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

Abstract

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. The basal nitrite release and mucosal cyclic guanosine 3′,5′‐monophosphate (cyclic GMP) production were similar in control and BH4‐deficient ileum. 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. 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. 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. 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.

Vagotomy inhibits the jejunal fluid secretion activated by luminal ileal Escherichia coli STa in the rat in vivo

“…Instillation of the nitric oxide synthase substrate l -arginine into the ileum also induced both ileal and jejunal secretion, but equivalent d -arginine did not alter fluid transport, indicating that the fluid secretion induced was not an osmotic effect. Recently, the nitric oxide (NO) synthase cofactor tetrahydrobiopterin was implicated in the regulation of electrogenic secretion stimulated by STa and l -arginine in the mouse ileum in vitro 9. This strongly suggests that NO is involved in intestinal secretion, and our present results show that NO is implicated in the activation of remote jejunal secretion.…”

Tetrahydrobiopterin deficiency induces gastroparesis in newborn mice

“…The newborn hph-1 mice has been previously reported to have pyloric muscle hypertrophy (2), and reduced bowel tissue L-arginine-stimulated NO generation was documented in adult animals of this BH4-deficient strain (29). Together these findings suggest that the reduced gastric emptying in newborn hph-1 mice involves reduced NO-dependent pyloric relaxation.…”

“…We have previously reported on the lungs of the newborn hph-1 mice, where we documented a 30-fold lower tissue BH4 content when compared with wild-type control animals of similar age (4). The hph-1 mice tissue BH4 content increases with age through an unknown mechanism (8,9), and the adult hph-1 mice ileal tissue BH4 content is only threefold less than age-matched control animals (29).…”

Gastrointestinal Function Regulation by Nitrergic Efferent Nerves

“…In the isolated ileum of wild-type mice, L-arginine increased NO release, cyclic GMP production, and electrogenic Cl Ϫ secretion. However, these actions were reduced in tetrahydrobiopterin (BH 4 )-deficient hph-1 mice, suggesting that BH 4 might be a target for the modulation of electrogenic ion transport; this highlights the complexity of the interactions between NO and cyclic GMP in the gut (Rolfe et al, 1997). It has been reported that BH 4 is a critical factor in producing NO from L-arginine (Kwon et al, 1989), and BH 4 deficiency not only reduces the production of NO but also enhances superoxide generation (Pou et al, 1992;Shinozaki et al, 1999).…”