In an attempt to study regulation of C1 channels in intact sweat secretory coils in cystic fibrosis and controls in the least invasive manner, isolated secretory coils were superfused with various drugs and K-efflux was determined as an indirect measure of C1 movement. C1 channel activity was also determined from the drug-induced cell volume increase in gramicidin (GC)-treated dissociated eccrine clear cells. We observed that while MCh-induced K-efflux from the CF secretory coils was entirely normal, K-efflux in the presence of isoproterenol (ISO), forskolin (FK), or IBMX was absent in CF, suggesting that these agents failed to stimulate C1 movement. C1 channel activity of dissociated CF clear cells, as studied by cell volume analysis, was entirely normal when stimulated by Ca-elevating agents but was defective when stimulated by cAMP-elevating agents. TPA (phorbol ester) does not appear to stimulate C1 channel activity nor does it modify the effect of other agents. The following observations from the present and previous studies are not necessarily consistent with the traditional thesis that the observed C1 movement is due to cAMP: CT-cAMP had no effect on cell swelling or on K-efflux; ISO is more potent in accumulating tissue cAMP than IBMX yet the latter is more potent in stimulating K-efflux; IBMX increases cytoplasmic [Ca] yet is unable to stimulate K-efflux in CF; K-efflux stimulated by cAMP-elevating agents was inhibited by removal of Ca from the bath; and, cell swelling of GC-treated cells in response to cAMP elevating agents was inhibited by removal of Ca. The inability of IBMX to stimulate C1 channels in the face of elevated cytoplasmic [Ca] and cAMP in CF cells deserves further scrutiny.