Small‐conductance Cl‐ channels in rabbit parietal cells activated by prostaglandin E2 and inhibited by GTP gamma S.

The Journal of Physiology

Sato

Hamada

et al. 1997

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. 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. 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. 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. We conclude, therefore, that the irinotecan‐induced endogenous TXA2 is a novel stimulant of the Cl− secretion from the crypt cells of distal colon.

Section: Crypt Isolation and Patch-clamp Experimentsmentioning

confidence: 99%

Thromboxane A₂, released by the anti‐ tumour drug irinotecan, is a novel stimulator of Cl⁻ secretion in isolated rat colon

The Journal of Physiology

Sato

Hamada

et al. 1997

“…We found previously that the whole-cell Cl-current of a rabbit gastric parietal cell arose from opening of one kind of housekeeping Cl-channel (Sakai et al,1992;Sakai & Takeguchi, 1993). A unit conductance of the channel was 0.3-0.4 picosiemens (Sakai et al, 1992), which was too small to be detected in patches of single channel recordings (Sakai et al, 1989).…”

Section: Resultsmentioning

confidence: 92%

“…Recently, we reported that the sub-picosiemens (pS) CP channel in rabbit gastric parietal cells was activated via a prostaglandin EP3 receptor-mediated Ca2+/NO/cyclic GMP pathway , and inhibited by GTPyS-induced intracellular production of superoxide anion (Sakai & Takeguchi, 1993;1995). This Cl-channel is physiologically important because it has a housekeeping role via dominating the cell membrane potential (Sakai et al, 1989;.…”

Section: Discussionmentioning

confidence: 99%

“…Whole-cell currents recorded from rabbit parietal cells in the isolated gastric glands were previously established to be due to the current through the basolateral membrane (Sakai et al, 1992;Sakai & Takeguchi, 1993). An EPC-7 patch clamp system (List Electronic, Darmstadt, Germany) was used for whole-cell recordings, and necessary corrections were made as described elsewhere (Hamill et al, 1981;Sakai et al, 1992).…”

Section: Patch-clamp Experimentsmentioning

confidence: 99%

“…We have recently reported a membrane potential-dominating (housekeeping) Cl-channel with sub-picosiemens conductance in the basolateral membrane of rabbit gastric parietal cells (Sakai et al, 1992;1995;Sakai & Takeguchi, 1993;. Prostaglandin E2 (PGE2) activates this Cl-channel via the EP3 receptor-mediated Ca2+/ nitric oxide (NO)/cyclic GMP pathway: that is, activation of the EP3 receptor stimulates Ca2+-dependent NO synthase, inducing the subsequent activation of guanylate cyclase .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A cyclic GMP‐dependent housekeeping Cl⁻ channel in rabbit gastric parietal cells activated by a vasodilator ecabapide

Ikari

Kumano

et al. 1996

British J Pharmacology

Eicosanoid-mediated Cl? secretion induced by the antitumor drug, irinotecan (CPT-11), in the rat colon

Naunyn-Schmiedeberg's Arch Pharmacol

Diener

Gartmann

et al. 1995

Irinotecan (CPT-11) is active against a broad range of human cancer. One of the side-effects of irinotecan is a strong diarrhoea. In order to investigate the mechanism underlying this diarrhoea, the effect of irinotecan on anion secretion across the isolated rat distal colon was studied. Irinotecan caused a concentration-dependent increase in short-circuit current (Isc). The increase in Isc was completely dependent on the presence of Cl- ions and was suppressed by furosemide and the Cl- channel blocker NPPB (5-nitro-2-(3-phenylpropylamino)-benzoate), indicating that it is caused by a Cl- secretion. The secretory response was inhibited by indomethacin, 1-benzylimidazole, a thromboxane synthase inhibitor, and SK&F 88046 ((N,N'-bis[7-(3-Chlorobenzeneaminosulfonyl)-1,2,3,4-tetrahydroi soquinolyl) disulfonylimide), a thromboxane A2 receptor blocker. In isolated crypts irinotecan had no effect on the membrane potential. Consequently, the secretion induced by irinotecan is an indirect one, caused by the stimulation of eicosanoid production, e.g. thromboxane A2, in the subepithelial tissue.