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Adenosine Receptors and Phosphodiesterase Inhibitors Stimulate Cl^- Secretion in Calu-3 Cells

Departments of Human Genetics, Medicine, and Pediatrics, and Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama

Address correspondence to: Dr. J. P. Clancy, M.D., Associate Professor, Department of Pediatrics, Associate Scientist, Gregory Fleming James Cystic Fibrosis Research Center, 1600 7th Avenue South, Suite 620 ACC, Birmingham, AL 35233. E-mail: jclancy{at}peds.uab.edu

We investigated cystic fibrosis transmembrane conductance regulator (CFTR) activation by clinically used phosphodiesterase inhibitors (PDEis) in Calu-3 cell monolayers alone and in combination with A_2B adenosine receptor stimulation. This receptor pathway has previously been shown to activate wild-type and mutant CFTR molecules. Several PDEis, including milrinone, cilostazol (Pletal), papaverine, rolipram, and sildenafil (Viagra), produced a short circuit current (I_sc) that was glibenclamide-sensitive, achieving 20–85% of forskolin-stimulated I_sc. Papaverine, cilostazol, and rolipram also augmented both the magnitude and the duration of I_sc following low dose stimulation of adenosine receptors with Ado (0.1–1.0 µM, P < 0.01). Subsequent studies demonstrated that very low concentrations of cilostazol or papaverine ( 1/2 peak serum concentrations) were sufficient to activate I_sc, and both agents markedly augmented Ado-stimulated I_sc (1 µM, P < 0.01). Our results provide evidence that select PDEis, at concentrations achieved as part of systemic therapies, can activate CFTR-dependent I_sc in Calu-3 cell monolayers. These studies also indicate that PDEis have the capacity to augment an endogenous CFTR-activating pathway in an "in vivo"–like model system, and supports future investigations of these agents relevant to cystic fibrosis.

Abbreviations: adenosine deaminase, ADA • cystic fibrosis, CF • cystic fibrosis transmembrane conductance regulator, CFTR • cilostazol, Cil • 8-Cyclopentyl-1,3-dipropylxanthine, DPCPX • hexokinase, HEXO • short circuit current, I_sc • milrinone, Mil • papaverine, Pap • phosphodiesterase, PDE • PDE inhibitor, PDEi • rolipram, Rol • theophylline, Theo

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