Am J Physiol Renal Physiol 2002 Oct 01;2834:F765-70. doi: 10.1152/ajprenal.00253.2001.

On the natriuretic effect of verapamil: inhibition of ENaC and transepithelial sodium transport.

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The natriuretic effect of Ca(2+) channel blockers has been attributed to hemodynamic changes and to poorly defined direct tubular effects. To test the possibility that verapamil may inhibit Na(+) reabsorption at the distal tubule, its effect on transepithelial Na(+) transport in aldosterone-stimulated A6 cells was determined. Cells were grown on permeable supports, and short-circuit current (I(sc)) measured in an Ussing chamber was used as a surrogate marker for transepithelial Na(+) transport. Application of 300 microM verapamil to the apical side inhibited I(sc) by 77% and was nearly as potent as 100 microM amiloride, which inhibited I(sc) by 87%. Verapamil-induced inhibition of I(sc) was accompanied by a significant increase in transepithelial resistance, suggesting blockade of an apical conductance. Its action on transepithelial Na(+) transport does not appear to occur through inhibition of L-type Ca(2+) channels, since I(sc) was unaffected by removal of extracellular Ca(2+). Verapamil also does not appear to inhibit I(sc) by modulating intracellular Ca(2+) stores, since it fails to inhibit transepithelial Na(+) transport when added to the basolateral side. The effect on Na(+) transport is specific for verapamil, since nifedipine, Ba(2+), 4-aminopyridine, and charybdotoxin do not significantly affect I(sc). A direct effect of verapamil on the epithelial Na(+) channel (ENaC) was tested using oocytes injected with the alpha-, beta-, and gamma-subunits. We conclude that verapamil inhibits transepithelial Na(+) transport in A6 cells by blocking ENaC and that the natriuresis observed with administration of verapamil may be due in part to its action on ENaC.

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