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Cholecystokinin (CCK) analogs, JMV-180 and OPE, release Ca from intracellular stores and induce oscillations in the concentration of cytosolic Ca ([Ca]), but do not generate a detectable rise in inositol 1,4,5-trisphosphate (Ins P) levels. In contrast, high concentrations of CCK elevate Ins P, as well [Ca], to a peak which decreases to near basal levels without oscillations. The mechanisms which underlie inhibition of [Ca] oscillations observed with high CCK concentrations are unclear, but are believed to involve a low-affinity CCK receptor state. Alternately, CCK analogs may be weak partial agonists of the phospholipase C pathway, whereas native CCK, as a full agonist of this pathway, stimulates low levels of protein kinase C (PKC) activity. Preincubation of acini with 1 nM 12 O-tetradecanoyl-phorbol 13-acetate (TPA) for 15 min at 37°C did not affect OPE binding to acini, but abolished OPE-induced (at 1 μM) [Ca] oscillations without affecting the initial [Ca] spike. These transformed OPE-induced [Ca] responses mimicked those induced by supramaximal CCK octapeptide (CCK-8) concentrations. Inhibition of [Ca] oscillations by 1 nM TPA was reversed by the PKC inhibitor staurosporine (0.2 μM). After [Ca] oscillations were induced with OPE or low concentrations of CCK-8 (20 pM), 1 nM TPA caused a gradual slowing of oscillation frequency over 15-20 min without affecting [Ca] spike amplitude. In contrast, 1 μM TPA inhibited OPE binding and caused a more generalized inhibition of OPE- and CCK-evoked Ca signals. These data suggest that inhibitory effects of low-level PKC activation on agonist-evoked Ca signalling are distinct from the effects of high-level PKC activation by 1 μM TPA, and do not require the transition of the CCK receptor from a high-affinity to a low-affinity state. [ABSTRACT FROM AUTHOR]

The role of Ca in protein secretion from the isolated perfused cat's pancreas, the effect of the dibutyryl analogues of cAMP and cGMP, and the interrelation of Ca and the nucleotides were studied. The following results were obtained: The findings indicate that extracellular Ca is involved in the mechanism of enzyme secretion and that Ca and cyclic nucleotides have a synergistic action on the target. [ABSTRACT FROM AUTHOR]

The isolated rabbit pancreas secretes protein and α-amylase at a relatively constant rate during an eight-hour period. Ouabain (10 and 10 M) did not alter enzyme secretion, but inhibited flow (65% and 28% respectively). Acetazolamide (10 M) had no effect on pancreatic enzyme secretion, while flow was inhibited by 25%. Na azide (10 M) failed to affect protein and α-amylase secretion. Flow was inhibited by approximately 88%. NaF (10M) increased both protein and α-amylase secretion, while flow remained virtually unchanged. Gassing of the bathing fluid with 95% N−5% CO reduced protein and α-amylase secretion by 57 and 64% respectively, while flow was decreased by 77%. Lowering of the sodium concentration in the bathing fluid by 85% decreased α-amylase secretion by 46%. Flow was inhibited by 77%. Return to the standard solution caused initially an increase of α-amylase secretion (86%), followed by a decrease. These results strongly suggest that the enzyme secretion of the pancreas is not coupled to the sodium pump, responsible for fluid and electrolyte secretion. [ABSTRACT FROM AUTHOR]