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CELLULAR AND MOLECULAR

Nucleotide-Induced Restoration of Conjunctival Chloride and Fluid Secretion in Adenovirus Type 5-Infected Pigmented Rabbit Eyes

Departments of Pharmaceutical Sciences (A.A.K., H.J.G., M.H.I.S., V.H.L.L.), Ophthalmology (M.D.T., R.W.R., V.H.L.L.), Molecular Microbiology and Immunology (M.D.T.), Molecular Pharmacology and Toxicology (K.-J.K.), Physiology and Biophysics (K.-J.K.), Biomedical Engineering (K.-J.K.), Medicine (K.-J.K.), Doheny Eye Institute (M.D.T., D.S., R.W.R.), and Will Rogers Institute Pulmonary Research Center (K.-J.K.), University of Southern California, Los Angeles, California

We evaluated the role of extracellular UTP and other nucleotides in the regulation of chloride (J_Cl) and fluid secretion (J_Cl) across the pigmented rabbit conjunctiva. J_v was determined in freshly excised conjunctival tissues mounted between two buffer reservoirs maintained in an enclosed environment at 37°C. Short circuit current (I_sc) and ³⁶Cl flux were measured using modified Ussing-type chambers. Fluid flux measurements were made with a pair of capacitance probes. After observing the baseline for 15 to 30 min, fluid flux was measured in the presence of mucosally applied nucleotides (10 µM) for a period of 30 min. Mucosal application of 10 µM each of UTP, UDP, ATP, ADP, AMP, adenosine, and ATP--S transiently stimulated fluid secretion across the conjunctiva to a significant extent for 10 to 15 min. Other nucleotides did not show any significant effect. The stimulation of fluid secretion correlated well with the stimulation in I_sc (r² = 0.85). UTP (0.1–1000 µM) led to a maximal increase in fluid secretion by 11.72 ± 0.48 µl/(h · cm²) with an EC₅₀ value of 10.39 ± 1.08 µM. ATP (0.1–1000 µM) caused a maximal increase in fluid secretion by 11.89 ± 0.88 µl/(h · cm²) with an EC₅₀ value of 17.23 ± 2.63 µM. Adenovirus type 5 (Ad5) infection significantly decreased both net ³⁶Cl secretion across the conjunctiva by 56% and the rate of fluid secretion by 56%. UTP (10 µM), but not 1 mM 8-bromo-cAMP, was able to elicit a normal stimulatory response in the Ad5-infected tissues. In conclusion, mucosal application of purinergic nucleotides may be therapeutically important in restoring ion and fluid secretion in the diseased conjunctiva.

Address correspondence to: Dr. Vincent H. L. Lee, Department of Pharmaceutical Sciences, School of Pharmacy, 1985 Zonal Ave., University of Southern California, Los Angeles, CA 90089-9121. E-mail: vincentl{at}usc.edu

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