Abstract | OBJECTIVE: DESIGN: RESULTS:
Caffeine, dimethylxanthines and non- xanthine PDE inhibitors blocked IP3-mediated Ca2+ oscillations, while monomethylxanthines had little effect. Caffeine and dimethylxanthines inhibited uncaged IP3-induced Ca2+ rises, toxin-induced Ca2+ release, mitochondrial depolarisation and necrotic cell death pathway activation; cAMP/cGMP did not inhibit toxin-induced Ca2+ rises. Caffeine significantly ameliorated CER-AP with most effect at 25 mg/kg (seven injections hourly); paraxanthine or theophylline did not. Caffeine at 25 mg/kg significantly ameliorated TLCS-AP and FAEE-AP. Mean total serum levels of dimethylxanthines and trimethylxanthines peaked at >2 mM with 25 mg/kg caffeine but at <100 µM with 25 mg/kg paraxanthine or theophylline. CONCLUSIONS:
Caffeine and its dimethylxanthine metabolites reduced pathological IP3R-mediated pancreatic acinar Ca2+ signals but only caffeine ameliorated experimental AP. Caffeine is a suitable starting point for medicinal chemistry.
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Authors | Wei Huang, Matthew C Cane, Rajarshi Mukherjee, Peter Szatmary, Xiaoying Zhang, Victoria Elliott, Yulin Ouyang, Michael Chvanov, Diane Latawiec, Li Wen, David M Booth, Andrea C Haynes, Ole H Petersen, Alexei V Tepikin, David N Criddle, Robert Sutton |
Journal | Gut
(Gut)
Vol. 66
Issue 2
Pg. 301-313
(02 2017)
ISSN: 1468-3288 [Electronic] England |
PMID | 26642860
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/. |
Chemical References |
- Fatty Acids, Monounsaturated
- Inositol 1,4,5-Trisphosphate Receptors
- Phosphodiesterase Inhibitors
- Xanthines
- taurolithocholic acid 3-sulfate
- palmitoleic acid
- Caffeine
- Ethanol
- Taurolithocholic Acid
- Inositol 1,4,5-Trisphosphate
- Ceruletide
- Cyclic AMP
- Cyclic GMP
- Calcium
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Topics |
- Acinar Cells
(drug effects, metabolism)
- Animals
- Caffeine
(pharmacology, therapeutic use)
- Calcium
(metabolism)
- Cell Death
(drug effects)
- Cells, Cultured
- Ceruletide
- Cyclic AMP
(metabolism)
- Cyclic GMP
(metabolism)
- Cytosol
(metabolism)
- Ethanol
- Fatty Acids, Monounsaturated
- Inositol 1,4,5-Trisphosphate
(metabolism)
- Inositol 1,4,5-Trisphosphate Receptors
(antagonists & inhibitors)
- Male
- Mice
- Microscopy, Confocal
- Mitochondria
(drug effects, physiology)
- Necrosis
(diagnostic imaging)
- Pancreas
(pathology)
- Pancreatitis
(blood, chemically induced, prevention & control)
- Phosphodiesterase Inhibitors
(pharmacology, therapeutic use)
- Signal Transduction
(drug effects)
- Taurolithocholic Acid
(analogs & derivatives)
- Xanthines
(blood, pharmacology)
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