Troglitazone inhibits bicarbonate secretion in rat and human duodenum.
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 (I(sc)) was measured in rat and human duodenal mucosa in Ussing chambers. Five minutes later, the serosal addition of troglitazone caused I(sc) to decrease gradually, and after 50 min, I(sc) reached the peak of decrease. EC(50) values and maximum response to I(sc) in rat and human mucosa were 8.4 and 8.7 microM and 8.56 +/- 1.0 and 8.00 +/- 2.0 microA/cm(2), respectively. In an HCO(3)(-)/CO(2)-free system, the decrease in I(sc) caused by troglitazone was 1.31 +/- 0.83 microA/cm(2). When 10 mM acetazolamide was preadministered, the small decrease in I(sc) evoked by troglitazone (20 microM) was 4.56 +/- 0.22 microA/cm(2), whereas the preadministration of 100 microM amiloride and 100 nM tetrodotoxin did not influence the decrease in I(sc) evoked by troglitazone. The serosal preadministration of 100 nM vasoactive intestinal peptide potently enhanced the decrease in I(sc) evoked by 20 microM troglitazone (21.1 +/- 1.63 microA/cm(2)). The cyclic AMP contents of rat duodenal mucosa incubated with and without troglitazone (20 microM) 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 I(sc) that is induced by troglitazone may be inhibition of electrogenic bicarbonate secretion. The alteration of intestinal ion transport by troglitazone could cause edema.
Hosokawa
M
M
Department of Metabolism and Clinical Nutrition, Faculty of Medicine, Kyoto University, Kyoto, Japan.
Tsukada
H
H
Fukuda
K
K
Oya
M
M
Onomura
M
M
Nakamura
H
H
Kodama
M
M
Yamada
Y
Y
Seino
Y
Y
D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002839:Chromans / Q000009:adverse effects / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004386:Duodenum / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology*; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007419:Intestinal Secretions / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014867:Water / Q000378:metabolism
D001639:Bicarbonates; D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D014867:Water; D000242:Cyclic AMP; D000077288:Troglitazone