The coupling of the spinal postsynaptic density-95 (PSD-95) with the glutamatergicN-methyl-d-aspartate receptor NR2B subunit and the subsequent NR2B phosphorylation contribute to pain-related plasticity. Increasing evidence reveals that kalirin, a Rho-guanine nucleotide exchange factor, modulates PSD-95-NR2B-dependent neuroplasticity. Our laboratory recently demonstrated that serum-inducible and glucocorticoid-inducible kinase 1 (SGK1) participates in inflammation-associated pain hypersensitivity by modulating spinal glutamatergic neurotransmission. Because kalirin is one of the proteins in PSD that is highly phosphorylated by various kinases, we tested whether kalirin could be a downstream target of spinal SGK1 that participates in neuropathic pain development via regulation of the PSD-95–NR2B coupling-dependent phosphorylation of NR2B. We observed that spinal nerve ligation (SNL, L5) in male Sprague Dawley rats resulted in behavioral allodynia, which was associated with phosphorylated SGK1 (pSGK1), kalirin, and phosphorylated NR2B (pNR2B) expression and an increase in pSGK1–kalirin–PSD-95–pNR2B coprecipitation in the ipsilateral dorsal horn (L4–L5). SNL-enhanced kalirin immunofluorescence was coincident with pSGK1, PSD-95, and pNR2B immunoreactivity. Small-interfering RNA (siRNA) that targeted spinal kalirin mRNA expression (10 μg, 10 μl; i.t.) reduced SNL-induced allodynia, kalirin and pNR2B expression, as well as kalirin–PSD-95 and PSD-95–pNR2B coupling and costaining without affecting SGK1 phosphorylation. Daily administration of GSK-650394 (an SGK1 antagonist; 100 nm, 10 μl, i.t.) not only exhibited effects similar to the kalirin mRNA-targeting siRNA but also attenuated pSGK1–kalirin costaining and SGK1–kalirin coupling. We suggest that nerve injury could induce spinal SGK1 phosphorylation that subsequently interacts with and upregulates kalirin to participate in neuropathic pain development via PSD-95–NR2B coupling-dependent NR2B phosphorylation.

Aims: Though the pressure‐volume analysis (PVA), a method based on thermodynamics, is broadly used for assaying cardiac functions, its potential application on the physiology/pathophysiology of the urinary bladder, which processes resemble thermodynamic cycles to the heart, has not been established.Methods: Cystometry recording intravesical pressure (IVP) and intravesical volume (IVV) of rhythmic voiding contractions caused by a constant saline infusion (0.04 mL/min) were carried out in forty urethane‐anesthetized female Sprague‐Dawley rats, and the PVA was established by plotting IVP against IVV.Results: Pressure‐volume points shaped coincident enclosed loops, and loop‐associated urodynamic parameters kept stable under a constant infusion rate (0.04 mL/min). Enhancing preload (by elevating infusion rates to 0.08 and 0.12 mL/min) increased the area enclosed by the loop (Apv) and shifted loops to the right and slightly upward. Augmenting afterload (by enhancing resistances using 1/4 and 1/2 urethra clamping) increased Apv and shifted loops markedly to the right and upward. Without affecting Apv, muscarine (0.01 and 0.1 mM)‐induced inotropic states shifted loop to the left and upward that was as opposed to the atropine (0.01 and 0.1 mM)‐induced anti‐inotropic state.Conclusions: Not only consistently assayed baseline bladder functions, PVA but also validly measured modified bladder functions due to altered extrinsic environment and intrinsic contractility of the bladder itself. In accompanied by cystometry, PVA could provide a clear concept about the relationship between time, pressure, and volume in the voiding activity.

Importance: It needs to be clarified whether trans-obturator tape (TOT)-enhanced urethral resistance could impact the voiding function.Objective: Although TOT has been well-recognized for enhancing urethral resistance to restore continence in stress urinary incontinence (SUI) patients, whether the bladder’s voiding functions adapt to the TOT-enhanced resistance has not been adequately investigated. This study thereby aimed to investigate whether TOT impacts the bladder’s thermodynamic efficacy during the voiding phase.Design: A retrospective analysis of urodynamics performed before and after TOT was assessed.Setting: A tertiary referral hospital in Taiwan.Participants: A total of 26 female SUI patients who underwent urodynamic investigations before and after TOT.Main outcomes and measures: The area enclosed by the pressure-volume loop (Apv), which represents the work performed by the bladder during voiding, in a pressure-volume analysis established by plotting the detrusor pressure versus intra-vesical volume was retrospectively analyzed. Paired Student’s t-tests were employed to assess the difference in values before and after the operation. Significance in difference was set at p < 0.05.Results: TOT increased Apv in 20 of 26 (77%) patients and significantly increased the mean Apv compared to the preoperative control (2.17 ± 0.18 and 1.51 ± 0.13 × 10³ cmH₂O-ml, respectively p < 0.01). TOT also increased the mean urethral resistance (1.03 ± 0.30 vs. 0.29 ± 0.05 cmH2O-sec/ml, p < 0.01) and mean voiding pressure (25.87 ± 1.72 and 19.30 ± 1.98 cmH2O p < 0.01) but did not affect the voided volume and voiding time. Moreover, the TOT-induced Apv increment showed a moderate correlation with the changes in urethral resistance and voiding pressure (both r > 0.5) but no correlation with changes in voided volume or voiding time. It is remarkable that the TOT-induced urethral resistance increment showed a strong correlation with changes in voiding pressure (r > 0.7).Conclusion and Relevance: The bladder enhances thermodynamic efficacy by adapting the voiding mechanism to increased urethral resistance caused by TOT. Further studies with higher case series and longer follow-ups should assess whether this effect could be maintained over time or expire in a functional detrusor decompensation, to define diagnostic criteria that allow therapeutic interventions aimed at its prevention during the follow-up.Clinical Trial Registration: (clinicaltrials.gov), identifier (NCT05255289)

Although trans-vaginal mesh (TVM) offers a successful anatomical reconstruction and can subjectively relieve symptoms/signs in pelvic organ prolapse (POP) patients, its objective benefits to the voiding function of the bladder have not been well established. In this study, we investigated the therapeutic advantage of TVM on bladder function by focusing on the thermodynamic workload of voiding. The histories of 31 POP patients who underwent TVM repair were retrospectively reviewed. Cystometry and pressure volume analysis (PVA) of the patients performed before and after the operation were analyzed. TVM postoperatively decreased the mean voiding resistance (mRv, p < 0.05, N = 31), reduced the mean and peak voiding pressure (mPv, p < 0.05 and pPv, p < 0.01, both N = 31), and elevated the mean flow rate (mFv, p < 0.05, N = 31) of voiding. While displaying an insignificant effect on the voided volume (Vv, p < 0.05, N = 31), TVM significantly shortened the voiding time (Tv, p < 0.05, N = 31). TVM postoperatively decreased the loop-enclosed area (Apv, p < 0.05, N = 31) in the PVA, indicating that TVM lessened the workload of voiding. Moreover, in 21 patients who displayed postvoiding urine retention before the operation, TVM decreased the residual volume (Vr, p < 0.01, N = 21). Collectively, our results reveal that TVM postoperatively lessened the workload of bladder voiding by diminishing voiding resistance, which reduced the pressure gradient required for driving urine flow.

Aims: Pressure in the bladder, which is a high compliance organ, is only slightly elevated to a considerable filling volume during storage. Although cystometry off-line offers mean compliance, no protocol is available for real-time assays of the dynamics of bladder compliance, and the potential impact of solifenacin and mirabegron on dynamic bladder compliance has not been established.Methods: Along with constantly infused cystometry, a pressure-volume analysis (PVA) was performed by plotting intra-vesical volume against pressure in Sprague-Dawley rats. The instant compliance was assayed as the slope of the trajectory, and the mean compliance (Cm) was determined by the slope of the line produced by regression of the data points at the end of the first, second, and third quarters of the filling phase.Results: Under a steady-state, the PVA trajectory moved clockwise which shaped coincident enclosed loops with stable compliance. Though administering to naïve animals solifenacin, but not mirabegron (both 1 × 10⁻⁵−1 × 10⁻¹ mg/kg, i.a.) decreased the peak pressure, both of these reagents exhibited acute increments in the trajectory slope and Cm of the filling phase in a dose-dependent manner (ED₅₀ = 1.4 × 10⁻⁴ and 2.2 × 10⁻⁵ mg/kg, respectively). Resembling urine frequency/urgency in OAB patients, the voiding frequency of a capacity-reduced bladder was increased in association with decreased compliance which was ameliorated by both acute solifenacin and mirabegron injections (both 1 × 10−1 mg/kg).Conclusion: In addition to their well-known anti-inotropic/relaxative effects, solifenacin, and mirabegron induce an acute increase in bladder compliance to ameliorate OAB-like syndromes. Together with time-domain cystometry, PVA offers a platform for investigating the physiology/pathophysiology/pharmacology of bladder compliance which is crucial for urine storage.