Cyclosporine A inhibits protein-kinase-C-mediated amylase release from isolated rat pancreatic acini.
The present study was performed to characterize a direct influence of cyclosporine A (CsA) on exocrine pancreatic enzyme secretion. CsA inhibited dose-dependently amylase release from isolated rat pancreatic acini in response to carbachol or cholecystokinin octapeptide (CCK-8). A significant reduction in amylase release by 17% was observed at 0.2 mumol/l CsA (p < 0.001) when compared to controls. At 0.2 mmol/l, CsA reduced amylase release in response to both secretagogues by maximally 45%, whereas basal secretion was not affected. CsA had no influence on CCK-8-stimulated increase in intracellular Ca2+ concentrations or amylase release in response to the Ca2+ ionophore A 23187. In contrast, the dose-response curve for amylase secretion induced by the phorbol ester phorbolmyristate-13-acetate was shifted to the right without a reduction of the maximal secretory response. Unexpectedly, vasoactive-intestinal-polypeptide- and secretin-stimulated acinar secretion was not diminished by CsA. In isolated pancreatic lobules exposed to 0.1 mmol/l CsA, amylase release stimulated by cerulein or veratridine was reduced by 26.7 +/- 2 or 28.3 +/- 4%, respectively. CsA had no influence on the displacement of 125I-Bolton-Hunter-labeled CCK-8 from acinar CCK receptors. The ultrastructure of cellular organelles in isolated lobules was not altered after incubation with 0.1 mmol/l CsA for 60 min. Our data suggest that CsA interferes with protein-kinase-C-mediated signal transduction in isolated rat pancreatic acini, without affecting cAMP-dependent signalling.
Höcker
M
M
1st Department of Medicine, Christian Albrechts University, Kiel, Germany.
Waschulewski
I H
IH
Kern
H F
HF
Domagk
K A
KA
Schwarzhoff
R
R
Fölsch
U R
UR
Schmidt
W E
WE
D000681:Amylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D046508:Culture Techniques; D016572:Cyclosporine / Q000494:pharmacology*; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism / Q000648:ultrastructure; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D012844:Sincalide / Q000378:metabolism; D013217:Starvation
D000001:Calcimycin; D016572:Cyclosporine; D011493:Protein Kinase C; D000681:Amylases; D012844:Sincalide; D002118:Calcium