Troglitazone inhibits bicarbonate secretion in rat and human duodenum

Troglitazone is a new, orally effective antidiabetic agent that decreases p lasma glucose in obese patients with non-insulin-dependent diabetes mellitu s. Unfortunately, troglitazone also has a propensity to cause edema. This s tudy was designed to determine how troglitazone affects intestinal ion tran sport and water absorption. Short circuit current (I-sc) was measured in ra t and human duodenal mucosa in Ussing chambers. Five minutes later, the ser osal addition of troglitazone caused I-sc to decrease gradually, and after 50 min, I-sc reached the peak of decrease. EC50 values and maximum response to I-sc in rat and human mucosa were 8.4 and 8.7 mu M and 8.56 +/- 1.0 and 8.00 +/- 2.0 mu A/cm(2), respectively. In an HCO3-/CO2- free system, the d ecrease in I-sc caused by troglitazone was 1.31 +/- 0.83 mu A/cm(2). When 1 0 mM acetazolamide was preadministered, the small decrease in I-sc evoked b y troglitazone (20 mu M) was 4.56 +/- 0.22 mu A/cm(2), whereas the preadmin istration of 100 nM amiloride and 100 nM tetrodotoxin did not influence the decrease in I-sc evoked by troglitazone;The serosal preadministration of 1 00 nM vasoactive intestinal peptide potently enhanced the decrease in I-sc evoked by 20 mu M troglitazone (21.1 +/- 1.63 mu A/cm(2)). The cyclic AMP c ontents of rat duodenal mucosa incubated with and without troglitazone (20 mu M) for 50 min were 3.2 +/- 0.25 and 5.8 +/- 0.46 pmol/mg protein, respec tively (P < .01). These results indicate that the ionic basis for the decre ase in I-sc that is induced by troglitazone maybe inhibition of electrogeni c bicarbonate secretion. The alteration of intestinal ion transport by trog litazone could cause edema.