The aim of many medical therapies for glaucoma is to slow aqueous secretion by the ciliary epithelium. However, little is known about the transport physiology of aqueous formation. Anisosmotic changes in cell volume will be imposed to probe the ionic mechanisms and regulation of aqueous secretion. This strategy is guided by 4 considerations: (i) Perturbation of cell volume (vc) is an effective probe for defining the transport mechanisms and regulation of many cells; (ii) Preliminary data have documented the value of this approach to ciliary epithelial cells; (iii) Some of the mechanisms needed for transepithelial transport are also used for volume regulation, and many others must be affected by the electrophysiologic and biochemical changes triggered by the volume-regulatory mechanisms; and (iv) Regulation of vc is intrinsically important for normal aqueous secretion since solutes and water pass through the ciliary cells at a high rate. Without such regulation, fluctuations in secretion rate could lead to cell swelling and disruption. The experimental approach will be to use electronic cell sizing to study vc and patch clamping to study membrane transport events while fixing the compositions of the fluids bathing both surfaces of the membranes. These measurements will be supplemented with intracellular and transepithelial electrical recording, fluorometric analysis of intracellular pH and Ca2+, and chemical analysis of intracellular ions and water. Nonpigmented and pigmented ciliary epithelial cells will be studied separately in continuous and primary cultures, avoiding tissue and cellular heterogeneity. Rabbit iris- ciliary body will be studied electrophysiologically in parallel, to confirm that the measurements of cells in culture are physiologically relevant. The specific issues to be addressed include: (i) the ionic mechanisms for the regulatory volume responses following anisosmotic perturbations of cell volume, (ii) possible regulatory roles of intracellular ph and Ca2+ activity in the volume regulatory responses, and (iii) the possible effects and modes of action of pharmacologic agents and hormones on volume regulation. Agents to be studied include: clinically significant antiglaucomatous drugs, agents (such as desmopressin) which increase aqueous secretion, and hormones (such as atriopeptin) whose role in aqueous secretion is currently controversial.

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National Eye Institute (NEI)
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Visual Sciences A Study Section (VISA)
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University of Pennsylvania
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McLaughlin, Charles W; Zellhuber-McMillan, Sylvia; Macknight, Anthony D C et al. (2007) Electron microprobe analysis of rabbit ciliary epithelium indicates enhanced secretion posteriorly and enhanced absorption anteriorly. Am J Physiol Cell Physiol 293:C1455-66
Do, C W; Civan, M M (2006) Swelling-activated chloride channels in aqueous humour formation: on the one side and the other. Acta Physiol (Oxf) 187:345-52
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Do, Chi-Wai; Peterson-Yantorno, Kim; Mitchell, Claire H et al. (2004) cAMP-activated maxi-Cl(-) channels in native bovine pigmented ciliary epithelial cells. Am J Physiol Cell Physiol 287:C1003-11
Civan, Mortimer M; Macknight, Anthony D C (2004) The ins and outs of aqueous humour secretion. Exp Eye Res 78:625-31
Do, C W; Civan, M M (2004) Basis of chloride transport in ciliary epithelium. J Membr Biol 200:1-13
McLaughlin, Charles W; Zellhuber-McMillan, Sylvia; Macknight, Anthony D C et al. (2004) Electron microprobe analysis of ouabain-exposed ciliary epithelium: PE-NPE cell couplets form the functional units. Am J Physiol Cell Physiol 286:C1376-89
Civan, Mortimer M (2003) Foreword to symposium ""forty years of epithelial transport-specificity and commonality"": a tribute to Professor Jose A Zadunaisky. J Exp Zool A Comp Exp Biol 300:3-4

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