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This Article Full Text Full Text (PDF) All Versions of this Article: 93/8/969    most recent expphysiol.2008.042283v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Shamsuddin, A. K. M. Articles by Quinton, P. M. PubMed PubMed Citation Articles by Shamsuddin, A. K. M. Articles by Quinton, P. M. Related Collections GI & Epithelial

¹ School of Medicine, Department of Pediatrics, University of California, San Diego, CA, USA ² Division of Biomedical Sciences, University of California, Riverside, CA, USA

With the advent of numerous candidate drugs for therapy in cystic fibrosis (CF), there is an urgent need for easily interpretable assays for testing their therapeutic value. Defects in the cystic fibrosis transmembrane conductance regulator (CFTR) abolished β-adrenergic but not cholinergic sweating in CF. Therefore, the β-adrenergic response of the sweat gland may serve both as an in vivo diagnostic tool for CF and as a quantitative assay for testing the efficacy of new drugs designed to restore CFTR function in CF. Hence, with the objective of defining optimal conditions for stimulating β-adrenergic sweating, we have investigated the components and pharmacology of sweat secretion using cell cultures and intact sweat glands. We studied the electrical responses and ionic mechanisms involved in β-adrenergic and cholinergic sweating. We also tested the efficacy of different β-adrenergic agonists. Our results indicated that in normal subjects the cholinergic secretory response is mediated by activation of Ca²⁺-dependent Cl^– conductance as well as K⁺ conductances. In contrast, the β-adrenergic secretory response is mediated exclusively by activation of a cAMP-dependent CFTR Cl^– conductance without a concurrent activation of a K⁺ conductance. Thus, the electrochemical driving forces generated by β-adrenergic agonists are significantly smaller compared with those generated by cholinergic agonists, which in turn reflects in smaller β-adrenergic secretory responses compared with cholinergic secretory responses. Furthermore, the β-adrenergic agonists, isoproprenaline and salbutamol, induced sweat secretion only when applied in combination with an adenylyl cyclase activator (forskolin) or a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine, aminophylline or theophylline). We surmise that to obtain consistent β-adrenergic sweat responses, levels of intracellular cAMP above that achievable with a β-adrenergic agonist alone are essential. β-Adrenergic secretion can be stimulated in vivo by concurrent iontophoresis of these drugs in normal, but not in CF, subjects.

(Received 15 February 2008; accepted after revision 25 April 2008; first published online 25 April 2008)
Corresponding author P. M. Quinton: Department of Pediatrics, UC San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0831, USA. Email: pquinton{at}ucsd.edu