Dual action of Mn++ upon the secretion of insulin and glucagon from the isolated, perfused canine pancreas

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Abstract
Since Mn++ apparently interferes with excitation-contraction coupling by both reducing inward movement of Ca++ across the cell membrane and by displacing Ca++ from an intracellular store, studies were performed in the isolated, perfused canine pancreas to elucidate the existence of a similar effect in stimulus-secretion coupling and to draw comparisons with the effect of Mg++, which antagonizes Ca++ at the cell membrane. The results show: 1. that Mn++ (0.05, 0.125, and 0.25 mmol/l) inhibits the release of insulin and glucagon in a dose-dependent fashion during the first 3–4 min of infusion followed by a dose-dependent increase in hormone release, the ‘escape phase’. 2. The inhibitory action of Mn++ (0.25 mmol/l) upon release of both hormones is progressively counteracted when perfusate calcium is increased from 0.7 to 1.3 to 5.0 mmol/l. 3. Mg++ (5 mmol/l) inhibits the release of both hormones with no sign of an ‘escape phase’. 4. Mn++ (0.5 mmol/l) during calcium depletion causes a gradual stimulation of the release of both hormones. The dual action of Mn++ upon hormone release from the endocrine pancreas suggests that Mn++ can cross the cell membrane and can interfere with stimulus-secretion coupling both at the membrane level, by competitively inhibiting the Ca++ influx, and at some intracellular level by releasing calcium from an intracellular store.