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Am J Physiol Cell Physiol (October 23, 2002). doi:10.1152/ajpcell.00276.2002
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Articles in PresS, published online ahead of print October 23, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00276.2002
Submitted on June 14, 2002
Accepted on October 16, 2002

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

Wolfram Nagel1* and Uri Katz2

1 Physiology, University of Munich, Munich, Germany
2 Biology, Technion, Haifa, Israel

* To whom correspondence should be addressed. E-mail: w.nagel{at}lrz.uni-muenchen.de.

This notion is strengthened by the lack of influence on intracellular cAMP content, which is consistent with the observations on 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. The effect of xanthine derivatives on the voltage-activated Cl- conductance GCl of amphibian skin was analyzed. IBMX and the recently synthesized xanthine derivatives X-32 and X-33, which lack inhibitory effects on phosphodiesterases in CHO and Calu-3 cells, increased the voltage-activated GCl without effect on the baseline conductance at inactivating voltage. Half-maximal stimulation of GCl occurred at 108±9 µM for X-32/33 after apical or basolateral application. The stimulation of GCl, which occurs only in the presence of Cl- in the mucosal solution, is caused by a shift of the voltage-sensitivity to lower clamp potential 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-permeable, non-metabolized analogues of cAMP, and indicate that the xanthines stimulate GCl directly. This notion is strengthened by the lack of influence on intracellular cAMP content, which is consistent with the observations on 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.




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