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B. E. Argent, R. M. Case^* and Frances C. Hirst

Department of Physiology, University Medical School, Newcastle upon Tyne, NE1 7RU

1. Mn²⁺ evoked an atropine-resistant secretion of amylase from the isolated pancreas of the young rat. The lowest effective concentration of Mn²⁺ was 10^-3 M. The response to 10^-2 M-Mn²⁺ was biphasic, an initial peak being followed by a slow sustained rise in amylase output. The maximal effect of 10^-2 M-Mn²⁺ was to double the basal rate of amylase secretion after 70 min incubation.

2. Co²⁺ (10^-2 M) also stimulated amylase secretion. The maximal rate, about three times the basal value, was attained after 20 min incubation. Atropine partially inhibited this effect.

3. Ca²⁺ (10^-2 M) evoked an atropine-resistant amylase secretion similar in both magnitude and time course to the sustained phase observed with 10^-2 M-Mn²⁺.

4. Mn²⁺ (10^-4-10^-2 M) also increased the rate of ⁴⁵Ca efflux from the gland. Maximal efflux rates were attained after 30 min incubation and thereafter declined to basal values. A small increase was also observed with 10^-2 M-Co²⁺, but not with 10^-2 M-Ca²⁺. The effect of Co²⁺ was almost completely abolished by atropine.

5. Reducing the extracellular Ca²⁺ concentration from 2·5 x 10^-3 to 10^-5 M did not reduce amylase secretion in response to 10^-2 M-Mn²⁺, but secretion was abolished in a Ca²⁺-free medium containing EGTA. The increase in ⁴⁵Ca efflux rate evoked by Mn²⁺ was inversely related to the extracellular Ca²⁺ concentration.

6. Mn²⁺ (10^-2 M) increased the concentration of cyclic 3',5'-guanosine monophosphate (cyclic GMP) within the pancreas. Also, Mn²⁺ accumulated within the cellular pool of the gland. The time course of both these effects was similar to the time course of ⁴⁵Ca efflux.

7. Mn²⁺ displaced Ca²⁺ bound to isolated pancreatic microsomal membranes. The cation-binding sites on these membranes probably have a higher affinity for Mn²⁺ than Ca²⁺.

8. We conclude that Mn²⁺ stimulates enzyme secretion by displacing membrane-bound Ca²⁺, the resulting increase in cytosolic Ca²⁺ concentration activating the secretory mechanism.

9. Mn²⁺ partially inhibited amylase secretion stimulated by optimal doses of either acetylcholine (ACh) or caerulein. Maximal inhibition (about 60%) occurred with 10^-3 M-Mn²⁺ (i.e. the lowest concentration required to stimulate secretion in the absence of secretagogues). Decreasing the extracellular Ca²⁺ concentration reduced the inhibitory effect of Mn²⁺.

10. When glands were exposed to ACh and Mn²⁺ simultaneously, the time required for inhibitory effects to develop was inversely related to the dose of ACh and the concentration of Mn²⁺.

11. Mn²⁺ did not alter the acceleration of ⁴⁵Ca efflux evoked by ACh or by caerulein in a medium containing 2·5 x 10^-3 M-Ca²⁺. However, under conditions of Ca²⁺ deprivation ACh-stimulated ⁴⁵Ca efflux was greatly enhanced.

12. Mn²⁺ reduced the total amount of Ca²⁺ accumulated into the cellular pool of the pancreas after 60 min incubation, but had no effect on the initial, rapid phase of Ca²⁺ uptake.

13. The effects of Mn²⁺ on the relationship between ACh dose, amylase release and the extracellular Ca²⁺ concentration suggest that the inhibitory actions of Mn²⁺ cannot be explained by a simple, competitive interaction with the stimulant or with extracellular Ca²⁺. However, the time course of inhibition is consistent with a requirement for Mn²⁺ to accumulate within the acinar cells.

14. Mn²⁺ partially inhibited amylase secretion stimulated by hyperosmolarity and also increased the ⁴⁵Ca efflux rate under these conditions.

15. Our results are not consistent with Mn²⁺ exerting its inhibitory effect on secretagogue-stimulated enzyme secretion solely by blocking Ca²⁺ influx from the extracellular space. We conclude that inhibition probably depends on the ability of Mn²⁺ to displace Ca²⁺ from binding sites involved in secretion, presumably coupled with a reduced ability of Mn²⁺ to replace Ca²⁺ in the secretory process.

Present address: School of Pharmacy, Sunderland Polytechnic, Langham Tower, Ryhope Road, Sunderland, SR2 7EE.