Sickle cell disease (SCD) is associated with overactive bladder (OAB). Detrusor overactivity, a component of OAB, is present in a SCD mouse, but the molecular mechanisms for this condition are not well defined. We hypothesize that NO/RhoA/ROCK dysregulation is a mechanism for detrusor overactivity and that NO-releasing nanoparticles (NO-np), a novel NO delivery system, may serve to treat this condition. Male adult SCD transgenic, combined eNOS/nNOS knockout (dNOS-/-), and wild-type (WT) mice were used. Empty-np or NO-np was injected into the bladder, followed by cystometric studies. The expression levels of phosphorylated eNOS (Ser-1177), Akt (Ser-473), nNOS (Ser-1412), and MYPT1 (Thr-696) were assessed in the bladder. SCD and dNOS-/- mice had a greater (P<0.05) number of voiding and non-voiding contractions compared to WT mice, and they were normalized by NO-np treatment. eNOS (Ser-1177) and AKT (Ser-473) phosphorylation were decreased (P<0.05) in the bladder of SCD compared to WT mice and reversed by NO-np. Phosphorylation of myosin phosphatase target subunit 1 (P-MYPT1), a marker of the RhoA/ROCK pathway, was increased (P<0.05) in the bladder of SCD mice compared to WT and reversed by NO-np. nNOS phosphorylation on positive (Ser-1412) regulatory site was decreased (P<0.05) in the bladder of SCD mice compared to WT and was not affected by NO-np. NO-np did not affect any of the measured parameters in WT mice. In conclusion, dysregulation of NO and RhoA/ROCK pathways are associated with detrusor overactivity in SCD mice; NO-np reverses these molecular derangements in the bladder and decreases detrusor overactivity. SIGNIFICANCE STATEMENT: Voiding abnormalities commonly affect SCD patients but are problematic to treat. Clarification of the science for this condition in an animal model of SCD may lead to improved interventions for it. Our findings suggest that novel topical delivery of a vasorelaxant agent nitric oxide into the bladder of these mice corrects overactive bladder by improving deranged bladder physiology regulatory signaling.
The Journal of pharmacology and experimental therapeutics. 2020 Mar 06 [Epub ahead of print]
Serkan Karakus, Biljana Musicki, Mahantesh S Navati, Joel M Friedman, Kelvin P Davies, Arthur L Burnett
The James Buchanan Brady Urological Institute; ., The James Buchanan Brady Urological Institute., Department of Physiology and Biophysics, Albert Einstein College of Medicine.