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Vol. 292, Issue 2, 778-787, February 2000

Stimulation of Clminus Secretion by Chlorzoxazone1

Ashvani K. Singh, Daniel C. Devor, Aaron C. Gerlach, Margaret Gondor, Joseph M. Pilewski and Robert J. Bridges

Departments of Cell Biology and Physiology (A.K.S., D.C.D., A.C.G., J.M.P., R.J.B.), and Medicine and Pediatrics (M.G., J.M.P.), University of Pittsburgh, Pittsburgh, Pennsylvania.

We previously demonstrated that 1-ethyl-2-benzimidazolone (1-EBIO) directly activates basolateral membrane calcium-activated K+ channels (KCa), thereby stimulating Cl- secretion across several epithelia. In our pursuit to identify potent modulators of Cl- secretion that may be useful to overcome the Cl- secretory defect in cystic fibrosis (CF), we have identified chlorzoxazone [5-chloro-2(3H)-benzoxazolone], a clinically used centrally acting muscle relaxant, as a stimulator of Cl- secretion in several epithelial cell types, including T84, Calu-3, and human bronchial epithelium. The Cl- secretory response induced by chlorzoxazone was blocked by charybdotoxin (CTX), a known blocker of KCa. In nystatin-permeabilized monolayers, chlorzoxazone stimulated a basolateral membrane IK, which was inhibited by CTX and also stimulated an apical ICl that was inhibited by glibenclamide, indicating that the GCl responsible for this ICl may be cystic fibrosis transmembrane conductance regulator (CFTR). In membrane vesicles prepared from T84 cells, chlorzoxazone stimulated 86Rb+ uptake in a CTX-sensitive manner. In excised, inside-out patches, chlorzoxazone activated an inwardly-rectifying K+ channel, which was inhibited by CTX. 6-Hydroxychlorzoxazone, the major metabolite of chlorzoxazone, did not activate KCa, whereas zoxazolamine (2-amino-5-chlorzoxazole) showed a similar response profile as chlorzoxazone. In normal human nasal epithelium, chlorzoxazone elicited hyperpolarization of the potential difference that was similar in magnitude to isoproterenol. However, in the nasal epithelium of CF patients with the Delta F508 mutation of CFTR, there was no detectable Cl- secretory response to chlorzoxazone. These studies demonstrate that chlorzoxazone stimulates transepithelial Cl- secretion in normal airway epithelium in vitro and in vivo, and suggest that stimulation requires functional CFTR in the epithelia.

1 This work was supported by Cystic Fibrosis Foundation Fellowship I-974 (to A.K.S), Q-933 (to J.M.P), F-986 and Devor96PO (to D.C.D), and by National Institutes of Diabetes and Digestive and Kidney Diseases Grant DK-45970 (to R.J.B). R.J.B was also a Cystic Fibrosis research scholar (E841).

0022-3565/00/2922-0778$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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