Control Of Lower Urinary Tract Function Research Articles

Targeting bladder function with network-specific epidural stimulation after chronic spinal cord injury

Profound dysfunctional reorganization of spinal networks and extensive loss of functional continuity after spinal cord injury (SCI) has not precluded individuals from achieving coordinated voluntary activity and gaining multi-systemic autonomic control. Bladder function is enhanced by approaches, such as spinal cord epidural stimulation (scES) that modulates and strengthens spared circuitry, even in cases of clinically complete SCI. It is unknown whether scES parameters specifically configured for modulating the activity of the lower urinary tract (LUT) could improve both bladder storage and emptying. Functional bladder mapping studies, conducted during filling cystometry, identified specific scES parameters that improved bladder compliance, while maintaining stable blood pressure, and enabled the initiation of voiding in seven individuals with motor complete SCI. Using high-resolution magnetic resonance imaging and finite element modeling, specific neuroanatomical structures responsible for modulating bladder function were identified and plotted as heat maps. Data from this pilot clinical trial indicate that scES neuromodulation that targets bladder compliance reduces incidences of urinary incontinence and provides a means for mitigating autonomic dysreflexia associated with bladder distention. The ability to initiate voiding with targeted scES is a key step towards regaining volitional control of LUT function, advancing the application and adaptability of scES for autonomic function.

Urethral dysfunction in a rat model of chemically induced prostatic inflammation: potential involvement of the MRP5 pump.

Prostate inflammation (PI) is a clinical condition associated with infection and/or inflammation of the prostate. It is a common disease frequently associated to lower urinary tract (LUT) symptoms. The urethra is an understudied structure in the LUT and plays a fundamental role in the urinary cycle. Here, we proposed to evaluate the effect of PI on the urethra tissue. Male Sprague-Dawley rats were used, and PI was induced by formalin injection into the ventral lobes of the prostate. The pelvic urethra at the prostatic level was harvested for histological analysis, contraction (electrical field stimulation and phenylephrine), and relaxation (sodium nitroprusside/MK-571) experiments. Various gene targets [cytochrome c oxidase subunit 2, transforming growth factor-β1, interleukin-1β, hypoxia-inducible factor-1α, α1A-adrenoceptor, inositol 1,4,5-trisphosphate receptor type 1, voltage-gated Ca2+ channel subunit-α1D, neuronal nitric oxide synthase, soluble guanylyl cyclase, phosphodiesterase 5A, protein kinase CGMP-dependent 1, and multidrug resistance-associated protein 5 (MRP5; ATP-binding cassette subfamily C member 5)] were quantified, and cGMP levels were measured. No histological changes were detected, and functional assays revealed decreased contraction and increased relaxation of urethras from the PI group. The addition of MK-571 to functional assays increased urethral relaxation. Genes associated with inflammation were upregulated in urethras from the PI group, such as cytochrome oxidase c subunit 2, transforming growth factor-β1, interleukin-1β, and hypoxia-inducible factor-1α. We also found increased expression of L-type Ca2+ channels and the neuronal nitric oxide synthase enzyme and decreased expression of the MRP5 pump. Finally, cGMP production was enhanced in urethral tissue of PI animals. The results indicate that PI is associated with proinflammatory gene expression in the urethra without histologically evident inflammation and that PI produces a dysfunctional urethra and MRP5 pump downregulation, which results in cGMP accumulation inside the cell. These findings would help to better understand LUT dysfunctions associated with PI and the role of MRP pumps in the control of LUT function.

Role of Central 5‐Hydroxytryptamine Receptors in Micturition Control

5‐Hydroxytryptamine (5‐HT) receptors in the central nervous system have been implicated in the control of micturition. In rats and cats, spinal and supraspinal reflex pathways involved in lower urinary tract (LUT) function exhibit dense serotonergic innervation and multiple 5‐HT receptors. At present, the most investigated 5‐HT receptor that has been shown to play a role in the control of micturition is the 5‐HT1A receptor, followed by 5‐HT7, 5‐HT2, and 5‐HT3 receptors. Most studies focus on the effects of these receptors on the parasympathetic outflow to the bladder and the somatic outflow to the external urethral sphincter (EUS) in rats. Earlier studies have shown that the activation of 5‐HT‐containing brain areas (the raphe nuclei in the caudal brainstem) inhibits bladder activity. However, 5‐HT1A and 5‐HT7 receptors have recently been suggested to have an excitatory role in the control of bladder function. 5‐HT1A receptors act at both a spinal and supraspinal level, while 5‐HT7 receptors act only at a supraspinal level. The activation of 5‐HT2A receptors in rats results in an increase in EUS activity. Overall, the pharmacological manipulation of the central serotonergic system can be a promising treatment strategy for LUT dysfunction. However, more studies are mandatory to fully understand the role of multiple 5‐HT receptors in the control of LUT function.