The proposed work is divided into four related categories, all converging on the problems of aqueous humor formation and treatment of glaucoma: Development of new drugs (topical carbonic anhydrase inhibitors); study of ionic reactions underlying secretion of aqueous; exploration of the effect of A1C13 and other acids on aqueous secretion and pH of ciliary processes; effect of autonomic drugs and Na-K-ATPase inhibitors on electrolyte movement from plasma to aqueous. 1.) We are searching for a topical carbonic anhydrase inhibitor with properties such that 1 drop of solution will lower intraocular pressure in man for 6-12 hours. This demands a continuing effort in organic synthesis, analysis of physico-chemical properties of compounds, and aqueous humor dynamics in animals and man. Feasibility of this goal seems reasonable; it has already been achieved in the rabbit. Almost certainly, such a compound will have no systemic toxicity in man, or any other effect on the eye. 2.) We believe it possible (likely?) that in aqueous humor (and other secretory sites, as cerebrospinal fluid and pancreas), the observed linkage of Na+ and HCO3- has a specific chemical basis, in ion pairing of NaCO3- and NaHCO3-degrees. This has not been considered for epithelial secretion but has been entertained as a basis for HCO3- - Cl- exchange in red cells. In this view Na+ is not the moving force for fluid formation, but Na is incorporated into an anion or undissociated molecule. We shall investigate this; if true, the new concept should profoundly affect studies of ion transport. 3.) We continue to study our finding that protonation by Lewis or Bronsted acids reduces or abolishes aqueous humor secretion. This has theoretical implications for mechanisms of secretion and offers the possibility of reduction of aqueous secretion by new methods. In this context we shall also study the pH of ciliary process and how this may be changed by acids or by carbonic anhydrase inhibitors. 4.) We shall measure the rates of ion movement from plasma to aqueous humor, before and after administration of various classes of drugs known to affect aqueous secretion, as we have done with carbonic anhydrase inhibitors. This is a neglected aspect of ocular pharmacology; we shall study ouabain, timolol, pilocarpine, epinephrine, and several others. Such measurements should throw light on their (presently unknown) mechanism.
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