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Iontophoretic beta-adrenergic stimulation of human sweat glands: possible assay for cystic fibrosis transmembrane conductance regulator activity in vivo.
Exp Physiol. 2008 Aug; 93(8):969-81.EP

Abstract

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 beta-adrenergic but not cholinergic sweating in CF. Therefore, the beta-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 beta-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 beta-adrenergic and cholinergic sweating. We also tested the efficacy of different beta-adrenergic agonists. Our results indicated that in normal subjects the cholinergic secretory response is mediated by activation of Ca(2+)-dependent Cl(-) conductance as well as K(+) conductances. In contrast, the beta-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 beta-adrenergic agonists are significantly smaller compared with those generated by cholinergic agonists, which in turn reflects in smaller beta-adrenergic secretory responses compared with cholinergic secretory responses. Furthermore, the beta-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 beta-adrenergic sweat responses, levels of intracellular cAMP above that achievable with a beta-adrenergic agonist alone are essential. beta-Adrenergic secretion can be stimulated in vivo by concurrent iontophoresis of these drugs in normal, but not in CF, subjects.

Authors+Show Affiliations

Department of Pediatrics, UC San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0831, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18441335

Citation

Shamsuddin, A K M., et al. "Iontophoretic Beta-adrenergic Stimulation of Human Sweat Glands: Possible Assay for Cystic Fibrosis Transmembrane Conductance Regulator Activity in Vivo." Experimental Physiology, vol. 93, no. 8, 2008, pp. 969-81.
Shamsuddin AK, Reddy MM, Quinton PM. Iontophoretic beta-adrenergic stimulation of human sweat glands: possible assay for cystic fibrosis transmembrane conductance regulator activity in vivo. Exp Physiol. 2008;93(8):969-81.
Shamsuddin, A. K., Reddy, M. M., & Quinton, P. M. (2008). Iontophoretic beta-adrenergic stimulation of human sweat glands: possible assay for cystic fibrosis transmembrane conductance regulator activity in vivo. Experimental Physiology, 93(8), 969-81. https://doi.org/10.1113/expphysiol.2008.042283
Shamsuddin AK, Reddy MM, Quinton PM. Iontophoretic Beta-adrenergic Stimulation of Human Sweat Glands: Possible Assay for Cystic Fibrosis Transmembrane Conductance Regulator Activity in Vivo. Exp Physiol. 2008;93(8):969-81. PubMed PMID: 18441335.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Iontophoretic beta-adrenergic stimulation of human sweat glands: possible assay for cystic fibrosis transmembrane conductance regulator activity in vivo. AU - Shamsuddin,A K M, AU - Reddy,M M, AU - Quinton,P M, Y1 - 2008/04/25/ PY - 2008/4/29/pubmed PY - 2008/9/26/medline PY - 2008/4/29/entrez SP - 969 EP - 81 JF - Experimental physiology JO - Exp. Physiol. VL - 93 IS - 8 N2 - 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 beta-adrenergic but not cholinergic sweating in CF. Therefore, the beta-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 beta-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 beta-adrenergic and cholinergic sweating. We also tested the efficacy of different beta-adrenergic agonists. Our results indicated that in normal subjects the cholinergic secretory response is mediated by activation of Ca(2+)-dependent Cl(-) conductance as well as K(+) conductances. In contrast, the beta-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 beta-adrenergic agonists are significantly smaller compared with those generated by cholinergic agonists, which in turn reflects in smaller beta-adrenergic secretory responses compared with cholinergic secretory responses. Furthermore, the beta-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 beta-adrenergic sweat responses, levels of intracellular cAMP above that achievable with a beta-adrenergic agonist alone are essential. beta-Adrenergic secretion can be stimulated in vivo by concurrent iontophoresis of these drugs in normal, but not in CF, subjects. SN - 0958-0670 UR - https://www.unboundmedicine.com/medline/citation/18441335/Iontophoretic_beta_adrenergic_stimulation_of_human_sweat_glands:_possible_assay_for_cystic_fibrosis_transmembrane_conductance_regulator_activity_in_vivo_ L2 - https://doi.org/10.1113/expphysiol.2008.042283 DB - PRIME DP - Unbound Medicine ER -