Rat pancreas pieces spontaneously released PGE2 (2.3 ng/100 mg x 45 min) and PGF2 alpha (7.6 ng/100 mg x 45 min). This release corresponds probably to a neo-synthesis since it was abolished by indomethacin. Carbamylcholine (greater than or equal to 10 microM), caerulein (greater than or equal to 10 nM) and secretin (greater than or equal to 10 nM) stimulated the release of PGE2 and PGF2 alpha: the concentrations of stimulators required to increase PGs release were thus much higher than those which trigger enzyme secretion. Atropine specifically inhibited the cholinergic stimulation, whereas indomethacin blocked the stimulatory effects of all secretagogues. Stimulation of PGE2 and PGF2 alpha release was reduced in a Ca++-free medium, abolished by EGTA and mimicked by the ionophore A23187, underscoring the crucial role of Ca++ in the regulation of PGs synthesis by the pancreas. Neither PGE2 nor PGF2 alpha stimulated enzyme secretion in this system and indomethacin did not inhibit the secretory effect of carbamylcholine. Increased synthesis of prostaglandins in response to pancreatic secretagogues does not appear to be involved in the process of enzyme secretion.

The effects of caerulein, vinblastine (VB), deuterium oxide (D2O), and cytochalasin B upon both the structure and the function of the pancreatic acinar cell were studied in vitro using rat pancreatic fragments. Caerulein (10 ng. per ml.) stimulates the release of enzymes and induces the appearance of numerous exocytotic images at the apical part of the acinar cell. Whereas VB (5.10(-5) M) and D2O (55 per cent) inhibit the secretory response to caerulein, they do not affect the general ultrastructure of the acinar cell. Prolonged incubation in the presence of VB provoked the disappearance of microtubles and the massive precipiation of microcrystalline material in all parts of the cytoplasmic space. Numerous microtubules were found in the acinar cell after exposure to D2O. Although VB and D2O do not alter the microfilamentous network localized at the apical part of the cell, cytochalasin B (2.10(-5) M) disrupts it. This drug decreases the number of microvilli projecting into the enlarged acinar lumen. Whether cytochalasin B is used alone or in association with VB or D2O, it inhibits the secretory response to caerulein and prevents the process of exocytosis. Thus, it is suggested that microfilaments act on a later step of the secretory cycle, i.e., exocytosis, than microtubules. The probable site of action of these latter organelles in the migration of zymogen granules toward the acinar lumen is discussed.

Vinblastine did not affect the basal secretion of enzymes from the rat pancreas, but it potentiates the secretory response to dibutyryl cyclic AMP. This potentiation is confirmed by the observation of numerous pictures of exocytosis at the apical part of the acinar cell. Dibutyryl cyclic GMP by itself, or associated with vinblastine, failed to modify the spontaneous release of enzymes or the secretion induced by dibutyryl cyclic AMP.

DbcAMP≥0.1 mM induces the discharge of exportable enzymes from rat pancreas fragments incubated in vitro. This effect is qualitatively similar to the action of physiological secretagogues acting via hormone receptors: 1) it is accompanied by the appearance of exocytotic images at the acinar cell apex; 2) it is energy dependent but energy supply is low while that required for the carbamylcholine or caerulein response is high and can only be afforded by oxidative phosphorylation; 3) it is calcium dependent, but no alteration of inward or outward calcium movement can be observed; 4) it is altered by agents known to disrupt the microfilamentous microtubular system [41]. However, the secretory response to DbcAMP is quantitatively less than that obtained with hormonal stimuli. A damaging effect of DbcAMP on pancreatic acinar cells is ruled out on histological and biochemical grounds: there is no significant leakage of LDH; protein synthesis, 2-deoxy-d-glucose andl-leucine uptake are unaltered. The secretagogue effect of DbcAMP is reversible, dose-related and specific. It is not mediated by neuro-transmitter release or by interaction with their receptors. The evidence presented points to a direct interaction of DbcAMP on the pancreatic acinar cell and suggests the last step of the secretory cycle as the most probable site of action of the nucleotide derivative.

Peculiar cytoplasmic inclusions with crystalline pattern are described in the obese hyperglycaemic mouse pancreas acinar cells. They are generally associated with filamentous structures. However, crystalline and filamentous inclusions have also been observed in isolated forms. These inclusions are not digested by pronase. Since they have also been encountered in normal mice, it seems that the hyperglycaemic syndrome does not play a role in inducing their formation.