Inhibition of erythrocyte anion exchange by tolrestat, an inhibitor of aldose reductase.
Tolrestat, and aldose-reductase inhibitor, was shown to be a rapid and potent inhibitor of chloride exchange on the band 3 protein of human erythrocytes. Tolrestat binds to a site distinct from the chloride transport site and binds to one half of the transporters at 5 x 10(-7) mol/L in the absence of chloride and at 3.6 x 10(-5) mol/L in physiologic chloride concentrations. Although these concentrations are 20- to 1,000-fold greater than the IC50 for aldose-reductase inhibition by tolrestat, they are achieved during routine pharmacologic therapy in humans. Consequently, Cl/HCO3 exchange rates may be reduced and there may be decreased CO2 clearance from coronary and respiratory center capillary beds and inappropriate hyperpnea. There also may be transitory intracellular alkalinization in cells with a Cl/HCO3 exchanger in their plasma membrane.
Gunn
R B
RB
Department of Physiology, Emory University School of Medicine, Atlanta 30322.
Gunn
H B
HB
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D001457:Anion Exchange Protein 1, Erythrocyte / Q000378:metabolism; D000838:Anions; D001665:Binding Sites; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002712:Chlorides / Q000097:blood*; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009281:Naphthalenes / Q000494:pharmacology*; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D001457:Anion Exchange Protein 1, Erythrocyte; D000838:Anions; D002712:Chlorides; D009281:Naphthalenes; C040550:tolrestat; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase