Tetrahydrobiopterin regulates cyclic GMP-dependent electrogenic Cl- secretion in mouse ileum in vitro.
1. Basal 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. 2. The basal nitrite release and mucosal cyclic guanosine 3',5'-monophosphate (cyclic GMP) production were similar in control and BH4-deficient ileum. 3. Mucosally 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. 4. L-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. 5. Serosal 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. 6. E. 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.
Rolfe
V E
VE
Gastroenterology Unit, Institute of Child Health, University College London, UK. vivienr@wcpn.demon.co.uk
Brand
M P
MP
Heales
S J
SJ
Lindley
K J
KJ
Milla
P J
PJ
D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism*; D018679:Cholinergic Agonists / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D007082:Ileum / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D013997:Time Factors
D000975:Antioxidants; D018118:Chloride Channels; D018679:Cholinergic Agonists; D008070:Lipopolysaccharides; D009573:Nitrites; D001708:Biopterins; D009569:Nitric Oxide; D002217:Carbachol; D001120:Arginine; C003402:sapropterin; D006152:Cyclic GMP