Abstract
Bovine adrenal zona fasciculata cells express a novel K+current (IAC) that sets the resting potential while it couples adrenocorticotropin and angiotensin II receptors to membrane depolarization and cortisol secretion. IAC is distinctive among K+ channels both in its activation by ATP and its inhibition by cyclic AMP. Whole-cell and single-channel patch-clamp recording was used to establish a pharmacological profile of IAC K+ channels. IAC was blocked by antagonists of cyclic nucleotide-gated channels, including the diphenylbutylpiperidine (DPBP) antipsychotic pimozide andl-cis-diltiazem. Other DPBPs, including penfluridol and fluspirilene, also potently inhibited this channel. The inhibition of IAC by DPBPs was selective because 200-fold higher concentrations of penfluridol were required to inhibit voltage-gated IA K+ channels in adrenal zona fasciculata cells. Standard K+ channel antagonists blocked IAC at concentrations 100- to 100,000-fold higher than the DPBPs. IAC channels were also inhibited by the sulfonylureas glyburide and tolbutamide but at concentrations higher than those that typically block ATP-sensitive inward rectifier K+ channels. Overall, the relative order of potency and associated IC50 values for IAC antagonists were as follows: penfluridol (0.187 μM) > fluspirilene (0.232 μM) > pimozide (0.354 μM) ≫l-cis-diltiazem (24.9 μM) ≈ quinidine (24.1 μM) > bupivacaine (113.2 μM) > tolbutamide (784.4 μM) > BaCl2 (1027 μM) > 4-aminopyridine (2750 μM) > tetraethylammonium (24,270 μM). IAC channels are unique in combining the pharmacological properties of K+-selective channels with those of cyclic nucleotide-gated cation channels. The potent block of IACchannels identifies DPBPs as a new class of K+ channel antagonists and suggests additional targets for these neuroleptics in the central nervous system.
Footnotes
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Send reprint requests to: Dr. John J. Enyeart, Department of Pharmacology, The Ohio State University, College of Medicine, 5188 Graves Hall, 333 W. 10th Ave., Columbus, OH 43210-1239. E-mail:enyeart.1{at}osu.edu
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↵1 This work was supported by National Institute of Diabetes and Digestive and Kidney Grant DK47875 (to J.J.E.) and by American Heart Association, National Center, Grant-in-Aid 94011740 (to J.J.E.).
- Abbreviations:
- IAC
- noninactivating potassium current in bovine adrenal zona fasciculata cells
- IA
- rapidly inactivating voltage-dependent potassium current in bovine adrenal cells
- AZF
- adrenal zona fasciculata
- CNG
- cyclic nucleotide-gated
- DPBP
- diphenylbutylpiperidine
- 4-AP
- 4-aminopyridine
- TEA
- tetraethylammonium
- Received December 1, 1999.
- Accepted March 3, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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