Activation of airway cl- secretion in human subjects by adenosine.
We investigated cystic fibrosis (CF) transmembrane conductance regulator (CFTR) regulation by A2 adenosine (Ado) receptors and beta2 adrenergic receptors in CFTR-corrected CFBE41o- airway cells and human subjects. CFBE41o- cells stimulated with Ado (10 microM), isoproterenol (Iso, 10 microM), or Ado + Iso (10 microM each) elevated cyclic AMP (cAMP) above control conditions (P < 0.001), with the Iso conditions increasing cAMP approximately 10-fold above that produced by Ado alone (P < 0.001). All agonist conditions had similar effects on short circuit current at 10 and 25 microM, with no further currents produced by subsequent stimulation with forskolin (20 microM). CFTR dependence was demonstrated by glybenclamide block of agonist-stimulated currents. Nasal potential difference studies in normal (n = 50) subjects demonstrated that Ado (10 microM) and Ado + Iso (10 microM each) produced more polarization compared with Iso (10 microM Ado increase = 44%, 10 microM Ado + Iso increase = 52%, P < 0.05 for each condition compared with Iso alone). Studies completed in patients with CF (n = 10, "severe" genotypes) confirmed that Ado-stimulated polarization was CFTR-dependent. Together, these results indicate that Ado is a potent Cl- secretagogue in vivo, with relatively small effects on cAMP levels despite strong effects on CFTR-dependent short circuit current and nasal Cl- transport. These findings support growing evidence indicating a role for Ado regulation of CFTR-dependent Cl- secretion in vivo.
Hentchel-Franks
Karen
K
Departments of Pediatrics and Medicine, the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, 35233, USA.
Lozano
David
D
Eubanks-Tarn
Valerie
V
Cobb
Bryan
B
Fan
Lijuan
L
Oster
Robert
R
Sorscher
Eric
E
Clancy
J P
JP
D000241:Adenosine / Q000494:pharmacology*; D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D001980:Bronchi / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D006801:Humans; D017136:Ion Transport; D007545:Isoproterenol / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; C505032:CFTR protein, human; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000241:Adenosine; D007545:Isoproterenol