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INTRAVESICAL TROSPIUM CHLORIDE DEMONSTRATES DOSE-DEPENDENT PRESSURE CONTROL AND MODULATES COLLAGEN REMODELING GENE EXPRESSION IN A RAT NEUROGENIC BLADDER MODEL.
Venkat M. Ramakrishnan, M.D., Ph.D.1, Alex A. Bigger-Allen, Ph.D.1, Kyle P. Costa, B.S.1, Lina Dai, M.D., Ph.D.1, Gabriel L. Ocampo, M.S.1, Hatim Thaker, M.D.1, Andrea M. Sartori, Ph.D.2, Maryrose P. Sullivan, Ph.D.3, Vivian Cristofaro, Ph.D.3, Margot S. Damaser, Ph.D.4, Siam Oottamasathien, M.D.1, Carlos R. Estrada, Jr., M.D., M.B.A.1, Michael J. Cima, Ph.D.5, Rosalyn M. Adam, Ph.D.1.
1Boston Children's Hospital, Boston, MA, USA, 2Beth Israel Deaconess Medical Center, Boston, MA, USA, 3Boston Veterans Affairs Medical Center, West Roxbury, MA, USA, 4Cleveland Clinic Foundation, Cleveland, OH, USA, 5Massachusetts Institute of Technology, Cambridge, MA, USA.
BACKGROUND: Neurogenic lower urinary tract dysfunction (NLUTD) after spinal cord injury (SCI) is characterized by detrusor overactivity, reduced compliance, and fibrosis, with elevated storage pressures driving upper-tract deterioration. Oral anticholinergics such as trospium chloride (TrCl), a permanently charged quaternary amine (~428 Da), face challenges with systemic side effects and adherence. Intravesical TrCl achieves high local concentrations with minimal systemic absorption and is efficacious in idiopathic detrusor overactivity; however, its dose-response relationship and tissue-level mechanisms in NLUTD remain undefined.
We hypothesized that intravesical TrCl would demonstrate dose-dependent control of bladder storage pressures and modulate collagen remodeling gene expression in a rat SCI model of neurogenic bladder.
METHODS: Ten-week-old female Sprague-Dawley rats underwent suprapubic catheter implantation, followed by T8-T10 SCI transection seven days later. Animals were randomized to daily 500 µL intravesical instillations of vehicle (water) or TrCl at five concentrations spanning seven orders of magnitude: ultra-low (0.000065 µg/mL), low (0.0065 µg/mL), intermediate (0.065 µg/mL), therapeutic (0.65 µg/mL, matched to estimated human urinary concentrations after standard oral dosing), and supratherapeutic (65 µg/mL). At four weeks, bladder function was evaluated using conscious cystometry (60 µL/min saline infusion) for up to 3 hours. Pressure-distribution density plots were generated and the proportion of time at or above 20 cm H2O was calculated. A dose-response curve was modeled using a log-logistic approach in R. Bladder tissues were harvested for transcriptomic analysis comparing controls, SCI + vehicle, and SCI + therapeutic-dose TrCl. Statistical analysis was performed using the Dunn test.
RESULTS: Intravesical TrCl produced a dose-dependent redistribution of bladder pressure profiles toward lower, safer storage pressures. Therapeutic-dose TrCl reduced the proportion of cystometric time spent ≥ 20 cm H2O from 51% in vehicle controls to 2% (p = 0.028). Both therapeutic and supratherapeutic TrCl reduced the overall pressure area under the curve by 72% and 85% (p = 0.044 and 0.013 vs. vehicle respectively). Intermediate dosing yielded partial suppression, while ultra-low dosing demonstrated minimal deviation from controls. Log-logistic modeling defined a sigmoid dose-response curve with a clear therapeutic plateau and a predicted ED50 of 92.9 pg/mL (p = 4.006x10
-6). Transcriptomic analysis revealed significant TrCl-responsive changes in genes associated with fibroproliferative remodeling including those encoding collagen subunits (
Col1a1, Col1a2, and
Col3a1) and collagen cross-linking regulators dysregulated by SCI, as well as genes governing cytoskeletal remodeling (
Thbs2), apoptosis (
Bbc3), and inflammation (
IL6). Master regulator analysis identified increased expression of REST target genes and decreased activity of mechanosensitive AP-1 complex members (
Jun,
Jun-d,
Fosl1,
Fosl2) in TrCl-treated bladders, supporting a transcriptional response to attenuated pathological pressure.
CONCLUSIONS: Intravesical TrCl demonstrated a dose-dependent pressure control in neurogenic bladders after SCI, with the therapeutic dose effectively normalizing storage pressures. Critically, TrCl treatment modulated collagen and collagen cross-linking gene expression, providing molecular evidence that intravesical anticholinergic therapy may attenuate fibrotic remodeling driving NGB progression—not merely by suppressing detrusor overactivity. These findings establish the pharmacologic and mechanistic foundation for translating intravesical TrCl to children and adults with neurogenic bladder disease.
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