A cyclic nucleotide PDE5 inhibitor corrects defective mucin secretion in submandibular cells containing antibody directed against the cystic fibrosis transmembrane conductance regulator protein.
A selective cyclic nucleotide PDE5 inhibitor corrected the defective mucin secretion response to the beta-agonist isoproterenol in submandibular acinar cells inhibited by antibody directed against the cystic fibrosis transmembrane conductance regulator. The PDE5 inhibitor was as effective as cpt-cyclic AMP or a selective PDE4 inhibitor. However, the PDE5 inhibitor had no effect on basal or isoproterenol-stimulated cyclic AMP levels and did not stimulate mucin secretion. The results showing, for the first time, correction of the CFTR mucin secretion defect by a PDE5 inhibitor, which may involve cyclic GMP, will have a major impact in development of a rational drug treatment for cystic fibrosis.
McPherson
M A
MA
Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff, UK.
Pereira
M M
MM
Lloyd Mills
C
C
Murray
K J
KJ
Dormer
R L
RL
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000276:immunology* / Q000502:physiology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D009077:Mucins / Q000187:drug effects / Q000378:metabolism*; D011688:Purinones / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D020889:Rolipram / Q000494:pharmacology; D013363:Submandibular Gland / Q000187:drug effects / Q000378:metabolism*
D000906:Antibodies; C505032:CFTR protein, human; D009077:Mucins; D011688:Purinones; D011724:Pyridazines; D011725:Pyridines; C060368:SK&F 95654; C073025:2-(2-propoxyphenyl)-6-purinone; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; C517384:Pde5a protein, rat; D006152:Cyclic GMP; D020889:Rolipram; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine