No abstract

1 The cystic ®brosis gene protein, the cystic ®brosis 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 b-adrenergic stimulation of mucin secretion has not been determined. The present study has investigated the actions of adenosine A 1 and A 2 receptor antagonists to determine whether ability to stimulate mucin secretion correlates with correction of CFTR antibody inhibited b-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 A 1 receptor antagonist, 8 cyclopentyltheophylline (CPT) was a less potent stimulator of mucin secretion than was the A 2 receptor antagonist dimethylpropargylxanthine (DMPX). A concentration of CPT close to the K i for A 1 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 b-adrenergic induced increases in cyclic AMP. This aords real promise for the development of a selective drug treatment for cystic ®brosis.