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.
Biological substances with neurotrophic activities, such as nerve growth factor (NGF) and monosialoganglioside GM1, have been considered as agents for diabetic peripheral neuropathy. Because recent studies have suggested that decreased availability of these substances might contribute to the pathogenesis of diabetic peripheral neuropathy, some clinical trials of NGF for diabetic peripheral neuropathy have been conducted and have led to mixed conclusions. The major reasons were its limited delivery to the nervous system and adverse effects induced by subcutaneous injection, which was necessary because NGF is a polypeptide. The current study investigates whether an orally active sialic acid derivative, MCC-257, has neuroprotective properties in diabetic peripheral nerves. MCC-257 augmented NGF activity in cultured dorsal root ganglia and PC12 (pheochromocytoma 12) cells. Treatment with MCC-257 elevated NGF levels in the sciatic nerve, accompanied by improvement in nerve conduction velocity in strepotozotocin-induced diabetic animals. More importantly, MCC-257 ameliorated small fiber dysfunctions, including thermal hypoalgesia, substance P content, and histopthological innervation in the plantar skin of diabetic animals. Thus, the orally active neurotrophin enhancer provides a new option for the clinical treatment of diabetic peripheral neuropathy. Diabetes 55:616 -621, 2006
We have used Heidenhain-pouch dogs to investigate the effects of (+/-)-5-methoxy-2-{[(4-methoxy-3,5-dimethylpyrid-2-yl)methyl]sulph inyl}-1H-imidazo[4,5-b]pyridine (TU-199), an imidazopyridine derivative, on gastric acid secretion stimulated by histamine, carbachol and tetragastrin. We have also investigated the duration of the antisecretory effect of TU-199 using a measurement of intragastric pH for 24 h in gastric fistula dogs whose gastric acid secretion was stimulated by histamine. Single oral administration of TU-199 (0.1, 0.2 and 0.4mgkg(-1)) dose-dependently suppressed gastric acid secretion stimulated by histamine infusion. Oral treatment with TU-199 (0.2, 0.4 and 0.8 mg kg(-1)) also dose-dependently inhibited acid secretion induced by carbachol and tetragastrin. The inhibitory effect of TU-199 on stimulated gastric acid secretion was more potent than that of omeprazole, a well-known H+,K(+)-ATPase inhibitor in dogs. Repeated oral treatment with TU-199 at a dose of 0.2 mg kg(-1) once a day for seven days markedly suppressed histamine-stimulated gastric acid secretion in dogs. This inhibitory effect of TU-199 reached a maximum level after three or four doses and was more pronounced than that of omeprazole or lansoprazole. In gastric fistula dogs, the duration of intragastric pH-elevation by administration of TU-199 (0.3 mg kg(-1)) was much longer than that of omeprazole (0.6mgkg(-1)) or lansoprazole (0.9mgkg(-1)). The IC50 values (doses resulting in 50% inhibition) of TU-199, omeprazole and lansoprazole with regard to H+,K(+)-ATPase activity in dog gastric mucosal microsomes were 8.6, 8.8 and 9.9 microM, respectively. These results indicate that TU-199 inhibits gastric acid secretion via suppression of a H+,K(+)-ATPase activity. Our findings also suggest that TU-199 might have potent and long-lasting effects on gastric acid secretion.
Properties of hypotonically-activated Cl- channels in isolated rat hepatocytes were studied by the patch-clamp whole-cell technique. Hypotonic stress (140-150 mosmol kg 1 H2O) induced a hyperpolarization of the membrane of hepatocytes in the presence of an inwardly oriented Cl gradient, but had no effect on the membrane potential in the absence of Cl. An increase in the hypotonically-induced conductance was significantly inhibited by 4-acetamido-4'-isothiocyanatostilbene-2, 2'-disulfonic acid (SITS; 50 microM), but not by Ba2+ (1 mM). Pre-incubation with arachidonic acid (20 microM) significantly inhibited the hypotonically-activated conductance. The combined application of a cyclo-oxygenase inhibitor, indomethacin (50 microM) and a lipoxygenase inhibitor, esculetin (100 microM) also inhibited the conductance, whereas quinacrine (200 microM), a phospholipase A2 inhibitor, significantly induced a large steady conductance. Outward Cl- currents, but not cationic currents, were elicited by the hypotonic stress. The current did not show any rapid time-dependent inactivation during the voltage clamp of 0.1 s. The combined application of arachidonic acid, indomethacin and esculetin inhibited the hypotonically-activated Cl- currents. The present study has shown that the Cl- channel is activated by exposure to hypotonic stress and closed by an increase in arachidonic acid concentration in isolated rat hepatocytes.
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