title: Acute paraquat exposure impairs colonic motility by selectively attenuating nitrergic signalling in the mouse.
abstract: Paraquat, a common herbicide, is responsible for large numbers of deaths worldwide through both deliberate and accidental ingestion. Previous studies have eluded that the bioavailability of paraquat increases substantially with increasing dose and that these changes may in part be due to the effects that these high concentrations have on the gastrointestinal tract (GI tract). To date, the actions of acute, high concentrations (20mM for 60 min) of paraquat on the GI tract, particularly the colon which is a major site of paraquat absorption, are unknown. This study examined the effects of acute paraquat administration on colonic motility in the C57BL/6 mouse. Acute paraquat exposure decreased colonic motility and the amplitude of colonic migrating motor complexes (CMMCs), which are major motor patterns involved in faecal pellet propulsion. In isolated segments of distal colon, paraquat increased resting tension and markedly attenuated electrical field stimulation-evoked relaxations. Pharmacological dissection of paraquat's mechanism of action on both the CMMCs and field stimulated tissue using the nitric oxide synthase inhibitor NG-nitro-L-arginine and direct measurement of NO release from the myenteric plexus, demonstrated that paraquat selectively attenuates nitrergic signalling pathways. These changes did not appear to be due to alterations in colonic oxidative stress, inflammation or complex 1 activity, but were most likely caused by paraquat's ability to act as a redox couple. In summary, these data demonstrate that acute paraquat exposure attenuates colonic transit. These changes may facilitate the absorption of paraquat into the circulation and so facilitate its toxicity.
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Lucy
authors: L
authors: Diss
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Sarah
authors: S
authors: Dyball
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Tina
authors: T
authors: Ghela
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Jonathan
authors: J
authors: Golding
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Rachel
authors: R
authors: Morris
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Stephen
authors: S
authors: Robinson
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Rosemary
authors: R
authors: Tucker
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Talia
authors: T
authors: Walter
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Paul
authors: P
authors: Young
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Marcus
authors: M
authors: Allen
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Sara
authors: S
authors: Fidalgo
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Paul
authors: P
authors: Gard
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Jon
authors: J
authors: Mabley
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Bhavik
authors: B
authors: Patel
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK.
authors: Prabal
authors: P
authors: Chatterjee
authors: School of Pharmacy and Biomolecular Sciences, Huxley Building, College of Life, Health and Physical Sciences, University of Brighton, Brighton, East Sussex BN2 4GJ, UK. Electronic address: m.s.yeoman@brighton.ac.uk.
authors: Mark
authors: M
authors: Yeoman
mesh_terms: D000818:Animals; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism; D016065:Myoelectric Complex, Migrating / Q000187:drug effects; D009245:NADH Dehydrogenase / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D010269:Paraquat / Q000506:poisoning*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D019335:Nitroarginine; D009569:Nitric Oxide; D008315:Malondialdehyde; D009245:NADH Dehydrogenase; D010269:Paraquat
keywords: Colon motility; Colonic migrating motor complex; Paraquat and nitric oxide