Reabsorption of monocarboxylic acids in the proximal tubule of the rat kidney

Abstract

The 3.5 s efflux ofd-lactate (1 mmol/l) injected in the lumen of the late proximal convolution was measured. This efflux can be divided into a Na⁺-dependent, saturable component flowing through the brush border and a Na⁺-independent non-saturable component flowing through the paracellular pathway. The inhibitory potency of benzoate and its analogs, of phenyl-substituted acetate-, propionate-and butyrate analogs, of cinnamate and analogs, of heterocyclic monocarboxylic acids and related compounds added to the perfusate in a concentration of 10 mmol/l was measured. It was found that

• 1. benzoate added in a concentration of 10 mmol/l to the luminal perfusate inhibits transport ofd-lactate, and the meta- and para-substituted analogs of benzoate inhibit in a fashion predicted by Hammett's theory. Side groups which withdraw electrons from the COOH group inhibit while substitutes who deliver electrons toward the reaction center do not.

• 2. Replacement of a hydrogen atom by a phenyl ring at the C2 atom of acetate, glycolate and glyoxylate does not change the inhibitory pattern of these substances ond-lactate transport. Replacement of a hydrogen atom on the C2 atom of propionate and lactate reduces the ability of these molecules to inhibitd-lactate transport. But replacement of a hydrogen atom at the C3 atom of propionate, pyruvate and lactate abolishes the inhibitory potency. Similarly the inhibitory potency decreases from butyrate > 2-phenylbutyrate > 3-phenylbutyrate > 4 phenylbutyrate. The latter two are actually no longer inhibitory.

• 3. Trans-cinnamate, cis-cinnamate (3-phenyl trans or cis acrylic acid) and 3-phenylpropiolate are also not inhibitory. But introduction of an electron attracting CN group on C2 atom of cinnamate evokes inhibitory potency.

• 4. The heterocyclic compounds nicotinic acid and pyrazinoic acid exert strong inhibition ond-lactate transport, while picolinic acid and isonicotinic acid exert only moderate inhibition. Nicotinic and pyrazinoic acid show also a secretory component in their transport behaviour.

• 5. If the COOH group of benzoate is replaced by a SO₃H group (benzenesulfonic acid) or if a second ring is induced (1 or 2 naphthoic acid) the inhibitory potency is lost.

• 6. Amongst other organic anions which do not inhibitd-lactate transport are paraaminohippurate, urate, and taurocholate.

The data indicate that a main determinant of the specificity of the Na⁺-dependent aliphatic aromatic monocarboxylic acid reabsorption system in the renal brush border is the electron density at the reaction center, i.e. the free carboxylic group. Furthermore, the size of the molecule and its hydrophobicity at one cell pole is limiting for its ability to react with the carrier.