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1. The roles of Na and Ca ions in stimulus-secretion coupling were analysed in the isolated and perfused rat pancreas.

2. Partial replacement of NaCl with LiCl produced a diminution in both amylase output and pancreatic juice flow which were induced by 5 m-u. CCK-PZ/ml., and almost normal responses were usually regained immediately after the reintroduction of a standard concentration of NaCl. Nearly total replacement of NaCl with LiCl caused an almost complete inhibition of the responses, although 25 mM-NaHCO₃ and 1 mM-NaH₂PO₄ were still present, and only partial recovery was obtained after the re-introduction of a standard concentration of NaCl.

3. A quantitative relationship was found between the amount of amylase released by CCK-PZ and the [Na⁺]_o over the range 26-157 mM in the presence of 2·5 mM-Ca. A similar relationship was also observed when [Ca²⁺]_o was decreased to 1·0 mM, but the responses were reduced to about one half of those observed with 2·5 mM-Ca.

4. The most satisfactory theory which explains the cellular mechanism of CCK-PZ-induced amylase output, and which fits the experimental data, requires the dominant activity of a complex composed of a carrier molecule bearing one Ca and four Na molecules, if there is no interaction between Na⁺ and Li⁺.

5. A quantitative relationship was also found between the amount of pancreatic juice flow stimulated by CCK-PZ and [Na⁺]_o, over the range 26-157 mM, in the presence of 1·0 or 2·5 mM-Ca.

6. A similar quantitative relationship was found between the amount of amylase released by Ca-ionophore A23187 and [Na⁺]_o in the presence of 2·5 or 5·0 mM-Ca. The most satisfactory theory which fits this experimental data also requires the dominant activity of a complex composed of a carrier molecule bearing one Ca and four Na molecules, if there is no interaction between Na⁺ and Li⁺.