Timolol decreases aqueous humor flow but not Na+ movement from plasma to aqueous.
OBJECTIVE
To determine whether the well-known effect of timolol in reducing ocular pressure and aqueous humor (AH) flow is a function of reduced Na+ movement from plasma to aqueous. Previously, the authors have shown this to be the case for carbonic anhydrase inhibitors.


METHODS
The rate of appearance of 22Na in rabbit posterior aqueous was measured 1 to 3 minutes after the intravenous injection (time T) of the isotope. One hour before this, the animals received one of the following: two drops of 0.5% timolol, two drops of 3.5% pilocarpine, or 25 mg/kg intravenous methazolamide. At 1 minute (T + 1), a posterior chamber sample was taken; 2 minutes later (T + 3) a second sample was removed from the fellow eye. The rate constant of sodium accession is simply the difference between the two counts/2 minutes. Aqueous flow was measured by dilution of sulfacetamide marker as described previously.


RESULTS
The rate constant (k(in)) for sodium entering the posterior chamber was 0.036 +/- 0.004 minute-1 (n = 17). Corresponding to previous findings, methazolamide (25 mg/kg intravenous) reduced this to 0.023 +/- 0.003 minute-1 (n = 14). Conversely, timolol (two drops of 0.5% solution) had no effect on kin, which measured 0.037 +/- 0.004 minute-1 (n = 12). Similarly, as expected, pilocarpine had no effect on k(in) (0.035 +/- 0.003 minute-1). Control flow was 3.9 microliters/minute +/- 0.4; after timolol, 2.5 microliters/minute +/-0.1; after methazolamide, 2.4 microliters/minute +/-0.2; after pilocarpine, 3.6 microliters/minute +/- 0.2. These are converted to rate constants by dividing by volume of posterior aqueous (60 microliters). The control rate constant for fluid entry was 0.065 minute-1, 1.8-fold higher than for sodium.


CONCLUSIONS
A central dogma of the formation of AH (and cerebrospinal fluid) is that fluid moves isotonically from plasma to AH or cerebrospinal fluid and, therefore, that rate constant k(in) for fluid and for sodium are approximately the same. In the authors' hands, the fluid constant was modestly higher than for sodium. This holds for normal function and also for the reduced k(in) for fluid and sodium after carbonic anhydrase inhibition. The k(in) for neither flow nor sodium was affected by pilocarpine. Surprisingly, however timolol, which reduces flow, had no effect on Na+ entry.
Maren
T H
TH
Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, USA.
Godman
D R
DR
Pancorbo
B M
BM
Vogh
B P
BP
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D008704:Methazolamide / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D011817:Rabbits; D012964:Sodium / Q000097:blood / Q000378:metabolism*; D013999:Timolol / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D002257:Carbonic Anhydrase Inhibitors; D010862:Pilocarpine; D013999:Timolol; D012964:Sodium; D008704:Methazolamide