Weekly Acute Intermittent Hypoxia Elicits Sustained Beneficial Improvements in Reflex Bladder Function in Rats with Moderate Contusion SCI

Abstract

Acute intermittent hypoxia (AIH) administered either as daily or weekly therapy has been shown to improve both respiratory and motor function in preclinical and clinical studies in spinal cord injury (SCI). SCI can also severely impact bladder function, leading to problems with urine storage and emptying of the bladder that include detrusor overactivity, decreased voiding efficiency, and increased residual volume. Ongoing work in our laboratory has been evaluating the impact of AIH treatments delivered as either a single episode or daily episodes for 7 consecutive days as a strategy to promote improvements in bladder function in rats with moderate contusion SCI. In our studies, a single AIH treatment results in immediate short‐term reductions in bladder overactivity (i.e., non‐voiding bladder contractions, NVCs) and induction of more efficient voiding, while daily (7‐d) AIH treatments result in sustained similar improvements and restoration of urination pattern. In the current study, we investigated the effects of weekly AIH (wAIH) treatment administered 3x per week for 4 weeks on SCI‐induced bladder dysfunction in adult female SD rats with mid‐thoracic moderate contusion SCI. wAIH treatment consisted of five alternating 3‐min episodes of 12% O2 and 21% O2 and was initiated 4 weeks after SCI; weekly normoxia (wNx; 21% O2 episodes using the same timing) served as a gas delivery control. Prior to initiating weekly gas treatments, the magnitude of SCI‐induced deficits and progression of spontaneous recovery of both hindlimb motor function (BBB scores) and lower urinary tract (LUT) function (manual expression of urine volumes during post‐operative care) were assessed. These measurements revealed that the deficits and initial stages of recovery were similar in rats assigned to both treatment groups. 2 weeks after completion of the weekly gas treatments (which corresponds to 10 weeks after SCI), reflex bladder function was assessed during bladder filling and voiding in urethane‐anesthetized rats. For these experiments, reflex micturition events (rMEs) were elicited by continuous infusion of saline (0.04‐0.09 ml/min) into the bladder while intravesical bladder pressure (BP) was continuously measured. We found that in nearly all of the wAIH‐treated rats (~86%), the BP record during filling was characterized by an almost complete absence of NVCs per voiding contraction (VC), while in nearly all of the wNx‐treated rats (~80%), the BP record during filling was characterized by a severe degree of LUT dysfunction that included 3‐10 NVCs preceding each VC. Comparisons of VC features between these groups of rats revealed that wNx‐treated rats exhibited long inter‐contraction intervals (ICI; despite higher infusion rates; P=0.0326) and correspondingly larger fill (P=0.0187) and void (P=0.0029) volumes while wAIH‐treated rats exhibited shorter contraction duration (P=0.0381) and contraction area (P=0.0110). These findings suggest that wAIH treatment elicits sustained beneficial improvements in rME behaviors, resulting in a mild degree of LUT dysfunction in rats with chronic SCI.