Urinary Bladder Dysfunction in Transgenic Sickle Cell Disease Mice

Abstract

BackgroundUrological complications associated with sickle cell disease (SCD), include nocturia, enuresis, urinary infections and urinary incontinence. However, scientific evidence to ascertain the underlying cause of the lower urinary tract symptoms in SCD is lacking.ObjectiveThus, the aim of this study was to evaluate urinary function, in vivo and ex vivo, in the Berkeley SCD murine model (SS).MethodsUrine output was measured in metabolic cage for both wild type and SS mice (25-30 g). Bladder strips and urethra rings were dissected free and mounted in organ baths. In isolated detrusor smooth muscle (DSM), relaxant response to mirabegron and isoproterenol (1nM-10μM) and contractile response to (carbachol (CCh; 1 nM-100μM), KCl (1 mM-300mM), CaCl2 (1μM-100mM), α,β-methylene ATP (1, 3 and 10 μM) and electrical field stimulation (EFS; 1-32 Hz) were measured. Phenylephrine (Phe; 10nM-100μM) was used to evaluate the contraction mechanism in the urethra rings. Cystometry and histomorphometry were also performed in the urinary bladder.ResultsSS mice present a reduced urine output and incapacity to produce typical bladder contractions and bladder emptying (ex vivo), compared to control animals. In DSM, relaxation in response to a selective β3-adrenergic agonist (mirabegron) and to a non-selective β-adrenergic (isoproterenol) agonist were lower in SS mice. Additionally, carbachol, α, β-methylene ATP, KCl, extracellular Ca2+ and electrical-field stimulation promoted smaller bladder contractions in SS group. Urethra contraction induced by phenylephrine was markedly reduced in SS mice. Histological analyses of SS mice bladder revealed severe structural abnormalities, such as reductions in detrusor thickness and bladder volume, and cell infiltration.ConclusionsTaken together, our data demonstrate, for the first time, that SS mice display features of urinary bladder dysfunction, leading to impairment in urinary continence, which may have an important role in the pathogenesis of the enuresis and infections observed the SCD patients.

Autonomic dysregulation at multiple sites is implicated in age‐associated underactive bladder in female mice

“…Compared with young mice, we observed a three times higher response ( E max ) to the selective β 3 ‐adrenoceptor agonist mirabegron in old mice, whereas no significant alterations to the nonselective β‐adrenoceptor agonist isoprenaline were found between groups. Of interest, the bladder relaxations to isoprenaline are higher than mirabegron in rats, whereas the opposite is seen in mouse bladder . In the human bladder, the relaxing response is comparable between isoprenaline and mirabegron .…”

“…Of interest, the bladder relaxations to isoprenaline are higher than mirabegron in rats, 16 whereas the opposite is seen in mouse bladder. 17 In the human bladder, the relaxing response is comparable between isoprenaline and mirabegron. 16 Therefore, we may not exclude that differences between isoprenaline and mirabegron in our study rely on the animal species used or specific methodological characteristics such as the agent used to produce precontraction and attained levels of precontraction.…”

Nocturnal Enuresis in Children and Adolescent with Sickle cell Anemia

“…The increased bladder pressure in addition to the reduced urethral contraction that was observed in the transgenic Sickle Cell Disease Mice [56] could explain the increased frequency of NE in children with SCA and OSA.…”

“…An increase in the maximum functional bladder capacity with age could be another possible explanation [50][51][52][53][54][55]. In a recent report, Claudino et al [56] evaluated the urinary bladder function in a transgenic Sickle Cell Disease Mice. They found the following; reduced urine output, incapacity to produce typical bladder contraction and bladder emptying, lower detrusor muscle relaxation, small bladder contraction and reduced urethral contraction.…”

Where will the next generation of medical treatments for overactive bladder syndrome come from?

“…For instance, detrusor overactivity and non‐voiding contractions are the closest proxy parameter of urgency in animal models . They can be observed in a variety of animal models, including spontaneously hypertensive rats, rats with renovascular hypertension or congestive heart failure, mice with sickle cell disease, and various rodent models of type 1 and 2 diabetes . If patients presenting with OAB represent a group of underlying pathologies, it is unlikely that a single master switch exists.…”