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Na+-dependent transport; D-Lactate transport; Small fatty acids; 3-Hydroxybutyrate; Acetoacetate
Abstract:
The 3.5 s efflux ofd-lactate (1 mmol/l) injected in the lumen of the late proximal convolution as well as the zero net flux transtubular concentration difference ofd-lactate, which is a measure of its active transtubular transport rate, were determined. The inhibitory potency of small fatty acids and their analogs added to the perfusate in a concentration of 10 mmol/l on both, the 3.5 s efflux and in most cases also the 45 s transtubular concentration difference ofd-lactate was measured. It was found that.
1. small fatty acids from acetate to octanoate inhibit 3.5s efflux ofd-lactate, the largest inhibition being exerted by propionate and butyrate. With increasing chain length the inhibitory potency decreased and disappeared with decanoate.
2. Considering the acetate-, propionate- and butyrate analogs, introduction of an electron attracting group such as Cl, Br, I, CN, SH, N3 on C atom 2 increased the inhibitory potency, compared to the unsubstituted fatty acid. An OH on C2 increased or did not change the inhibition while an OH on C atom 3 reduced or blunted the inhibition. A keto-group, as it is present in glyoxylate prevented inhibition, but pyruvate inhibited to the same extent as lactate, and acetoacetate was even more inhibitory than 3-hydroxybutyrate. Cl substitution on C3 preserved the strong inhibitory potency, while 4-Cl butyrate, was only sparsely inhibitory. A NH+3 group at any position precludes inhibition.
3. As seen with Cl or OH substituted propionate and butyrate the inhibitory potency increased with decreasing pKa of the compounds.
4. Increasing the chain length by a CH3 as from acetate to propionate, from glycolate to lactate and also from glyoxylate to pyruvate increased the inhibitory potency.
5. When tested against the 3.5 s efflux ofl-lactate, the same inhibitory pattern was seen as withd-lactate.
6. The transport of chloroacetate, glycolate and acetoacetate, which were available in a radio-labeled form of high specific activity, was measured directly in 3.5 s efflux studies. It was Na+-dependent and could be inhibited by 10 mmol/ll-lactate. Glyoxylate, on the other hand, which did not inhibitd-lactate transport, did also not show a Na+-dependent,l-lactate inhibitable efflux from the tubular lumen.
The data indicate that a variety of short chain fatty acids and their analogs are transported by the same Na+-dependent transport system in the brush border which transportsl- andd-lactate. The specificity is determined by the molecule size, hydrophobicity of one part of the molecule, the electron attracting abilities of substitutes on C-atom 2 or 3 and the charge distribution on the molecule.
