Daily acute intermittent hypoxia therapy 1‐week after moderate contusion spinal cord injury improves lower urinary tract function in rats

Abstract

There is an increasing interest in the use of non-invasive acute intermittent hypoxia (AIH) as a therapeutic intervention to improve respiratory and locomotor function in spinal cord injury (SCI). SCI, however, also significantly disrupts normal bladder function, leading to detrusor overactivity, decreased voiding efficiency, and increased residual volume. Ongoing studies in our laboratory investigating the effects of AIH exposure in rats as a strategy for improving lower urinary tract (LUT) function following mid-thoracic SCI indicate that a single bout of AIH decreases the incidence of non-voiding bladder contractions (NVCs) and increases voiding efficiency. In the current study, we begin to evaluate the potential for AIH to be used as a therapy for inducing long-lasting improvements in SCI-induced LUT dysfunction. To accomplish this, we examined the effects of daily AIH (dAIH) administered for 7 consecutive days on both spontaneous awake micturition patterns and reflex micturition event (rME) behaviors in adult female Sprague-Dawley rats with mid-thoracic moderate contusion (200 kdyn) SCI. For these experiments, dAIH composed of five alternating 3-min exposures of hypoxia (12% O2) and normoxia (21% O2) was initiated 1-week after SCI, with awake micturition patterns being evaluated by overnight metabolic chamber measurements weekly for 2-3-weeks before and 4 weeks after SCI and rME behaviors elicited by continuous infusion of saline (0.04-0.09 ml/min) into the bladder being evaluated by cystometry at 4-weeks after SCI; daily normoxia (dNx; 21% O2 episodes) served as a control. The impact of SCI on hindlimb motor and LUT function prior to initiating dAIH or dNx treatment was evaluated using BBB scores and manually expressed urine volumes during post-operative care, and these measurements revealed that deficits and initial stages of recovery were similar (as expected) in both treatment groups. Serial metabolic chamber measurements in both dAIH- and dNx-treated rats that exhibited functional voids at 1-week post-SCI demonstrated that most rats exhibited some degree of functional recovery of micturition pattern behaviors. Only dAIH-treated rats, however, exhibited a recovery of void frequency pattern (i.e., number of voids and inter-void interval)to pre-SCI levels albeit with slightly increased void volumes; dNx-treated rats also had increased void volumes. Intravesical bladder pressure (BP) measurements during terminal cystometry experiments in urethane-anesthetized (1.4 g/kg) rats revealed that dAIH-treated rats exhibited a decreased incidence of NVCs and that voiding contractions had increased delta BP (peak BP-minimum BP) and dynamic voiding efficiency (void volume/fill volume) compared to dNx-treated rats. Taken together, these findings suggest that dAIH treatment produces beneficial improvements in LUT function lasting at least two weeks that include more efficient voiding and decreased NVCs, and further support the use of dAIH therapy to treat SCI-induced LUT dysfunction.