PMID: 8996186Jan 1, 1997Paper

Renal and cerebrospinal fluid formation pharmacology of a high molecular weight carbonic anhydrase inhibitor

The Journal of Pharmacology and Experimental Therapeutics
T H MarenD R Godman

Abstract

To achieve selective inhibition of cytosolic and membrane-bound carbonic anhydrase (CA II and CA IV, respectively), we synthesized a polymer of molecular weight 3500 from polyoxyethylene bis acetic acid and aminobenzolamide. The new compound, designated F (for Florida) 3500, is stable, water soluble and nontoxic. It is excreted largely unchanged by glomerular filtration. The Ki at 37 degrees C against CA II is 0.14 microM and against CA IV 4.0 microM, some 20 times more than the parent aminobenzolamide and about three times more than acetazolamide or methazolamide. F 3500 does not penetrate red cells and is confined to extracellular fluid. Relations of dose to renal HCO3-excretion was studied by i.v. injection into rats. Peak effect was reached with 100 mg/kg, eliciting 40 mM HCO3- in urine; this is taken to be the effect of inhibiting CA IV. This compares to a peak of 103 mM HCO3- after 3 mg/kg aminobenzolamide, which agrees with previous data on other low molecular weight sulfonamides and defines the effect on CA II and CA IV. We conclude that both isozymes are necessary for normal full renal reabsorption of HCO3-. We studied the effect of perfusing F 3500 (100-4000 microM) through the ventriculo-cisternal system of rats on c...Continue Reading

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