Oxidative stress disrupts purinergic neuromuscular transmission in the inflamed colon. (8th July 2013)

• Record Type: Journal Article
• Authors: Roberts, Jane A.; Durnin, Leonie; Sharkey, Keith A.; Mutafova‐Yambolieva, Violeta N.; Mawe, Gary M.
• Is Part Of: Journal of physiology. Volume 591:Number 15(2013:Aug.)
• Page Start: 3725
• Page End: 3737
• Publication Date: 2013-07-08
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2013.254136
• Languages: English
• ISSNs: 0022-3751

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Key points</title> <p> <list id="l1" list-type="simple"> <list-item> <label> </label> <p>Colitis is associated with an attenuation of purinergic inhibitory neuromuscular transmission.</p> </list-item> <list-item> <label> </label> <p>In this study we tested the hypothesis that purine release is disrupted due to an effect of oxidative stress on mitochondrial purine synthesis.</p> </list-item> <list-item> <label> </label> <p>Stimulus‐induced release of purines was decreased in inflamed colons.</p> </list-item> <list-item> <label> </label> <p>Disruption of mitochondrial purine synthesis, or induction of oxidative stress, mimicked the effects of inflammation on purinergic neuromuscular transmission.</p> </list-item> <list-item> <label> </label> <p>Treatment of animals with a free radical scavenger resulted in a protection of the purinergic neuromuscular transmission.</p> </list-item> <list-item> <label> </label> <p>Treatment with a free radical scavenger also resulted in an improvement of propulsive motility in inflamed colons.</p> </list-item> </list> </p> <p> <bold>Abstract </bold> Colitis, induced by trinitrobenzene sulfonic acid (TNBS) in guinea pig, leads to decreased purinergic neuromuscular transmission resulting in a reduction in inhibitory junction potentials (IJPs) in colonic circular muscle. We explored possible mechanisms responsible for this inflammation‐induced neurotransmitter plasticity. Previous studies have suggested that the deficit in inflamed tissue involves decreased ATP release. We therefore hypothesized that decreased purinergic transmission results from inflammation‐induced free radical damage to mitochondria, leading to decreased purine synthesis and release. Stimulus‐induced release of purines was measured using high‐performance liquid chromatography, and quantities of all purines measured were significantly reduced in the inflamed colons as compared to controls. To test whether decreased mitochondrial function affects the IJP, colonic muscularis preparations were treated with the mitochondrial ATP synthase inhibitors oligomycin or dicyclohexylcarbodiimide, which resulted in a significant reduction of IJP amplitude. Induction of oxidative stress <italic>in vitro</italic>, by addition of H<sub>2</sub>O<sub>2</sub> to the preparation, also significantly reduced IJP amplitude. Purinergic neuromuscular transmission was significantly restored in TNBS‐inflamed guinea pigs, and in dextran sodium sulfate‐inflamed mice, treated with a free radical scavenger. Furthermore, propulsive motility in the distal colons of guinea pigs with TNBS colitis was improved by <italic>in vivo</italic> treatment with the free radical scavenger. We conclude that oxidative stress contributes to the reduction in purinergic neuromuscular transmission measured in animal models of colitis, and that these changes can be prevented by treatment with a free radical scavenger, resulting in improved motility.</p> </abstract>