Nouval Shahab

Endogenous Cardiac Troponin T Modulates Ca2+-Mediated Smooth Muscle Contraction

Mechanisms linked to actin filaments have long been thought to cooperate in smooth muscle contraction, although key molecules were unclear. We show evidence that cardiac troponin T (cTnT) substantially contributes to Ca2+-mediated contraction in a physiological range of cytosolic Ca2+ concentration ([Ca2+]i). cTnT was detected in various smooth muscles of the aorta, trachea, gut and urinary bladder, including in humans. Also, cTnT was distributed along with tropomyosin in smooth muscle cells, suggesting that these proteins are ready to cause smooth muscle contraction. In chemically permeabilised smooth muscle of cTnT+/− mice in which cTnT reduced to ~50%, the Ca2+-force relationship was shifted toward greater [Ca2+]i, indicating a sizeable contribution of cTnT to smooth muscle contraction at [Ca2+]i < 1 μM. Furthermore, addition of supplemental TnI and TnC reconstructed a troponin system to enhance contraction. The results indicated that a Tn/Tn-like system on actin-filaments cooperates together with the thick-filament pathway.

Obstruction enhances rho-kinase pathway and diminishes protein kinase C pathway in carbachol-induced calcium sensitization in contraction of α-toxin permeabilized guinea pig detrusor smooth muscle†‡

We investigated the relative important role of rho kinase (ROK) and protein kinase C (PKC) pathways in carbachol (CCh)‐induced Ca2+ sensitization in α‐toxin permeabilized Guinea pig detrusor smooth muscle (DSM) following bladder outlet obstruction (BOO).

Voiding dynamics in women with stress urinary incontinence and high‐stage cystocele

Objectives:  The aim of this study was to identify the urodynamic features of women with stress urinary incontinence (SUI) or with high‐stage (stage 3 or greater) cystocele (HSC) as compared with symptom‐free women.

The profiles and patterns of detrusor overactivity and their association with overactive bladder symptoms in men with benign prostatic enlargement associated with detrusor overactivity

To investigate the association of both the urodynamic profiles and patterns of detrusor overactivity (DO) with the severity of the symptoms related to overactive bladder (OAB) in men with benign prostatic enlargement (BPE) associated with DO.

Actions of cAMP on calcium sensitization in human detrusor smooth muscle contraction

To clarify the effect of cAMP on the Ca2+‐sensitized smooth muscle contraction in human detrusor, as well as the role of novel exchange protein directly activated by cAMP (Epac) in cAMP‐mediated relaxation.

Diphosphate Regulation of Adenosine Triphosphate Sensitive Potassium Channel in Human Bladder Smooth Muscle Cells

PURPOSE To clarify the properties of adenosine triphosphate sensitive K+ channel in human detrusor smooth muscle we examined the effect of the representative nicotinic acid derivatives β-nicotinamide adenine dinucleotide, cyclic adenosine diphosphate ribose and nicotinic acid adenine dinucleotide phosphate (Sigma-Aldrich®) on human detrusor adenosine triphosphate sensitive K+ channels. MATERIALS AND METHODS Patch clamp procedures were done in human detrusor cells. Reverse transcriptase and real-time polymerase chain reaction were performed to clarify the subunit components of adenosine triphosphate sensitive K+ channels. RESULTS The K+ channel opener levcromakalim induced a long lasting outward current that was inhibited by glibenclamide (Sigma-Aldrich) under the whole cell configuration. The single channel study revealed that the unitary conductance of the adenosine triphosphate sensitive K+ channel in the human detrusor was 11 pS and nucleotide diphosphates increased its open probability. Applying β-nicotinamide adenine dinucleotide also activated the adenosine triphosphate sensitive K+ channel but applying cyclic adenosine diphosphate ribose or nicotinic acid adenine dinucleotide phosphate had little effect on channel activation. Molecular studies indicated that Kir6.1 and SUR2B were the predominant components of the adenosine triphosphate sensitive K+ channel in the human detrusor. CONCLUSIONS To our knowledge we report the first single channel study of the adenosine triphosphate sensitive K+ channel in the human detrusor. The properties of this channel, ie unitary conductance, adenosine triphosphate sensitivity and diphosphate activation, were consistent with those of other smooth muscle organs. β-Nicotinamide adenine dinucleotide has the potency to activate adenosine triphosphate sensitive K+ channels in the human detrusor. This channel likely has some role during ischemic conditions as well as physiological muscle motion leading to the activation of cell metabolism.

Novel effect of 2-aminoethoxydiphenylborate through inhibition of calcium sensitization induced by Rho kinase activation in human detrusor smooth muscle.

Since the introduction of 2-aminoethoxydiphenylborate (2-APB) as a membrane permeable modulator of inositol (1,4,5)-trisphosphate receptors, subsequent studies have revealed additional actions of this chemical on multiple Ca(2+)-permeable ionic channels in the plasma membrane. However, no reports have yet examined 2-APB as a modulator targeting contractile machinery in smooth muscle, independent of Ca(2+) mobilization, namely Ca(2+) sensitization. Here, we assessed whether or not 2-APB affects intracellular signaling pathways of Ca(2+) sensitization for contraction using α-toxin permeabilized human detrusor smooth muscle. Although contractions were induced by application of Ca(2+)-containing bath solutions, 2-APB had little effect on contractions induced by 1 µM Ca(2+) alone but significantly reversed the carbachol-induced augmentation of Ca(2+)-induced contraction in the presence of guanosine triphosphate (carbachol-induced Ca(2+) sensitization). The rho kinase inhibitor Y-27632 and protein kinase C inhibitor GF-109203X also reversed the carbachol-mediated Ca(2+) sensitization. Additional application of 2-APB caused a small but significant further attenuation of the contraction in the presence of GF-109203X but not in the presence of Y-27632. Like carbachol, the rho kinase activator; sphingosylphosphorylcholine, protein kinase C activator; phorbol 12,13 dibutyrate, and myosin light chain phosphatase inhibitor; calyculin-A all induced Ca(2+) sensitization. However, the inhibitory activity of 2-APB was limited with sphingosylphosphorylcholine-induced Ca(2+) sensitization. This study revealed a novel inhibitory effect of 2-APB on smooth muscle contractility through inhibition of the rho kinase pathway.

Biofeedback Therapy for Stress Urinary Incontinence: Is Urodynamic Assessment Necessary?

Dear Editor In the recent issue of Nephro-Urology Monthly Journal, Bayrak et al. (1) presented a prospective, single institutional study to evaluate the effects of biofeedback therapy (BFT) on stress urinary incontinence (SUI) in women. The International Consultation on Incontinence Questionnaire – Short Form (ICIQ-SF) was utilized and ICIQ-SF scores were measured to evaluate the severity of their urinary incontinence symptoms. In addition, urodynamic investigation was performed and its parameters were examined. The results of this study demonstrated the remarkable improvement of ICIQ-SF scores following BFT while urodynamic parameters were not affected. The authors concluded that BFT is a good alternative to surgical treatment of SUI and urodynamic assessment is not recommended prior to BFT, as the values of urodynamic parameters did not change following BFT. The subject matter of this study is important and highly relevant as BFT has been intensively studied in women with urinary incontinence. Its potential efficacy has also been suggested in men, (2) and even in children (3) with urinary incontinence. A previous Cochrane systematic review and meta-analysis study (4) that critically evaluated 12 randomized control trials in the management of female urinary (stress, urge, and mixed) incontinence, demonstrated that pelvic floor muscle training (PFMT) alone gave better improvement of symptoms and continence specific quality of life, when compared to other treatments (no treatment, placebo, sham treatment, or other inactive control treatments), particularly in women with SUI alone, who seemed to have a greater treatment effect. In the management of SUI, BFT is a common adjunct used along with pelvic floor muscle training (PFMT) to improve training performance. Previous evidence also supported the possibility that BFT may provide benefits in addition to PFMT in women with urinary incontinence, the question remains as to what will be the impact of this study in supporting the benefits of using BFT for SUI. With respect to the important messages delivered, the methodology utilized requires critical appraisal in the absence of treatment control. Therefore, the improvement of ICIQ-SF may not only be affected by BFT, but may also be influenced by other behavioral treatments. Regardless of its limitations, the results support what has been demonstrated in other previous studies, as summarized by Herderschee et al. (5) in a more recent Cochrane systematic review and meta-analysis study. Among the 17 control trials and contributing data that was evaluated, they concluded that BFT in addition to PMFT may provide benefits in women with urinary incontinence. Nevertheless, further research is required as suggested by the authors, to differentiate whether the BFT, or some other differences between the trials, such as more contact with health professionals caused the beneficial effects. Unnecessary urodynamic evaluation prior to BFT as suggested in this study, is also questionable, if only based on this trial. As a matter of fact, urodynamic study is not routinely used prior to conservative or non-surgical treatment for SUI. Recently, urodynamic investigation has become controversial even for use prior to the surgical treatment of SUI. The inconclusive results regarding its ability to predict the outcome following surgery, due to the limited number of good clinical evidence, was considered to be one of the reasons. In contrast to the unchanged urodynamic parameters (bladder capacity, detrusor instability, sensation of the bladder, and residual urine volume) following BFT as reported in this trial, Capelini et al. (6) observed a significant increase in Valsalva leak point pressure, cystometric capacity and bladder volume at first desire to void following BFT. However, only a small number of patients (14) with SUI were included and accordingly, that may decrease the study’s reliability. Although both studies applied different types of validated questionnaire (ICIQ-SF versus King’s Health Questionnaire), the improvement in symptoms was consistent in both studies. As only a few studies have reported the effect of BFT on voiding performance, which focused on urodynamic assessment, this study represents a valuable and noteworthy addition to the field. Moreover, this trial also highlights an important point regarding the efficacy of BFT in patients who bordered on obese. The present trial and previous series provide us with valuable evidence that has rarely been found in other series.

Dysfunctional Voiding of Non-Neurogenic Neurogenic Bladder: A Urological Disorder Associated with Down Syndrome

Down syndrome (DS), the most common chromosomal abnormality with a prevalence of 1 case per 600 live births (Dennis & Marder,2001), has many manifestations that can affect multiple organ systems (American Academy of Pediatrics Comittee on Genetics, 2001; Kallen et al., 1996) including urological abnormalities which have been recognized throughout urinary tract (Ariel et al., 1991; Berg et al.,1960; Ahmed, 1990; Kravtzova et al., 1975; Handel et al., 2003; Kupferman et al., 1996; Bielek et al., 1996; Narashiman & Gupta, 2004; Koksal et al., 2003; Lang et al., 1987; Paulozzi et al., 1997). The extra copy of chromosome 21 has been suggested as an actor underlying the accompanied phenotypic abnormalities in the syndrome (Lejeune, 1959). Berg et al. described the first cases of urological anomalies associated with DS in their study of 141 DS autopsy cases and found 1 patient (0.7%) with renal agenesis and 5 patients (3.6%) with horseshoe kidney (Berg et al., 1960). Glomerular microcysts, renal hypoplasia and obstructive uropathy have also been recognized as the most common upper urinary tract anomalies in DS and their incidences were reported by Ariel et al. who examined 124 autopsy cases of DS for abnormalities in urinary tract system to be as high as 23.7% (23 of 97 patients), 21.4% (18 of 84 patients), and 6.45% (8 of the 124 cases), respectively (Ariel et al., 1991). In addition, simple renal cysts were also found in 7 of 124 cases (5.6%). Anomalies in ureteral structure has also been identified in DS (Ariel et al., 1991; Kravtzova et al., 1975; Handel et al., 2003). The incidence of obstructed megaureter or hydroureteronephrosis was reported in 2 of 124 cases (1.6%), while ureteral atresia was seen in 1 of 124 cases (0.8%) (Ariel et al., 1991). In addition, vesicoureteral reflux (Kravtzova et al., 1975), ureterovesical junction and ureteropelvic junction obstructions have also been described in patients with trisomy 21 (Handel et al., 2003). Trisomy 21 is one of genetic disorders that can also be accompanied by some urological abnormalities in lower urinary tract. Non-neurogenic neurogenic bladder (NNB) has been reported as a functional lower urinary tract abnormality seen in DS. Handel et al. retrospectively reviewed 26 patients with trisomy 21 and found 4 patients (15.4%) with NNB (Handel et al., 2003). Posterior urethral valve has also been identified in patients with trisomy 21 (Bielek et al., 1996; Narashiman & Gupta, 2004; Koksal et al., 2003; Lang DJ et al., 1987). Bielek et al who reviewed 48 cases of posterior urethral valves found 4 patients with