Coote, Kevin, Atherton, Hazel, Young, Alice, Sugar, Rosemary, Burrows, Rachel, Smith, Nicola, Schlaeppi, Jean-Marc, Groot-Kormelink, Paul, Gosling, Martin and Danahay, Henry (2008) The guinea-pig tracheal potential difference as an in vivo model for the study of epithelial sodium channel function in the airways. British Journal of Pharmacology, 155 (7). pp. 1025-1033. ISSN 1476-5381

Abstract

BACKGROUND AND PURPOSE: The epithelial sodium channel (ENaC) is a key regulator of airway mucosal hydration and mucus clearance. Negative regulation of airway ENaC function is predicted to be of clinical benefit in the cystic fibrosis lung. The aim of this study was to develop a small animal model to enable the direct assessment of airway ENaC function in vivo. EXPERIMENTAL APPROACH: Tracheal potential difference (TPD) was utilized as a measure of airway epithelial ion transport in the guinea-pig. ENaC activity in the trachea was established with a dose-response assessment to a panel of well-characterized direct and indirect pharmacological modulators of ENaC function, delivered by intra-tracheal (i.t.) instillation. KEY RESULTS: The TPD in anaesthetized guinea-pigs was attenuated by the direct ENaC blockers: amiloride, benzamil and CF552 with ED(50) values of 16, 14 and 0.2 microg kg(-1) (i.t.), respectively. 5-(N-Ethyl-N-isopropyl) amiloride, a structurally related compound but devoid of activity on ENaC, was without effect on the TPD. Intra-tracheal dosing of the Kunitz-type serine protease inhibitors aprotinin and placental bikunin, which have previously been demonstrated to inhibit proteolytic activation of ENaC, likewise potently attenuated TPD in guinea-pigs, whereas alpha(1)-antitrypsin and soya bean trypsin inhibitor were without effect. CONCLUSIONS AND IMPLICATIONS: The pharmacological sensitivity of the TPD to amiloride analogues and also to serine protease inhibitors are both consistent with that of ENaC activity in the guinea-pig trachea. The guinea-pig TPD therefore represents a suitable in vivo model of human airway epithelial ion transport.

Item Type:	Article
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez...
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Keywords:	ion transport; cystic fibrosis; mucokinetic; ENaC; animal model; amiloride; benzamil; CF552; aprotinin; channel-activating protease
Related URLs:	http://www.ncbi.nlm.nih.gov/sites/entrez...
Date Deposited:	14 Dec 2009 13:48
Last Modified:	31 Jan 2013 00:56
URI:	https://oak.novartis.com/id/eprint/1322