptide contract isolated rat urinary bladder preparations, however, the mechanisms are not fully understood. In the present study, we examined the role of bradykinin in contractions induced by trypsin and the PAR-2 agonist 2-furoyl-LIGRL-NH(2) in urinary bladders isolated from control or cyclophosphamide (CYP)-induced cystitis rats. The contractile effects of trypsin were significantly greater in the preparations obtained from CYP-treated rats than in those from controls. The bradykinin B2 receptor antagonist Hoe 140 did not affect trypsin-induced contractions in control rat bladders, whereas it significantly reduced the contractile effects of trypsin on bladders from CYP-treated rats. On the other hand, Hoe 140 failed to affect contractions induced by the PAR-2 agonist 2-furoyl-LIGRL-NH(2). These results suggest that the actions of trypsin on urinary bladders in cystitis rats are partly exerted through stimulation of bradykinin B2 receptor in a PAR-2-independent manner. This mechanism seems to be involved in the enhancement of trypsin-induced bladder contractions observed after induction of cystitis with CYP in rats.

Contribution of Cyclooxygenase-Dependent Mechanisms to Contractile Responses to Donepezil in the Rat Urinary Bladder

Donepezil, an inhibitor of acetylcholinesterase, is used to improve cholinergic neurotransmission and cognitive function in Alzheimer’s disease. In the present study, contractile effects of donepezil on the rat urinary bladder were examined and compared with those of the nonselective cholinesterase inhibitor neostigmine. Both donepezil and neostigmine produced concentration-dependent contractile responses of the isolated rat urinary bladder strips. The neostigmine-induced contractions were abolished by atropine. However, donepezil produced contractions of urinary bladders partly through atropine-insensitive mechanisms. The atropine-resistant component of donepezil-induced contraction was significantly reduced by the cyclooxygenase inhibitor indomethacin. These results suggest that cyclooxygenase-derived prostanoids contribute, at least in part, to contractile effects of donepezil in the rat urinary bladder.

The M2-Muscarinic Receptor Inhibits the Development of Streptozotocin-Induced Neuropathy in Mouse Urinary Bladder

We investigate the role of M(2)-muscarinic receptors in maintaining neurogenic bladder contraction during hyperglycemia. Mice were injected with a single dose of streptozotocin (125 mg/kg), and neurogenic contraction of urinary bladder from wild type and M(2)-muscarinic receptor knockout (M(2) KO) mice was measured at 8 to 24 weeks after treatment. In wild-type bladder lacking urothelium, the summation of the cholinergic (64%) and purinergic (56%) components of the electrical-field-stimulated response exceeded 100%, indicating a reserve capacity. Although the cholinergic component was slightly less in the M(2) KO mouse, the total electrical-field-stimulated contraction was the same as wild type. The cholinergic and purinergic components of contraction in wild-type bladder were minimally affected by streptozotocin treatment. In M(2) KO bladder, streptozotocin treatment reduced both the cholinergic (after 8-9 and 20-24 weeks) and purinergic (after 20-24 weeks only) components. The loss of function was approximately 50 to 70%. Similar results were observed in bladder with intact urothelium. M(2) KO bladder was more sensitive to the relaxant effect of isoproterenol compared with wild type, and this difference significantly increased at the early and late time points after streptozotocin treatment. In the presence of urothelium, however, this difference in isoproterenol sensitivity was smaller with streptozotocin treatment, but this trend reversed over time. Our results show that M(2) receptors oppose urinary bladder distension in wild-type bladder and inhibit streptozotocin-induced neuropathy.

Studies on the preparation, characterization and pharmacological evaluation of tolterodine PLGA microspheres

In this study, poly( d, l-lactide-co-glycolide) (PLGA) microspheres of tolterodine depot formulation were prepared using oil in water (o/w) method to investigate their potential pharmacokinetic and pharmacodynamic advantages over tolterodine l-tartrate tablets. Morphological studies of the microspheres showed a spherical shape and smooth surface with mean size of 50.69–83.01 μm, and the encapsulation efficiency was improved from 62.55 to 79.10% when the polymer concentration increased from 180 to 230 mg/ml. The addition of stearic or palmitic acids could significantly raise the drug entrapment efficiency but only slightly affected the in vitro release. A low initial burst followed by a proximately constant release of tolterodine was noticed in the in vitro release profiles. The in vivo study was carried out by intramuscular (i.m.) administration of tolterodine-loaded microspheres on beagle dogs, and a sustained release of drug from the PLGA microspheres was achieved until the 18th day with a low initial burst. Since the absence of hepatic first pass metabolism, only a single active compound—tolterodine was detected in the plasma. This avoided the coexistence of two active compounds in plasma in the case of oral administration of tolterodine, which may lead to a difficulty in dose control due to the different metabolic capacity of patients. In the pharmacodynamic study, the influence of tolterodine PLGA microspheres on the inhibition of carbachol-induced rat urinary bladder contraction was more significant than that of tolterodine l-tartrate tablets. There were invisible changes in rat bladder slices between tolterodine-loaded PLGA microspheres group and tolterodine l-tartrate tablets group. These results indicate that the continuous inhibition of muscarinic receptor may offer an alternative therapy of urge incontinence.

Effect of streptozotocin on neurogenic M2 and M3 muscarinic receptor‐mediated contractions in mouse urinary bladder

We studied the effect of streptozotocin (STZ) (125 mg/kg, 20 – 24 weeks prior to experiments) on the contractile roles of M2 and M3 muscarinic receptors in the electrical‐field‐stimulated mouse urinary bladder. Electrical‐field stimulation for 5 sec (20 Hz, 0.5 msec, 100 V) elicited contractions that were inhibited by the muscarinic antagonist, N‐methyl scopolamine approximately 50% in urinary bladder from both STZ‐ and vehicle‐treated, wild type mice. In bladder from M2 KO mice, STZ‐treatment caused a large inhibition of contraction compared to that measured in vehicle‐treated mice. The relaxant effect of isoproterenol on the electrical‐field‐stimulated contraction was similar in wild type urinary bladder from vehicle‐ and STZ‐treated mice. In contrast, the relaxant effect of isoproterenol was much greater in urinary bladder from M2 KO mice treated with STZ as compared to that from vehicle‐treated mice. Our data show that the contractile role of the M2 receptor in response to acetylcholine release is increased in urinary bladder following STZ‐treatment and that this mechanism may be critical for sustaining contractile function following the substantial loss of M3 receptor function induced by STZ. Supported by the MSTP grant, the ARCS Foundation, and NIH grants GM069829, UTN‐37775 and DK081289.

Activation of muscarinic M-1 cholinoceptors by curcumin to increase contractility in urinary bladder isolated from Wistar rats

Curcumin is an active principle contained in rhizome of Curcuma longa, and it has been recently mentioned to show affinity to muscarinic M-1 cholinoceptors (M 1-mAChR). In the present study, we found that curcumin caused a concentration-dependent increase of muscle tone in urinary bladder isolated from Wistar rats. This action was inhibited by pirenzepine at concentration enough to block M 1-mAChR. In radioligand-binding assay, specific binding of [ 3H]-oxotremorine (OXO-M) in the rat bladder homogenates was also displaced by curcumin in a concentration-dependent manner. In the presence of inhibitors for PLC–PKC pathway, either U73122 (phospholipase C inhibitor) or chelerythrine (protein kinase C inhibitor), curcumin-stimulated contraction in urinary bladder was markedly reduced. In conclusion, the obtained results suggest that curcumin can activate M 1-mAChR at concentrations lower than to scavenge free radicals to increase of muscle tone in urinary bladder through PLC–PKC pathway.

Diabetes mellitus- and cooling-induced bladder contraction: an in vitro study

The effects of diabetes mellitus during cooling on ACh- and KCl-induced responses were investigated in rat urinary bladder. Diabetes was induced in the rats by 50 mg/kg streptozotocin via an intraperitoneal injection. Rats' body and bladder weights were measured. The isometric tension to ACh (10(-9) - 3 × 10(-4) M) and KCl (5-100 mM) in strips of urinary detrusor muscle of diabetic and non-diabetic rats, in organ baths at 37 and 28ºC were recorded. The body weights were significantly decreased and the bladder weights increased in STZ-induced diabetic group compared to the non-diabetic group. ACh and KCl caused concentration-dependent contractions of urinary bladders from non-diabetic and STZ-induced diabetic rats. During cooling, the sensitivity and the maximal response were significantly higher than those during 37ºC, both in non-diabetic and diabetic preparations. Cooling of detrusor muscle preparations induces a graded contraction inversely proportional to the temperature in diabetic rats. It may be assumed that the cooling response involves the same mechanisms in the diabetic and non-diabetic animals.

The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Ameliorative Effect of Solifenacin Succinate (Vesicare ®), a Bladder-Selective Antimuscarinic Agent, on Overactive Bladder Symptoms, Especially Urgency Episodes

Overactive bladder (OAB) syndrome is a common condition that is most often observed in the elderly. Pharmacological treatment with muscarinic receptor antagonists has been most widely used for OAB. An antimuscarinic agent, solifenacin, showed the highest affinity for the muscarinic M3 receptor, which mediates urinary bladder contraction. In preclinical studies, solifenacin exhibited a highly bladder-selective profile compared with other antimuscarinic agents. Solifenacin was also shown to increase bladder capacity without affecting residual urine in an OAB model of rats. Urgency is now considered to result from overactivation of afferent nerves from the urinary bladder. It has been reported that afferent nerves are located adjacent to the urothelium, and stimulation of muscarinic receptors expressed on the urothelium may contribute to the activation of afferent nerves via non-neuronal ATP release. Solifenacin produces its inhibitory effect on bladder afferent activity partly via the suppression of non-neuronal ATP release. Clinically, solifenacin ameliorates all symptoms in OAB patients; and in particular, it produces a significant decrease in urgency episodes, which is the principal symptom of OAB. The pharmacological profile of solifenacin is therefore considered to contribute to its beneficial effects of high efficacy against OAB symptoms with good tolerability.