Tetrahydrobiopterin regulates cyclic GMP-dependent electrogenic chloride secretion in mouse ileum in vitro.

Basal electrogenic Cl- secretion, measured as the short-circuit current (I-SC), 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 I-SC 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 I-SC 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.