TY - JOUR T1 - Correlation of the Effects of Bretylium, Guanethidine, and <em>N,N</em>-Diisopropyl-<em>N</em>'-Isoamyl-<em>N</em>'-Diethylaminoethylurea (<em>P</em>-286) on the H<sup>+</sup> Electrochemical Gradient across the Chromaffin Granule Membrane and on Chromaffin Granule Function JF - Molecular Pharmacology JO - Mol Pharmacol SP - 606 LP - 610 VL - 18 IS - 3 AU - RONALD W. HOLZ Y1 - 1980/11/01 UR - http://molpharm.aspetjournals.org/content/18/3/606.abstract N2 - N,N-Diisopropyl-N'-isoamyl-N'-diethylaminoethylurea (P-286) (0.03-0.3 mM) reduced the ATP, Mg2+-induced electrical potential across the chromaffin granule membrane, inhibited ATP, Mg2+-dependent catecholamine uptake into chromaffin granules, and inhibited carbachol-induced secretion from cultured bovine chromaffin cells. P-286 did not alter the intragranular pH. Bretylium and guanethidine did not alter the H+ electrochemical gradient across the chromaffin granule membrane and did not alter the ATP, Mg2+-induced catecholamine uptake into chromaffin granules. The uptake of bretylium, a quaternary ammonium compound, into chromaffin granules responded to changes in membrane potential in a qualitatively similar manner to that of the lipid-soluble cation triphenylmethylphosphonium cation (TPMP+). This study provides further evidence that catecholamine uptake into chromaffin granules is coupled to the electrical component of the H+ electrochemical gradient and raises the possibility that chemiosmotic mechanisms of the granules may be involved in catecholamine secretion from chromaffin cells. The study also demonstrates that chemiosmotic processes of chromaffin granules can affect the uptake of drugs into the storage vesicles. ACKNOWLEDGMENTS I thank Dr. O. Humberto Viveros (Burroughs Wellcome Co. Research Triangle Park, N.C.) and Dr. Norman Kirschner (Duke University Medical Center, Durham, N.C.) for suggesting experiments with P-286. I am grateful to Dr. Raymond E. Counsell (University of Michigan Medical School) for synthesizing and providing [14C]bretylium. ER -