When added to the Na(+)-containing solution bathing the isolated toad skin, dinitrophenol (DNP, an uncoupler of oxidative phosphorilation) caused decreases in the baseline values of short circuit current (SCC) and transepithelial conductance (G). 2. DNP also inhibited the increases in SCC and G caused by theophylline, whether added prior to the xanthine, or after the effect of the latter was fully developed. 3. In skins exposed to theophylline and bathed in Cl(-)-free (sulfate Ringer's) solution, the changes in SCC and G had a similar time course (t1/2 > 15 min). In the presence of Cl- (skins bathed in Ringer's solution), SCC decreased with a similar rate, whereas the rate of the decrease in G was greater (t1/2 < 15 min). 4. DNP also decreased the SCC induced by a Cl- concentration gradient in skins exposed to theophylline (SCCg) with a time course similar to its effect on the theophylline-increased G in the presence of Cl-. DNP was effective irrespective of the presence of ambient Na+. 5. A similar difference was observed in skins bathed in CIR and exposed to forskolin. In contrast to theophylline, however, forskolin partially overcame the inhibition of G brought about by DNP; no such recovery was observed in SCC. 6. In contrast to its influence on the responses to theophylline and forskolin, DNP failed to prevent either the increase in G or the onset of SCCg in skins exposed to dibutyryl cyclic AMP. 7. Rotenone, an inhibitor of the electron-transport chain, significantly decreased SCC and G in the unstimulated skin. It also prevented the SCC response to theophylline, and decreased it if added after the effects of the xanthine were fully developed, but failed to modify the increase in G brought about by theophylline. The time course of SCC inhibition by rotenone was similar to that caused by DNP. 8. Ouabain, an inhibitor of Na+,K(+)-ATPase, decreased SCC in the theophylline-stimulated skin, without affecting G. 9. We conclude that, whereas integrity of oxidative energy metabolism is necessary to sustain SCC in the isolated toad skin, it is not a strict requirement for the increase of Cl(-)-dependent G activated by cAMP. 10. The effect of DNP on Cl(-)-dependent G activated by cAMP is probably exerted at the cAMP generation step, by inhibition of adenyl cyclase and/or a decrease in the availability of ATP.
