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Am J Physiol Cell Physiol 281: C865-C875, 2001;
0363-6143/01 $5.00
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Vol. 281, Issue 3, C865-C875, September 2001

Timolol may inhibit aqueous humor secretion by cAMP-independent action on ciliary epithelial cells

Charles W. McLaughlin1, David Peart2, Robert D. Purves3, David A. Carré4, Kim Peterson-Yantorno4, Claire H. Mitchell4, Anthony D. C. Macknight1, and Mortimer M. Civan4,5

Departments of 1 Physiology, 2 Ophthalmology, and 3 Pharmacology, University of Otago Medical School, Dunedin, New Zealand; and Departments of 4 Physiology and 5 Medicine, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania

The beta -adrenergic antagonist timolol reduces ciliary epithelial secretion in glaucomatous patients. Whether inhibition is mediated by reducing cAMP is unknown. Elemental composition of rabbit ciliary epithelium was studied by electron probe X-ray microanalysis. Volume of cultured bovine pigmented ciliary epithelial (PE) cells was measured by electronic cell sizing; Ca2+ activity and pH were monitored with fura 2 and 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, respectively. Timolol (10 µM) produced similar K and Cl losses from ciliary epithelia in HCO<UP><SUB>3</SUB><SUP>−</SUP></UP>/CO2 solution but had no effect in HCO<UP><SUB>3</SUB><SUP>−</SUP></UP>/CO2-free solution or in HCO<UP><SUB>3</SUB><SUP>−</SUP></UP>/CO2 solution containing the carbonic anhydrase inhibitor acetazolamide. Inhibition of Na+/H+ exchange by dimethylamiloride in HCO<UP><SUB>3</SUB><SUP>−</SUP></UP>/CO2 solution reduced Cl and K comparably to timolol. cAMP did not reverse timolol's effects. Timolol (100 nM, 10 µM) and levobunolol (10 µM) produced cAMP-independent inhibition of the regulatory volume increase (RVI) in PE cells and increased intracellular Ca2+ and pH. Increasing Ca2+ with ionomycin also blocked the RVI. The results document a previously unrecognized cAMP-independent transport effect of timolol. Inhibition of Cl-/HCO<UP><SUB>3</SUB><SUP>−</SUP></UP> exchange may mediate timolol's inhibition of aqueous humor formation.

electron probe X-ray microanalysis; cell volume; cell pH; cell calcium; chloride/bicarbonate exchanger; sodium/hydrogen exchanger


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C. W. McLaughlin, S. Zellhuber-McMillan, A. D. C. Macknight, and M. M. Civan
Electron microprobe analysis of rabbit ciliary epithelium indicates enhanced secretion posteriorly and enhanced absorption anteriorly
Am J Physiol Cell Physiol, November 1, 2007; 293(5): C1455 - C1466.
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M. Y. Avila, C. H. Mitchell, R. A. Stone, and M. M. Civan
Noninvasive Assessment of Aqueous Humor Turnover in the Mouse Eye
Invest. Ophthalmol. Vis. Sci., February 1, 2003; 44(2): 722 - 727.
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