Yokoyama, O. | Search bioRxiv

bioRxiv2024

Phosphodiesterase-5 inhibition inhibits epithelial ATP release and restores detrusor contractility in rats with type 2 diabetes via an increase in bladder blood flow

PurposeThe bladder dysfunction associated with type 2 diabetes mellitus (T2DM) involves urine storage and voiding disorders. We evaluated the pathologic conditions of bladder wall in a rat model of T2DM and evaluated the effects of the phosphodiesterase-5 (PDE-5) inhibitor tadalafil (TA). Materials and MethodsMale Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) rats comprised T2DM and control groups. TA was orally administered for 12 weeks. The bladder blood flow and ATP released from the bladder epithelium were measured using laser speckle imaging and an organ bath bladder distention test. The expression levels of markers of hypoxia, pro-inflammatory cytokines, and growth factors in the bladder wall were measured by real-time PCR and ELISA. The contractions of bladder strips in response to KCl and carbachol were monitored in OLETF rats. ResultsThe bladder blood flow was impaired and there was greater ATP release and vesicular nucleotide transporter (VNUT) expression in the OLETF rats than in the LETO rats, but these effects were suppressed by TA administration. Furthermore, the high expression of HIF-1, 8-OHdG, IL-6, TNF-, IGF-1, and bFGF in the OLETF rats was reduced by TA administration. In the OLETF rats, the contractile responses of bladder strips to KCl and carbachol were impaired, but were restored by TA administration. ConclusionsThe impairment of bladder blood flow in rats with T2DM is associated with greater ATP release and the upregulation of VNUT, markers of hypoxia, proinflammatory cytokines, and growth factors in the bladder epithelium. PDE5 inhibition has the potential to prevent the storage and voiding dysfunction associated with T2DM.

pharmacology and toxicology↗

bioRxiv2023

Future spinal reflex is embedded in primary motor cortex output

Mammals can execute intended limb movements despite the fact that spinal reflexes involuntarily modulate muscle activity. To generate appropriate muscle activity, the cortical descending motor output must coordinate with spinal reflexes, yet the underlying neural mechanism remains unclear. We simultaneously recorded activities in motor-related cortical areas, afferent neurons, and forelimb muscles of monkeys performing reaching movements. Motor-related cortical areas, primarily the primary motor cortex (M1), encode subsequent afferent activities attributed to forelimb movements. M1 also encodes a subcomponent of muscle activity evoked by these afferent activities, corresponding to spinal reflexes. Furthermore, selective disruption of the afferent pathway specifically reduced this subcomponent of muscle activity, suggesting that M1 output drives muscle activity not only through direct descending pathways but also through the "transafferent" pathway composed of descending plus subsequent spinal reflex pathways. Thus, M1 provides optimal motor output based on an internal forward model that prospectively computes future spinal reflexes.

neuroscience↗