Adenosine receptors and phosphodiesterase inhibitors stimulate Cl- secretion in Calu-3 cells.
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 A2B 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 (Isc) that was glibenclamide-sensitive, achieving 20-85% of forskolin-stimulated Isc. Papaverine, cilostazol, and rolipram also augmented both the magnitude and the duration of Isc following low dose stimulation of adenosine receptors with Ado (0.1-1.0 microM, P < 0.01). Subsequent studies demonstrated that very low concentrations of cilostazol or papaverine (approximately 1/2 peak serum concentrations) were sufficient to activate Isc, and both agents markedly augmented Ado-stimulated Isc (1 microM, P < 0.01). Our results provide evidence that select PDEis, at concentrations achieved as part of systemic therapies, can activate CFTR-dependent Isc 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.
Cobb
Bryan R
BR
Department of Human Genetics, Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, 35233, USA.
Fan
Lijuan
L
Kovacs
Timea E
TE
Sorscher
Eric J
EJ
Clancy
John P
JP
D000243:Adenosine Deaminase / Q000378:metabolism; D000838:Anions; D002460:Cell Line; D002713:Chlorine / Q000378:metabolism*; D000077407:Cilostazol; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004594:Electrophysiology; D004848:Epithelium / Q000473:pathology; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D020105:Milrinone / Q000494:pharmacology; D009154:Mutation; D010208:Papaverine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D020889:Rolipram / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors
D000838:Anions; C505032:CFTR protein, human; D007004:Hypoglycemic Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D018047:Receptors, Purinergic P1; D013450:Sulfones; D013777:Tetrazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D002713:Chlorine; D000068677:Sildenafil Citrate; D010208:Papaverine; D000242:Cyclic AMP; D000243:Adenosine Deaminase; D020105:Milrinone; D020889:Rolipram; D000077407:Cilostazol; D005905:Glyburide