Reduction in sensitivity to Cl- channel blockers by HCO3--CO2 in rabbit cortical collecting duct

K. Matsuzaki, V. L. Schuster, J. B. Stokes

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Abstract

We examined the ability of HCO3--CO2 to modify the potency of Cl- channel blockers in the renal cortical collecting duct (CCD) for the following two reasons. 1) From a practical point of view, there is, to our knowledge, no information regarding the effect of the HCO3--CO2 buffer system on the potency of Cl- channel blockers. 2) We showed in the companion manuscript [Am. J. Physiol. 257 (Cell Physiol. 26): C94-C101, 1989] that HCO3--CO2 stimulates transepithelial anion exchange in the CCD. Based on precedent in the literature, we postulated that HCO3- stimulates the basolateral membrane Cl- channel conductance. Here, we demonstrate that several Cl- channel blockers can reduce CCD Cl- self exchange when the solutions are buffered in N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES). Concentrations of blockers producing 80% inhibition in HEPES, pH 7.4, produced only 20% inhibition in 25 mM HCO3--CO2, pH 7.4. The ability of HCO3--CO2 to reduce blocker potency had an IC50 of only 2 mM. We also examined interactions of HCO3--CO2 and blockers with regard to the principal cell basolateral Cl- conductance. Blockers did not alter the Rb+ flux, a marker of K+ transport, but did reduce transepithelial conductance (G(T)), i.e., the blockers inhibited the principal cell basolateral Cl- conductance. As was the case with intercalated cell anion exchange, G(T) measurements indicated that HCO3--CO2 impaired the ability of Cl- channel blockers to inhibit the principal cell Cl- conductance. Two lines of evidence indicated that the effect is specific for the HCO3- (or CO2) molecule: 1) a series of other small anions did not reproduce the HCO3- effect; and 2) isohydric elevation of HCO3- in high-K+ nigericin-treated cells reproduced the effect, indicating that an intracellular pH shift is not necessary to desensitize the Cl- transport system to the blockers. These results imply that HCO3--CO2 sensitivity represents an important characteristic of some Cl- channels.

Original languageEnglish (US)
Pages (from-to)C103-C109
JournalAmerican Journal of Physiology - Cell Physiology
Volume257
Issue number1 (26/1)
StatePublished - Jan 1 1989
Externally publishedYes

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ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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