Abstract
Troglitazone is a new, orally effective antidiabetic agent that decreases plasma glucose in obese patients with non-insulin-dependent diabetes mellitus. Unfortunately, troglitazone also has a propensity to cause edema. This study was designed to determine how troglitazone affects intestinal ion transport and water absorption. Short circuit current (Isc) was measured in rat and human duodenal mucosa in Ussing chambers. Five minutes later, the serosal addition of troglitazone caused Isc to decrease gradually, and after 50 min, Isc reached the peak of decrease. EC50values and maximum response to Isc in rat and human mucosa were 8.4 and 8.7 μM and 8.56 ± 1.0 and 8.00 ± 2.0 μA/cm2, respectively. In an HCO3−/CO2-free system, the decrease in Isc caused by troglitazone was 1.31 ± 0.83 μA/cm2. When 10 mM acetazolamide was preadministered, the small decrease in Isc evoked by troglitazone (20 μM) was 4.56 ± 0.22 μA/cm2, whereas the preadministration of 100 μM amiloride and 100 nM tetrodotoxin did not influence the decrease in Isc evoked by troglitazone. The serosal preadministration of 100 nM vasoactive intestinal peptide potently enhanced the decrease in Iscevoked by 20 μM troglitazone (21.1 ± 1.63 μA/cm2). The cyclic AMP contents of rat duodenal mucosa incubated with and without troglitazone (20 μM) for 50 min were 3.2 ± 0.25 and 5.8 ± 0.46 pmol/mg protein, respectively (P < .01). These results indicate that the ionic basis for the decrease in Isc that is induced by troglitazone may be inhibition of electrogenic bicarbonate secretion. The alteration of intestinal ion transport by troglitazone could cause edema.
Footnotes
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Send reprint requests to: Dr. Masaya Hosokawa, Department of Metabolism and Clinical Nutrition, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan. E-mail:hosokawa{at}metab.kuhp.kyoto-u.ac.jp
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↵1 This study was supported by a grant-in-aid for Creative Basic Research (10670468 and 10NP0210) from the Ministry of Education, Science, Sports and Culture, Japan and a grant for the “Research for the Future” Program from the Japan Society for the Promotion of Science (JSPS-RFTF97I00201).
- Abbreviations:
- Isc
- short circuit current
- TTX
- tetrodotoxin
- cAMP
- cyclic AMP
- DMSO
- dimethyl sulfoxide
- VIP
- vasoactive intestinal peptide
- Received February 8, 1998.
- Accepted April 29, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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