P‐glycoprotein regulates a volume‐activated chloride current in bovine non‐pigmented ciliary epithelial cells.

Wu, Jin V.; Zhang, J. J.; Koppel, H.; Jacob, T. J. C.

doi:10.1113/jphysiol.1996.sp021254

Cited by 79 publications

(66 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Single outwardly rectifying Cl Ϫ channels, activated by hypotonic stimulation with a conductance of 19 pS, have been observed in rabbit osteoclasts (26) under conditions similar to those of this study. In agreement with our findings, swelling-activated whole-cell currents exhibit outward rectification and are blocked by NPPB in cultured human 407 intestinal cells (27) and rat epididymal cells (28), and similar P gluconate /P Cl permeability ratios, of 0.25 and 0.17, have been determined for volume-activated Cl Ϫ currents in HeLa cells (29) and in nonpigmented bovine ciliary epithelial cells (30), respectively, compared with 0.26 in the present study.…”

Section: Discussionsupporting

confidence: 89%

Volume regulation in the bovine lens and cataract. The involvement of chloride channels.

Zhang¹,

Jacob²

1996

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

The purpose of this study was to investigate volume regulation in the lens and its involvement in lens opacification (cataract) and the role of chloride channels in these processes. Single, isolated lens fiber cells from the lens were whole cell patch clamped. When exposed to hypotonic solution, an outwardly rectifying whole-cell current was activated. The current increased from 1.0 to 32.6 pA/pF, reversed at the chloride reversal potential (E Cl ϭ 0 mV), and was blocked by the chloride channel blockers 5, nitro-2-(3-phenylpropylamino) benzoate (NPPB) and tamoxifen. Replacing all but 5 mM of the external chloride with gluconate caused the reversal potential to shift ϩ 33 mV, consistent with a Cl Ϫ current with a gluconate/chloride permeability ratio of 0.26. When the whole lens of the eye was exposed to hypotonic solution, there was an initial increase in anteriorposterior diameter (5-8 min), representing lens swelling of 6.5%. This was followed by a decrease in volume to a new steady state value that lasted for up to 2 h. In the longer term ( Ն 2 h), the lenses began to swell again. The simultaneous exposure to hypotonic solution and tamoxifen or NPPB caused swelling and prevented this volume regulation. Lenses incubated in hypotonic solution and hypotonic solution containing tamoxifen became opaque after a 2-h incubation period. We conclude that the lens is able to volume regulate. It possesses volume-activated Cl Ϫ channels, the inhibition of which results in inhibition of volume regulation, lens swelling and opacification. Our data suggest the longterm prophylactic use of tamoxifen may make the patient more susceptible to cataract.

show abstract

Section: Discussionsupporting

confidence: 89%

Volume regulation in the bovine lens and cataract. The involvement of chloride channels.

Zhang¹,

Jacob²

1996

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the eye, P-gp is expressed in the retinal capillary endothelial cells (Holash and Stewart, 1993), retinal pigmented epithelial cells (Schlingemann et al, 1998), ciliary nonpigmented epithelium (Wu et al, 1996), conjunctival epithelial cells (Saha et al, 1998), and iris and ciliary muscle cells (Holash and Stewart, 1993). More recently, P-gp has been identified in the human and rabbit cornea for the first time in our laboratory (Dey et al, 2003).…”

mentioning

confidence: 84%

Pharmacokinetics of Erythromycin in Rabbit Corneas after Single-Dose Infusion: Role of P-Glycoprotein as a Barrier to in Vivo Ocular Drug Absorption

Dey

Gunda²,

Mitra³

2004

The Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Efflux pump like P-glycoprotein (P-gp) is known to be a major barrier to drug delivery. Functional P-glycoprotein has been recently identified in cornea and corneal cell lines. Thus, it is probable that P-glycoprotein may restrict in vivo ocular drug absorption, resulting in low ocular bioavailability. Experiments were designed using New Zealand albino (New Zealand White) rabbits to assess inhibitors of P-gp efflux to increase drug absorption. Anesthetized rabbits were given constant topical infusions of [14 C]erythromycin in the presence and absence of inhibitors. Testosterone, verapamil, quinidine, and cyclosporine A were selected as P-gp inhibitors. Transport experiments were conducted in Madin-Darby canine kidney cells transfected with the human mdr1 gene (MDCK-MDR1). Erythromycin exhibited significant efflux out of MDCK-MDR1 cells, suggesting that erythromycin is a good substrate for P-gp. Ocular pharmacokinetic studies were conducted using a topical single-dose infusion method. Maximum inhibition of P-gp mediated efflux was observed with 500 M testosterone. Area under the curve (AUC) 0-ϱ of erythromycin with 500 M testosterone was almost 4 times higher than AUC 0-ϱ without any inhibitor. Rate of elimination (k 10 ) for erythromycin and those with inhibitors was found to be similar (141 Ϯ 23 min), suggesting that elimination pathways were not altered. All the inhibitors were found to be nontoxic. Verapamil also inhibited the efflux pump with moderate change in AUC 0-ϱ and C max compared with control. Thus, P-gp is found to be active in vivo, and it restricts topical erythromycin absorption across the cornea, which can be inhibited by known P-gp inhibitors. Therefore, ocular bioavailability of P-gp substrates can be significantly enhanced by proper selection of P-gp inhibitors.

show abstract

“…Fourth, the current was inhibited by the conventional Cl Ϫ channel blockers NPPB ( see Refs. 18 and 27), tamoxifen (27,38,39), and extracellular ATP (11,36).…”

Section: Discussionmentioning

confidence: 99%

Cell cycle-dependent expression of volume-activated chloride currents in nasopharyngeal carcinoma cells

Chen

Wang

Zhu

et al. 2002

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Patch-clamping and cell image analysis techniques were used to study the expression of the volume-activated Cl− current, I Cl(vol), and regulatory volume decrease (RVD) capacity in the cell cycle in nasopharyngeal carcinoma cells (CNE-2Z). Hypotonic challenge caused CNE-2Z cells to swell and activated a Cl− current with a linear conductance, negligible time-dependent inactivation, and a reversal potential close to the Cl− equilibrium potential. The sequence of anion permeability was I− > Br− > Cl− > gluconate. The Cl− channel blockers tamoxifen, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), and ATP inhibited I Cl(vol). Synchronous cultures of cells were obtained by the mitotic shake-off technique and by a double chemical-block (thymidine and hydroxyurea) technique. The expression of I Cl(vol) was cell cycle dependent, being high in G1 phase, downregulated in S phase, but increasing again in M phase. Hypotonic solution activated RVD, which was cell cycle dependent and inhibited by the Cl− channel blockers NPPB, tamoxifen, and ATP. The expression of I Cl(vol) was closely correlated with the RVD capacity in the cell cycle, suggesting a functional relationship. Inhibition of I Cl(vol) by NPPB (100 μM) arrested cells in G0/G1. The data also suggest that expression of I Cl(vol) and RVD capacity are actively modulated during the cell cycle. The volume-activated Cl− current associated with RVD may therefore play an important role during the cell cycle progress.

show abstract

P‐glycoprotein regulates a volume‐activated chloride current in bovine non‐pigmented ciliary epithelial cells.

Cited by 79 publications

References 27 publications

Volume regulation in the bovine lens and cataract. The involvement of chloride channels.

Volume regulation in the bovine lens and cataract. The involvement of chloride channels.

Pharmacokinetics of Erythromycin in Rabbit Corneas after Single-Dose Infusion: Role of P-Glycoprotein as a Barrier to in Vivo Ocular Drug Absorption

Cell cycle-dependent expression of volume-activated chloride currents in nasopharyngeal carcinoma cells

Contact Info

Product

Resources

About