Improvement in Lower Urinary Tract Function Following a Single Bout of Acute Intermittent Hypoxia in Rats with Chronic Spinal Cord Injury

Abstract

Exposure to acute intermittent hypoxia (AIH) has been reported to improve respiratory and non‐respiratory somatic motor function in rodents and humans and has been proposed as a potential therapeutic intervention for treatment of chronic motor incomplete spinal cord injury (SCI). The goal of the present study is to characterize potential beneficial effects of AIH to improve lower urinary tract (LUT) function following incomplete SCI. To this end, female Sprague Dawley rats (225–250 g; n=11) received moderate midthoracic (T7–T9) spinal cord contusion injuries (200 kilodynes, Infinite Horizon Impactor; n=7) or sham injuries (spinal cord exposed, no injury; n=4) under isoflurane anesthesia. Following SCI, rats were inspected daily for SCI‐related issues (e.g., bladder/urinary tract infections, autophagia, overgrooming), and bladders were manually expressed until spontaneous voiding capability returned. Four weeks following the SCI/sham, bladder intravesical pressure and external urethral sphincter (EUS) EMG activity were recorded under urethane anesthesia (1.4 g/kg) during continuous infusion of saline (0.04 ml/min) into the bladder to elicit reflex micturition events (spontaneously breathing, vagus nerves intact). In addition, EMG data were acquired from the diaphragm and genioglossus muscles to assess effects on inspiratory motor outputs. Following 30–40 minutes of baseline recording, rats were exposed to a single bout of AIH consisting of three five‐minute episodes of hypoxia (10% O2; 90% N2) each separated by five‐minute exposures to room air. Following the AIH exposure, rats continued to spontaneously breathe room air, and data acquisition continued for up to 120 minutes. Prior to AIH, SCI rats exhibited pronounced rhythmic bladder activity consisting of both non‐voiding and voiding contractions. Typically, a series of non‐voiding bladder contractions with increasing amplitude preceded a voiding contraction, and the voiding contractions were incomplete resulting in continuous residual volume and an elevated minimum intravesical pressure. During each hypoxic episode during the AIH, the frequency of rhythmic bladder contraction increased and was associated with increased output volume and decreasing minimum intravesical pressure. In contrast, there was a marked decrease in rhythmic bladder activity during the normoxic period between hypoxic episodes with decreased output volume and increased minimum intravesical pressure. Immediately following the end of AIH, a similar decrease in rhythmic bladder contractions and output volume was observed and persisted for 5–10 minutes after which a more normal pattern of bladder activity (compared to baseline) emerged characterized by fewer non‐voiding contractions, increased output volume per volume per contraction, decreased minimum intravesical pressure, and a threshold‐driven pattern of bladder contraction that persisted up to 120 minutes post AIH. Sham operated rats exhibited a threshold‐driven pattern of bladder activity with efficient voiding and similar hypoxia‐dependent modulation of contraction frequency and increased output volume following AIH. These data suggest that AIH‐induced neuroplasticity results in improved LUT function in rats with chronic incomplete SCI and is a potentially promising therapeutic intervention for humans with SCI.Support or Funding InformationSupport for this project was provided by The Thomas Hartman Center for Parkinson's Research at Stony Brook University and The SUNY Brain Network of Excellence.