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

Abstract

Aims To evaluate the functional and molecular alterations of contractile and relaxant machinery in the bladder and urethra that lead to the underactive bladder (UAB) in old female mice. Methods Female young (3‐months) and old (18‐months) C57BL/6 mice were used. Urodynamic was assessed in awake and anaesthetized mice. Electrical‐field stimulation (EFS) and concentration‐response curves to contractile and relaxing agents in isolated bladders and urethras were performed. Messenger RNA (mRNA) expressions of muscarinic, adrenergic, and transient receptor potential vanilloid‐4 (TRPV4), and of the enzymes tyrosine hydroxylase and neuronal nitric oxide synthase (nNOS) were determined. Bladder cyclic adenosine monophosphate (cAMP) levels were measured. Results Cystometry in old mice showed incapacity to produce bladder emptying. On filter paper, old mice showed reduced urinary spots. Compared to the young group, bladder contractions induced by EFS and carbachol were lower in old mice. The β3‐adrenoceptor agonist mirabegron promoted higher bladder relaxation and elevation of cAMP levels in old mice. In old mice urethras, the α1a‐adrenoceptor agonist phenylephrine produced higher contractions, but no differences were found for the NO donor sodium nitroprusside‐induced relaxations. In old mice, increased mRNA expressions of β3‐ and α1a‐adrenoceptors in bladder and urethra were found, respectively, whereas the muscarinic M2 and M3 receptors and β2‐adrenoceptors did not change between groups. Reduced mRNA expressions of tyrosine hydroxylase and nNOS were found in old mouse urethras. Additionally, TRPV4 expression was reduced in bladder urothelium from old mice. Conclusion Age‐associated mouse UAB is the result of autonomic dysfunction at multiple levels leading to the less sensitive and overrelaxed bladder, along with urethral hypercontractility.

High percentage of neurologic deficits in the electrophysiology study of the lower urinary tract in patients with detrusor underactivity and chronic urinary retention

“…Recent research works on aging animal models have demonstrated that aging results in autonomic dysregulation, leading to a less sensitive and overrelaxed bladder. 23 The urethral flow-evoked voiding reflexes also decline with age. 24 Patients with DU after radical hysterectomy might benefit from urethral botulinum toxin A injection.…”

“…It suggested that they also had afferent or efferent neuropathy of the lower urinary tract. Recent research works on aging animal models have demonstrated that aging results in autonomic dysregulation, leading to a less sensitive and overrelaxed bladder 23 . The urethral flow‐evoked voiding reflexes also decline with age 24 .…”

Stretch‐ and carbachol‐induced ATP release from bladder wall preparations of young and aged mice

“…However, autonomic dysregulation has been described in aged female mice. 22 The reasons for these different ageing responses in various studies are unclear, but we normalized our data to cross-sectional area of the preparation that included mucosa. Thus, a greater proportion of acontractile mucosa as well as replacement of muscle with connective tissue would both contribute to reduced overall contractile function, accompanied by increased passive stiffness as quantified by a greater elastic modulus.…”

Detrusor Underactivity and Underactive Bladder in Women: What Is New?

“…This may explain the increase in DU in older groups. Recent work in female rats, comparing older and younger groups, have also suggested that autonomic dysfunction at various levels may also be contributory [13].…”