Effects of anion channel antagonists in canine colonic myocytes: Comparative pharmacology of Cl-, Ca2+ and K+ currents

Gregory M. Dick, In Deok Kong, Kenton M. Sanders

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

1. Volume-Sensitive, Outwardly Rectifying (VSOR) Cl- currents were measured in canine colonic myocytes by whole-cell patch clamp. Decreasing extracellular osmolarity 50 milliosmoles l-1 activated current that was carried by Cl- and 5-7 times greater in the outward direction. 2. Niflumic acid, an inhibitor of Ca2+-activated Cl- channels, did not inhibit VSOR Cl- current. Glibenclamide, an antagonist of CFTR, and anthracene-9-carboxylate (9-AC) inhibited current less than 25% at 100 μM. 3. DIDS (4,4-diisothiocyanato-stilbene-2,2'disulphonate) inhibited VSOR Cl- current more potently than SITS (4-acetamido-4'-isothiocyanato-stilbene-2,2'-disulphonate). IC50s were 0.84 and 226 μM, respectively. 4. VSOR Cl- current was strongly inhibited by tamoxifen ([Z]-1-[p-dimethylaminoethoxy-phenyl]-1,2-diphenyl-1-butene), an anti-oestrogen compound (IC50 = 0.57 μM). 5. Gd3+ antagonized VSOR Cl- current more potently than La3+. The IC50 for Gd3+ was 23 μM. In contrast, 100 μM La3+ inhibited current only 35 ± 7%. 6. Antagonists of VSOR Cl- current had non-specific effects. These compounds blocked voltage-dependent K+ and Ca2+ currents in colonic myocytes. Tamoxifen (10 μM) and DIDS (10 μM) inhibited L-type Ca2+ current 87 ± 7 and 31 ± 5%, respectively. Additionally, in the presence of 300 nM charybdotoxin, tamoxifen (1 μM) and DIDS (10 μM) inhibited delayed rectifier K+ current 38 ± 8 and 10 ± 2%, respectively. 7. The pharmacology of VSOR Cl- channels overlaps with voltage-dependent cation channels. DIDS and tamoxifen inhibited VSOR Cl- equally. However, because DIDS had much less effect on L-type Ca2+ and delayed rectifier K+ channels than did tamoxifen, it might be useful in experiments to investigate the physiological and pathophysiological role of this conductance in whole tissues.

Original languageEnglish
Pages (from-to)1819-1831
Number of pages13
JournalBritish Journal of Pharmacology
Volume127
Issue number8
DOIs
StatePublished - 1999

Keywords

  • DIDS
  • Delayed rectifier K channels
  • Smooth muscle
  • Tamoxifen
  • Voltage-gated Ca channels
  • Volume-sensitive Cl channels

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