Timolol may inhibit aqueous humor secretion by cAMP-independent action on ciliary epithelial cells.
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; Ca(2+) activity and pH were monitored with fura 2 and 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, respectively. Timolol (10 microM) produced similar K and Cl losses from ciliary epithelia in HCO/CO(2) solution but had no effect in HCO/CO(2)-free solution or in HCO/CO(2) solution containing the carbonic anhydrase inhibitor acetazolamide. Inhibition of Na(+)/H(+) exchange by dimethylamiloride in HCO/CO(2) solution reduced Cl and K comparably to timolol. cAMP did not reverse timolol's effects. Timolol (100 nM, 10 microM) and levobunolol (10 microM) produced cAMP-independent inhibition of the regulatory volume increase (RVI) in PE cells and increased intracellular Ca(2+) and pH. Increasing Ca(2+) with ionomycin also blocked the RVI. The results document a previously unrecognized cAMP-independent transport effect of timolol. Inhibition of Cl(-)/HCO exchange may mediate timolol's inhibition of aqueous humor formation.
McLaughlin
C W
CW
Department of Physiology, University of Otago Medical School, Dunedin, New Zealand.
Peart
D
D
Purves
R D
RD
Carré
D A
DA
Peterson-Yantorno
K
K
Mitchell
C H
CH
Macknight
A D
AD
Civan
M M
MM
D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects / Q000378:metabolism*; D001639:Bicarbonates / Q000494:pharmacology; D002245:Carbon Dioxide / Q000494:pharmacology; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D002924:Ciliary Body / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology*; D005260:Female; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008297:Male; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011188:Potassium / Q000378:metabolism; D011817:Rabbits; D012964:Sodium / Q000378:metabolism; D012996:Solutions; D013999:Timolol / Q000494:pharmacology*
D001639:Bicarbonates; D002712:Chlorides; D012996:Solutions; D002245:Carbon Dioxide; D013999:Timolol; D012964:Sodium; D000242:Cyclic AMP; D011188:Potassium