In vivo activation of CFTR-dependent chloride transport in murine airway epithelium by CNP.
Inhibitors of guanosine 3',5'-cyclic monophosphate (cGMP)-inhibited phosphodiesterases stimulate Cl- transport across the nasal epithelia of cystic fibrosis mice carrying the delta F508 mutation [cystic fibrosis transmembrane conductance regulator (CFTR) (delta F/delta F)], suggesting a role for cGMP in regulation of epithelial ion transport. Here we show that activation of membrane-bound guanylate cyclases by C-type natriuretic peptide (CNP) stimulates hyperpolarization of nasal epithelium in both wild-type and delta F508 CFTR mice in vivo but not in nasal epithelium of mice lacking CFTR [CFTR(-/-)]. With the use of a nasal transepithelial potential difference (TEPD) assay, CNP was found to hyperpolarize lumen negative TEPD by 6.1 +/- 0.6 mV in mice carrying wild-type CFTR. This value is consistent with that obtained with 8-bromoguanosine 3',5'-cyclic monophosphate (6.2 +/- 0.9 mV). A combination of the adenylate cyclase agonist forskolin and CNP demonstrated a synergistic ability to induce Cl- secretion across the nasal epithelium of CFTR(delta F/delta F) mice. No effect on TEPD was seen with this combination when used on CFTR(-/-) mice, implying that the CNP-induced change in TEPD in CFTR(delta F/delta F) mice is CFTR-dependent.
Kelley
T J
TJ
Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio 44106-4948, USA.
Cotton
C U
CU
Drumm
M L
ML
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009297:Nasal Mucosa / Q000502:physiology / Q000503:physiopathology*; D020098:Natriuretic Peptide, C-Type; D009599:Nitroprusside / Q000494:pharmacology; D011506:Proteins / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D062367:ortho-Aminobenzoates / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002712:Chlorides; D011506:Proteins; D062367:ortho-Aminobenzoates; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D020098:Natriuretic Peptide, C-Type; D009599:Nitroprusside; D005576:Colforsin; D000584:Amiloride; C001209:fenamic acid; D006152:Cyclic GMP; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid