Troglitazone stimulates basolateral rheogenic Na+/HCO3- cotransport activity in rabbit proximal straight tubules.
Thiazolidinedione derivatives, new insulin-sensitizing antidiabetic agents, are expected to have potential clinical use. Since these drugs cause edema in a variable proportion of patients, we examined whether troglitazone (Tro) has direct action on Na+ transport of rabbit proximal straight tubule perfused in vitro. For this purpose, we measured basolateral membrane voltage (V(B)) by conventional microelectrode techniques and intracellular pH (pH(i)) by microscopic fluorescence spectrophotometry with a pH-sensitive fluorescent dye, 2', 7'-bis-2-carboxyethyl-5-carboxyfluorescein. Tro at 50 microM in the bath significantly depolarized both transepithelial voltage and V(B). To examine whether the basolateral rheogenic Na+/HCO3- cotransport activity is affected by Tro, we observed V(B) deflection upon abrupt 10-fold decrease in bath HCO3- in the absence and presence of Tro. The apparent transference number of HCO3- (tHCO3), as calculated from the V(B) deflection, was significantly greater in the presence of Tro (50 microM) than that seen in its absence. Tro caused cell acidification and increased the intracellular acidification rates (dpH(i)/dt) upon abrupt 10-fold decreases in bath HCO3- and Na+ concentrations. The stimulatory effects of Tro on tHCO3 and dpH(i)/dt were dose dependent between 5 and 50 miccroM, but they were unaffected at 0.5 microM. From these results, we conclude that Tro acts on the proximal straight tubule and stimulates the basolateral rheogenic Na+/HCO3- cotransport activity. The stimulatory action of Tro may partly account for edema formation.
Muto
S
S
Department of Nephrology, Jichi Medical School, Kawachi, Tochigi, Japan. smuto@jichi.ac.jp
Miyata
Y
Y
Imai
M
M
Asano
Y
Y
D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects* / Q000502:physiology; D016764:Cell Polarity / Q000187:drug effects*; D002839:Chromans / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D017136:Ion Transport / Q000187:drug effects*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D010477:Perfusion; D011817:Rabbits; D012964:Sodium / Q000097:blood / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
D001639:Bicarbonates; D002839:Chromans; D017923:Sodium-Hydrogen Exchangers; D013844:Thiazoles; D045162:Thiazolidinediones; D012964:Sodium; D000077288:Troglitazone