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The role of sodium/hydrogen exchange in the teratogenic response to acetazolamide

ABSTRACT Administration of acetazolamide to pregnant rodents leads to postaxial forelimb ectrodactyly, generally right‐sided, in the offspring. We previously postulated that this uniquely localized malformation was caused by a reduction of intracellular PH(pHi) in the embryonic limb bud cells. The hypothesis is supported by numerous lines of evidence including the exacerbation of forelimb ectrodactyly by co‐administration of amiloride. One action of amiloride is to inhibit the activity of Na+/H+ exchangers (NHEs), the major mechanism by which most eukaryotic cells regulate their internal pH. A mouse without this exchange mechanism should theoretically be hypersensitive to acetazolamide‐induced postaxial forelimb ectrodactyly because the limb bud cells should be less able to recover from reduction of intracellular pH. To test this hypothesis we created a targeted knockout of NHE‐1 (Na+/H+ Exchanger‐1), to which we administered acteazolamide. The frequency and/or severity of forelimb ectrodactyly was no worse in NHE‐1 null fetuses than in wild type or heterozygous littermates. We interpret this negative result to suggest that there are compensatory pathways by which embryonic cells can rid themselves of excess protons. We examined this idea by co‐administration of acetazolamide and DIDS. This latter agent inhibits CI‐/HCO3 exchange, a common mechanism for regulation of pHi against acidosis. Although malformation frequency and severity were high after this combination treatment, NHE‐1 null embryos were not more affected with postaxial fore‐limb ectrodactyly than their heterozygous and wild type littermates. We presume that embryonic limb bud cells possess another pathway through which they can regulate cytoplasmic proton concentration under acidotic conditions.