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  • Title: Potential difference measurements of ocular surface Na+ absorption analyzed using an electrokinetic model.
    Author: Levin MH, Kim JK, Hu J, Verkman AS.
    Journal: Invest Ophthalmol Vis Sci; 2006 Jan; 47(1):306-16. PubMed ID: 16384978.
    Abstract:
    PURPOSE: Corneal and conjunctival epithelia are capable of transcellular Na+ absorption and Cl- secretion, which drives water movement across these tissues. A recent study demonstrated with a new open-circuit potential difference (PD) technique that Cl- moves across the ocular surface in mice through Ca2+- and cAMP-sensitive Cl- channels, the latter pathway being the cystic fibrosis (CF) transmembrane conductance regulator (CFTR). The purpose of the present study was to identify transporting mechanisms involved in Na+ absorption and to develop a mathematical model of ocular surface ion transport to quantify the relative magnitudes of and electrochemical coupling among transporting processes. METHODS: PDs across the fluid-bathed ocular surface were measured in anesthetized wild-type and CF mice in response to Na+, Cl-, and K+ ion substitution and transporter agonists, inhibitors, and substrates. An electrokinetic model of the ocular surface epithelium was developed to simulate PD measurements, which involved computation of membrane potentials and cell [Na+], [K+], [Cl-] and volume from transporter activities and extracellular ion concentrations. RESULTS: Na+ replacement produced a 6 +/- 2-mV depolarization that was blocked by amiloride (K(i) 0.8 microM) and benzamil (Ki 0.2 microM). The Na+-dependent depolarization by amiloride was significantly greater in CF mice (19 +/- 3 mV). In wild-type mice, D-, but not L-glucose produced a phloridzin-sensitive, 4.1-mV hyperpolarization in the presence of Na+ and amiloride, with a Km for D-glucose of 2.5 mM. Glycine and L-arginine also produced Na+-dependent hyperpolarizations. The epithelial transport model accurately reproduced experimental PD measurements. CONCLUSIONS: PD measurements coupled with model computations defined quantitatively the roles of Na+ and Cl- transport processes in ocular surface ion and fluid secretion, and indicated that CFTR-dependent changes in apparent epithelial Na+ channel (ENaC) activity could be accounted for by electrochemical coupling, without requiring ENaC-CFTR interactions. The data and modeling also predicted significant enhancement of ocular surface fluid secretion by ENaC inhibitors and CFTR activators as possible therapies for dry eye syndromes.
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