Effects of cyclic AMP and theophylline on chloride conductance across toad skin.

1. The effects of the phosphodiesterase inhibitors theophylline and isobutylmethylxanthine (IBMX) on baseline and voltage-activated Cl- conductance (gCl) of toad skin were compared with those of the potent 2-chlorophenylthio analogue of cAMP (CPT-cAMP). 2. Using intact and split skins of Bufo viridis we confirmed that theophylline and IBMX raised the voltage-activated gCl with a pattern identical to that seen under control conditions. This effect was small or missing if gCl was already high in the control. 3. CPT-cAMP, in contrast, increased the Cl(-)-specific conductance by up to 6 mS cm-2 at short circuit. The characteristic time-dependent, slow activation of gCl by serosa-positive clamp potentials was completely lost under these conditions. 4. Coinciding with the loss of voltage activation of gCl the plateau value of the Lorentzian component of fluctuation in current at serosa-positive clamp potentials decreased by almost 50%. The corner frequencies were not notably different. 5. After CPT-cAMP, the sigmoidal voltage-conductance relation that is characteristic of control conditions or after theophylline disappeared; the patterns were variable and incompatible with voltage activation. 6. The voltage-activated gCl under control conditions and with theophylline was blocked by mucosal NO3-, I- or SCN-, the last two being almost equally effective. In the presence of CPT-cAMP, mucosal NO3- had minimal influence on tissue conductance, whereas the effects of I- and SCN- were essentially unchanged. Br- on the mucosal side could substitute for Cl- under all conditions. 7. The results suggest that protein phosphorylation by supramaximal concentrations of cAMP induces maximal conductance through anion-specific routes, while the voltage sensitivity of this pathway is lost. The effects of theophylline and IBMX on the voltage-activated Cl-conductance of toad skin cannot be explained solely by inhibition of the phosphodiesterase.