On the natriuretic effect of verapamil: inhibition of ENaC and transepithelial sodium transport.
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.
Segal
Alan S
AS
University of Vermont, Burlington 05405, USA.
Hayslett
John P
JP
Desir
Gary V
GV
D000450:Aldosterone / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D053503:Epithelial Sodium Channels; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000378:metabolism; D009318:Natriuresis / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014667:Vasopressins / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology*; D014982:Xenopus laevis
D002121:Calcium Channel Blockers; D053503:Epithelial Sodium Channels; D007328:Insulin; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014667:Vasopressins; D000450:Aldosterone; D012964:Sodium; D014700:Verapamil; D009543:Nifedipine