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Marc H. Levin, Jung Kyung Kim, Jie Hu, A. S. Verkman; Potential Difference Measurements of Ocular Surface Na+ Absorption Analyzed Using an Electrokinetic Model. Invest. Ophthalmol. Vis. Sci. 2006;47(1):306-316. doi: 10.1167/iovs.05-1082.
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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 μM) and benzamil (K i 0.2 μM). 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 K m 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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