Tetrahydrobiopterin Regulates Cyclic GMP-Dependent Electrogenic Cl Secretion in Mouse Ileum In Vitro

Authors

  • V. E. Rolfe,

    Corresponding author
    1. Gastroenterology Unit, Institute of Child Health, 30 Guilford Street, University College London, London WC1N 1EH, UK
    • To whom correspondence should be addressed at the Waltham Centre for Pet Nutrition, Freeby Lane, Waltham-on-the-Wolds, Melton Mowbray, LE14 4RT, UK.

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  • M. P. Brand,

    1. Department of Neurochemistry, Institute of Neurology, Queens Square, University College London, London WC1N 3BG, UK
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  • S. J. R. Heales,

    1. Department of Neurochemistry, Institute of Neurology, Queens Square, University College London, London WC1N 3BG, UK
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  • K. J. Lindley,

    1. Gastroenterology Unit, Institute of Child Health, 30 Guilford Street, University College London, London WC1N 1EH, UK
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  • P. J. Milla

    1. Gastroenterology Unit, Institute of Child Health, 30 Guilford Street, University College London, London WC1N 1EH, UK
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Abstract

  • 1Basal electrogenic Cl secretion, measured as the short-circuit current (Isc), was variable in ileum removed from tetrahydrobiopterin (BH4)-deficient hph-1 mice and wild-type controls in vitro, although values were not significantly different.
  • 2The basal nitrite release and mucosal cyclic guanosine 3′,5′-monophosphate (cyclic GMP) production were similar in control and BH4-deficient ileum.
  • 3Mucosally added Escherichia coli heat-stable toxin (STa, 55 ng ml−1) increased the nitrite release, cyclic GMP levels and the Isc in control ileum, but its secretory actions were reduced in BH4-deficient ileum.
  • 4L-Arginine (1 mM) increased the nitrite release, cyclic GMP production and the Isc in control ileum, but the actions were reduced in BH4-deficient ileum.
  • 5Serosal carbachol (1 mM) stimulated maximum short-circuit currents of similar magnitude in both control and BH4-deficient ileum, whilst nitrite release and cyclic GMP production were minimal.
  • 6E. coli STa and L-arginine increased electrogenic Cl secretion across intact mouse ileum in vitro by releasing nitric oxide and elevating mucosal cyclic GMP. The inhibition of these processes in the hph-1 mouse ileum suggests that BH4 may be a target for the modulation of electrogenic transport, and highlight the complexity of the interactions between nitric oxide and cyclic GMP in the gut.

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