Preclinical evidence that sildenafil and vardenafil activate chloride transport in cystic fibrosis.
BACKGROUND
Sildenafil has been implicated in the activation of cystic fibrosis transmembrane conductance regulator (CFTR) protein. The effect was observed in vitro and in the presence of doses roughly 300 times larger than those commonly used for treating erectile dysfunction.


OBJECTIVE
To evaluate in vivo the therapeutic efficacy of clinical doses of sildenafil and vardenafil, two clinically approved phosphodiesterase 5 inhibitors, for activating ion transport in cystic fibrosis.


METHODS
We used transepithelial potential difference in vivo across the nasal mucosa as a measure of sodium and chloride transport. The effect of a single intraperitoneal injection of sildenafil (0.7 mg/kg) or vardenafil (0.14 mg/kg) was investigated in F508del, cftr knockout and normal homozygous mice.


RESULTS
In F508del mice, but not in cftr knockout mice, the chloride conductance, evaluated by perfusing the nasal mucosa with a chloride-free solution in the presence of amiloride and with forskolin, was corrected 1 hour after sildenafil administration. A more prolonged effect, persisting for at least 24 hours, was observed with vardenafil. The forskolin response was increased after sildenafil and vardenafil in both normal and F508del mutant animals. In F508del mice, the chloride conductance in the presence of 200 microM 4-4'-diisothiocyanostilbene-2,2'-disulphonic acid, an inhibitor of alternative chloride channels, was much higher after sildenafil injection than after placebo treatment. No effect on the sodium conductance was detected in any group of animals.


CONCLUSIONS
Our results provide preclinical evidence that both drugs stimulate chloride transport activity of F508del-CFTR protein.
Lubamba
Bob
B
Department of Clinical Chemistry, Université Catholique de Louvain, Brussels, Belgium.
Lecourt
Hugues
H
Lebacq
Jean
J
Lebecque
Patrick
P
De Jonge
Hugo
H
Wallemacq
Pierre
P
Leal
Teresinha
T
D000818:Animals; D002712:Chlorides / Q000378:metabolism*; D005576:Colforsin / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004195:Disease Models, Animal; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D017136:Ion Transport / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects*; D051379:Mice; D018181:Mice, Inbred CFTR; D009297:Nasal Mucosa / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D046188:Protein Modification, Translational; D011687:Purines / Q000008:administration & dosage / Q000493:pharmacokinetics; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014227:Triazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D000069058:Vardenafil Dihydrochloride
D002712:Chlorides; D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D000069058:Vardenafil Dihydrochloride; D000068677:Sildenafil Citrate