Actions of adenosine A1 and A2 receptor antagonists on CFTR antibody-inhibited beta-adrenergic mucin secretion response.
1. The cystic fibrosis gene protein, the cystic fibrosis transmembrane conductance regulator (CFTR) acts as a chloride channel and is a key regulator of mucin secretion. The mechanism by which 3-isobutyl-1-methylxanthine (IBMX) corrects the defect in CFTR mediated beta-adrenergic stimulation of mucin secretion has not been determined. The present study has investigated the actions of adenosine A1 and A2 receptor antagonists to determine whether ability to stimulate mucin secretion correlates with correction of CFTR antibody inhibited beta-adrenergic response and whether excessive cyclic AMP rise is required. 2. CFTR antibodies were introduced into living rat submandibular acini by hypotonic swelling. Following recovery, mucin secretion in response to isoproterenol was measured. 3. The adenosine A1 receptor antagonist, 8 cyclopentyltheophylline (CPT) was a less potent stimulator of mucin secretion than was the A2 receptor antagonist dimethylpropargylxanthine (DMPX). A concentration of CPT close to the Ki for A1 receptor antagonism (10 nM) did not stimulate mucin secretion. 4. DMPX, although a potent stimulator of mucin secretion, did not correct CFTR antibody inhibited mucin secretion. 5. CPT corrected defective CFTR antibody inhibited mucin secretion at a high (1 mM) concentration, suggesting a mechanism other than adenosine receptor antagonism. 6. DMPX potentiated the isoproterenol induced cyclic AMP rise, whereas CPT did not. 7. Correction of the defective CFTR mucin secretion response did not correlate with ability to stimulate mucin secretion and did not require potentiation of beta-adrenergic induced increases in cyclic AMP. This affords real promise for the development of a selective drug treatment for cystic fibrosis.
Pereira
M M
MM
Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff.
Lloyd Mills
C
C
Dormer
R L
RL
McPherson
M A
MA
D015056:1-Methyl-3-isobutylxanthine / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002850:Chromatography, Gel; D000242:Cyclic AMP / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000276:immunology / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004588:Electrophoresis, Cellulose Acetate; D009077:Mucins / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011233:Precipitin Tests; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013363:Submandibular Gland / Q000187:drug effects / Q000502:physiology; D013805:Theobromine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D013806:Theophylline / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
D000906:Antibodies; D009077:Mucins; D058915:Purinergic P1 Receptor Antagonists; D011943:Receptors, Adrenergic, beta; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C053907:8-cyclopentyl-1,3-dimethylxanthine; C057837:3,7-dimethyl-1-propargylxanthine; D013806:Theophylline; D000242:Cyclic AMP; D013805:Theobromine; D015056:1-Methyl-3-isobutylxanthine