Xanthine derivatives without PDE effect stimulate voltage-activated chloride conductance of toad skin

• Published in: American Journal of Physiology: Cell Physiology Vol. 284; no. 2; p. C521
• Main Authors: Nagel, Wolfram, Katz, Uri
• Format: Journal Article
• Language: English
• Published: 01.02.2003
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00276.2002

1  Department of Physiology, University of Munich, 80336 Munich, Germany; and 2  Department of Biology, Technion, Haifa, Israel The effect of xanthine derivatives on the voltage-activated Cl conductance ( G Cl ) of amphibian skin was analyzed. 3-Isobutyl-1-methylxanthine (IBMX) and the recently synthesized xanthine derivatives 3,7-dimethyl-1-propyl xanthine (X-32) and 3,7-dimethyl-1-isobutyl xanthine (X-33), which lack inhibitory effects on phosphodiesterases in CHO and Calu-3 cells, increased voltage-activated G Cl without effect on baseline conductance at inactivating voltage. Half-maximal stimulation of G Cl occurred at 108 ± 9 µM for X-32 and X-33 after apical or basolateral application. The stimulation of G Cl , which occurs only in the presence of Cl in the mucosal solution, is caused by a shift of the voltage sensitivity to lower clamp potentials and an increase of the maximally activated level. Furosemide reversed both the shift of sensitivity and the increase in magnitude. These patterns are fundamentally different from those seen after application of membrane-permeant, nonmetabolized analogs of cAMP, and they indicate that the xanthines stimulate G Cl directly. This notion is strengthened by the lack of influence on intracellular cAMP content, which is consistent with the observations in CHO and Calu-3 cells. We propose that the xanthine derivatives increase the voltage sensitivity of a regulative component in the conductive Cl pathway across amphibian skin. Bufo viridis ; furosemide; 3-isobutyl-1-methylxanthine; mitochondria-rich cells