[Show abstract][Hide abstract] ABSTRACT: While the symptomology of underactive bladder (UAB) may imply a primary dysfunction of the detrusor muscle, insights into pathophysiology indicate that both myogenic and neurogenic mechanisms need to be considered. Due to lack of proper animal models, the current understanding of the UAB pathophysiology is limited, and much of what is known about the clinical etiology of the condition has been derived from epidemiological data. We hereby review current state of the art in the understanding of the pathophysiology of and animal models used to study the UAB.
International Urology and Nephrology 09/2014; 46(Supplement 1):11-21. · 1.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Muscarinic agonists are the most commonly used agents for treating the underactive bladder (UAB). However, because of the absence of pharmacologic specificity for bladder-only effects and possibly as a result of degenerative and other post-synaptic changes involving detrusor smooth muscle cells, they are simply not effective and side effects are common. If safe and effective therapy for UAB is made available, then most experts agree that the potential market would exceed industry expectations, just as antimuscarinic agents for overactive bladder did in the late 1990s. The pharmaceutical and biotechnology industries that have a pipeline to urology and women's health should consider UAB as a potential target condition. A rational approach to treating the pathology of UAB is presented with a discussion of potential targets that may allow the development of safe and effective agents for the treatment of UAB.
International Urology and Nephrology 09/2014; 46(Supplement 1):35-44. · 1.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Little is known about electrophysiological differences of A-type transient K(+) (KA) currents in nociceptive afferent neurons that innervate somatic and visceral tissues. Staining with isolectin B4 (IB4)-FITC classifies L6-S1 dorsal root ganglion (DRG) neurons into three populations with distinct staining intensities: negative to weak, moderate, and intense IB4 staining. All IB4-intensely stained cells are negative for a fluorescent dye, Fast Blue (FB) injected into the bladder wall, whereas a fraction of somatic neurons labeled by FB injected to the external urethral dermis are intensely stained with IB4. In whole-cell patch clamp recordings, phrixotoxin 2, a Kv4 channel blocker, exhibits voltage-independent inhibition of the KA current in IB4-intensely stained cells, but not the one in bladder-innervating cells. The toxin also shows voltage-independent inhibition of heterologously-expressed Kv4.1 and Kv4.3 currents, whereas its inhibition of Kv4.2 current is totally voltage-dependent. Swapping four-amino acids at the carboxyl portion of the S3 region between Kv4.1 and Kv4.2 transfers this characteristic. RT-PCRs detected Kv4.1 and the long-isoform of Kv4.3 mRNAs without significant Kv4.2 mRNA in L6-S1 DRGs. Higher expression of Kv4.1 and Kv4.3 mRNA was also identified in laser-captured, IB4-stained neurons compared to bladder afferent neurons. These results indicate that phrixotoxin 2 differently acts on channels in the Kv4 family, and that Kv4.1 and/or Kv4.3 subunits functionally participate in the formation of KA channels in a subpopulation of somatic C-fiber neurons, but not in visceral C-fiber neurons innervating the bladder.
[Show abstract][Hide abstract] ABSTRACT: We characterized TRK-130, N-[(5R, 6R, 14S)-17-(cyclopropylmethyl)-4, 5-epoxy-3, 14-dihydroxymorphinan-6-yl] phthalimide (naltalimide), an opioid ligand, to clarify the therapeutic potential for overactive bladder (OAB). In radioligand binding assays with cells expressing human μ-opioid receptors (MORs), δ-opioid receptors (DORs), or κ-opioid receptors (KORs), TRK-130 showed high selectivity for MORs (Ki for MORs, DORs, and KORs = 0.268, 121, and 8.97 nM, respectively). In a functional assay (cyclic AMP accumulation) with cells expressing each human opioid receptor subtype, TRK-130 showed potent but partial agonistic activity for MORs [EC50 (Emax) for MORs, DORs, and KORs = 2.39 nM (66.1%), 26.1 nM (71.0%), and 9.51 nM (62.6%), respectively]. In isovolumetric rhythmic bladder contractions (RBCs) in anesthetized guinea pigs, TRK-130 dose-dependently prolonged the shutdown time (the duration of complete cessation of the bladder contractions) (ED30 = 0.0034 mg/kg, i.v.) without affecting amplitude of RBCs. Furthermore, TRK-130 ameliorated formalin-induced frequent urination at doses of higher than 0.01 mg/kg, p.o. in guinea pigs under the freely moving condition. Meanwhile, TRK-130 showed only a negligible effect on the gastrointestinal transit at doses of up to 10 mg/kg, s.c. in mice. These results indicate that TRK-130 is a potent and selective human MOR partial agonist without undesirable opioid adverse effects such as constipation and enhance the storage function by suppressing the afferent limb of the micturition reflex pathway, suggesting that TRK-130 would be a new therapeutic agent for OAB.
Journal of Pharmacology and Experimental Therapeutics 06/2014; · 3.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to analyze the mechanism underlying cross-sensitization between the colon and the bladder via activation of transient receptor potential A1 (TRPA1) channels.
Using female Sprague-Dawley rats, polyethylene catheters were inserted into the colon between two ligations at the levels of 40 and 60 mm rostral to the anus and into the bladder. (1) We examined changes in colon and bladder activity after the application of allyl isothiocyanate (AI, 50 mM, 300 μl), a TRPA1 activator, into the colon or the bladder in an awake condition. Inhibitory effects of the pretreatment with HC-030031 (HC, 3 mg/kg), a TRPA1 inhibitor, on colon-to-bladder cross-sensitization induced by AI instilled in the colon were also investigated. (2) We examined Evans blue (EB) dye extravasation after TRPA1 stimulation in the colon or the bladder to evaluate vascular permeability due to tissue inflammation.
(1) Intercontraction intervals during continuous saline infusion into the bladder (0.04 ml/min) were significantly decreased after the intracolonic AI application, which significantly increased mean intracolonic pressure, indicative of colon-to-bladder cross-sensitization. The AI-induced colon-to-bladder cross-sensitization was completely prevented by the pretreatment with intravenous application of HC. On the other hand, mean intracolonic pressure was significantly decreased after the intravesical AI application, which significantly increased mean intravesical pressure. (2) EB dye extravasation was significantly increased in the AI-treated inflamed organs and also in the bladder following intracolonic AI treatment.
Colon-to-bladder cross-sensitization is mediated via TRPA1 stimulation in the colon, although TRPA1 expressed in the bladder does not seem to participate in bladder-to-colon cross-sensitization.
International Urogynecology Journal 05/2014; · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the effects of activation of sensory neuron-specific receptors (SNSRs) on cyclophosphamide (CYP) bladder overactivity in rats.
Female Sprague-Dawley rats (235-258 g) were used. Rats were injected with either CYP (200 mg/kg, intraperitoneally) or saline (control). Continuous cystometrograms (0.04 ml/min) were recorded 48 h after CYP or saline injection under urethane anesthesia. After stable micturition cycles were established, a selective rat SNSR1 agonist, bovine adrenal medulla 8-22 (BAM8-22), was administered intravenously or intrathecally.
Cyclophosphamide treatment-induced higher baseline pressure and shorter intercontraction intervals compared with the control group. Intravenous administration of BAM8-22 at 10, 30 and 100 μg/kg significantly increased intercontraction intervals in the CYP-treated group. Intrathecal administration of BAM8-22 at 0.03, 0.1 and 0.3 μg also significantly increased intercontraction intervals in the CYP-treated group. Intravenous or intrathecal administration of BAM8-22 did not change baseline pressure or maximum voiding pressure in the CYP-treated group.
These findings indicate that activation of SNSRs can suppress CYP-induced bladder overactivity, probably due to suppression of bladder afferent activity.
International Urology and Nephrology 05/2014; · 1.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bladder pain syndrome/interstitial cystitis is a disease with lower urinary tract symptoms, such as bladder pain and urinary frequency, which results in seriously impaired quality of life of patients. The extreme pain and urinary frequency are often difficult to treat. Although the etiology of bladder pain syndrome/interstitial cystitis is still not known, there is increasing evidence showing that afferent hyperexcitability as a result of neurogenic bladder inflammation and urothelial dysfunction is important to the pathophysiological basis of symptom development. Further investigation of the pathophysiology will lead to the effective treatment of patients with bladder pain syndrome/interstitial cystitis.
International Journal of Urology 04/2014; 21 Suppl S1:18-25. · 1.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This article summarizes anatomical, neurophysiological, and pharmacological studies in humans and animals to provide insights into the neural circuitry and neurotransmitter mechanisms controlling the lower urinary tract and alterations in these mechanisms in lower urinary tract dysfunction. The functions of the lower urinary tract, to store and periodically release urine, are dependent on the activity of smooth and striated muscles in the bladder, urethra, and external urethral sphincter. During urine storage, the outlet is closed and the bladder smooth muscle is quiescent. When bladder volume reaches the micturition threshold, activation of a micturition center in the dorsolateral pons (the pontine micturition center) induces a bladder contraction and a reciprocal relaxation of the urethra, leading to bladder emptying. During voiding, sacral parasympathetic (pelvic) nerves provide an excitatory input (cholinergic and purinergic) to the bladder and inhibitory input (nitrergic) to the urethra. These peripheral systems are integrated by excitatory and inhibitory regulation at the levels of the spinal cord and the brain. Therefore, injury or diseases of the nervous system, as well as disorders of the peripheral organs, can produce lower urinary tract dysfunction, leading to lower urinary tract symptoms, including both storage and voiding symptoms, and pelvic pain. Neuroplasticity underlying pathological changes in lower urinary tract function is discussed.
[Show abstract][Hide abstract] ABSTRACT: Purpose. The following review focuses on the recent advancements in intravesical drug delivery, which brings added benefit to the therapy of detrusor overactivity and interstitial cystitis/painful bladder syndrome (IC/PBS). Results. Intravesical route is a preferred route of administration for restricting the action of extremely potent drugs like DMSO for patients of interstitial cystitis/painful bladder syndrome (IC/PBS) and botulinum toxin for detrusor overactivity. Patients who are either refractory to oral treatment or need to mitigate the adverse effects encountered with conventional routes of administration also chose this route. Its usefulness in some cases can be limited by vehicle (carrier) toxicity or short duration of action. Efforts have been underway to overcome these limitations by developing liposome platform for intravesical delivery of biotechnological products including antisense oligonucleotides. Conclusions. Adoption of forward-thinking approaches can achieve advancements in drug delivery systems targeted to future improvement in pharmacotherapy of bladder diseases. Latest developments in the field of nanotechnology can bring this mode of therapy from second line of treatment for refractory cases to the forefront of disease management.
[Show abstract][Hide abstract] ABSTRACT: The functional and molecular alterations of nerve growth factor (NGF) and Prostaglandin E2 (PGE2) and its receptors were studied in bladder and urine in streptozotocin (STZ)-induced diabetic rats.
PLoS ONE 01/2014; 9(7):e102644. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the efficacy of urine alkalization therapy using citrates in patients with hypersensitive bladder syndrome.
A total of 76 patients with urinary frequency were assessed for their symptoms using a 2-day voiding diary as well as the urine pH at each voiding during the screening period. Their symptoms were also assessed by pain score, King's health questionnaire, and O'Leary-Sant symptom and problem index scores. Finally, 50 patients were evaluated for changes in symptoms after oral treatment with citrates for 2-4 weeks after the screening period.
After the treatment, significant increases in the urine pH (from 5.8 ± 0.4 to 6.3 ± 0.4; increment of 0.5 ± 0.4; P < 0.01), and significant decreases in the number of micturitions per day (from 14.5 ± 6.5 to 13.5 ± 5.9; P = 0.02) and the number of episodes of pain/discomfort per day (from 7.8 ± 6.8 to 6.1 ± 7.1; P = 0.02) were observed. In the King's health questionnaire, the sleep/energy domain score was significantly improved (from 60.0 ± 25.0 to 50.3 ± 29.6; P < 0.01). In a subgroup analysis based on urine pH (urine pH <6.2 and ≥6.2), significant improvements in the voiding symptoms, the sleep/energy domain score and the O'Leary-Sant problem index were observed in the group with urine pH of ≥6.2. There were statistically significant differences between the subgroups in the volume per voiding, maximum volume per voiding and the problem index. In addition, the subgroup, in which patients had pain in the screening period, showed statistically significant improvements in the number of micturitions per day, episodes of pain/discomfort per day, the sleep/energy domain score and the problem index.
Urine alkalization therapy is likely to be effective in the treatment for hypersensitive bladder syndrome.
International Journal of Urology 11/2013; · 1.73 Impact Factor