Thromboxane A2, released by the anti-tumour drug irinotecan, is a novel stimulator of Cl- secretion in isolated rat colon
| Autor: | Akira Ikari, Takahiro Sato, Miyuki Yasue, Noriko Hamada, Bunpei Kakinoki, Noriaki Takeguchi, Hideki Sakai |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 1997 |
| Předmět: |
Patch-Clamp Techniques
Physiology Colon Cell Crypt Indomethacin Receptors Thromboxane Endogeny Tetrodotoxin Pharmacology Irinotecan Dinoprostone Membrane Potentials Thromboxane A2 chemistry.chemical_compound Chlorides Chloride Channels medicine Animals Benzoxepins Secretion Cyclooxygenase Inhibitors Intestinal Mucosa Rats Wistar Receptor biology Imidazoles Antineoplastic Agents Phytogenic digestive system diseases Rats medicine.anatomical_structure chemistry Nitrobenzoates biology.protein Benzimidazoles Camptothecin Carbachol Female Thromboxane-A synthase Thromboxane-A Synthase medicine.drug Research Article |
| Popis: | 1. A camptothecin derivative, irinotecan (Cpt-11), is a topoisomerase I inhibitor and has a strong activity against a broad range of human cancer. One of the side-effects of this drug is diarrhoea. Here, we tried to determine the mediator of the irinotecan-induced Cl- secretion which may underlie this diarrhoea, using isolated mucosae of rat distal colon. 2. Irinotecan increased Cl- secretory current in a concentration-dependent manner across the mucosa, set between Ussing chambers. Thromboxane A2 (TXA2) has not been reported to date as a physiological stimulant of Cl- secretion in the distal colon. However, the major part of the present irinotecan-induced current was inhibited by selective thromboxane A2 receptor antagonists (KW-3635 and ONO-3708), and a selective thromboxane synthase inhibitor (Y-20811). In fact, we found that irinotecan stimulated the release of TXA2 in a concentration-dependent manner from the isolated mucosa into the bathing solutions. 3. Furthermore, 9,11-epithio-11,12-methano-thromboxane A2 (STA2), a stable analogue of TXA2, induced Cl- secretion, which was almost completely inhibited by the TXA2 receptor antagonists. 4. In single cells of isolated crypts, STA2 depolarized the cell and increased the membrane conductance, indicating that STA2 opened the apical Cl- channel of the crypt cells. 5. We conclude, therefore, that the irinotecan-induced endogenous TXA2 is a novel stimulant of the Cl- secretion from the crypt cells of distal colon. |
| Databáze: | OpenAIRE |
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