Beta-adrenergic-mediated Cl secretion: evidence for additional non-cAMP-dependent pathway of effect.
It has been suggested that beta-adrenergic receptor antagonists with intrinsic sympathomimetic activity, like pindolol, are weak partial agonists for beta-adrenergic-stimulated adenylyl cyclase activation. To evaluate this possibility, beta-adrenergic-mediated chloride secretion was studied in tracheal epithelial cells maintained in primary culture. Pindolol caused a dose-dependent increase in chloride secretion with a half-maximal effective concentration of 91 pM to a maximum that was 30 +/- 3% that of isoproterenol. Pindolol-induced chloride secretion was antagonized by the beta-adrenergic antagonist nadolol. However, in contrast to isoproterenol, pindolol did not stimulate adenosine 3',5'-cyclic monophosphate (cAMP) accumulation, adenylyl cyclase activity, or protein kinase A activation. Further studies examined the coupling of beta-adrenergic stimulation of cAMP accumulation to beta-adrenergic stimulation of chloride secretion. Coincubation of cells with the phosphodiesterase inhibitor RA233 increased maximal isoproterenol-stimulated cAMP accumulation eightfold but did not significantly increase the potency or maximal effect of isoproterenol for chloride secretion. It is clear that beta-adrenergic-stimulated elevations in cAMP mediate chloride secretion. These studies also demonstrate that pindolol, a drug with intrinsic sympathomimetic activity, mediates a beta-adrenergic receptor-specific increase in chloride secretion without increasing adenylyl cyclase nor protein kinase A activities. Thus intrinsic sympathomimetic activity may represent a non-cAMP-dependent mechanism of beta-adrenergic effect.
Feldman
R D
RD
Department of Internal Medicine, College of Medicine, University of Iowa, Iowa City 52242.
Brotherton
A
A
Welsh
M J
MJ
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004072:Digitonin; D004285:Dogs; D004789:Enzyme Activation; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D007294:Inositol / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology*; D007700:Kinetics; D009130:Muscle, Smooth / Q000502:physiology; D010869:Pindolol / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D014132:Trachea / Q000502:physiology*
D002712:Chlorides; D007295:Inositol Phosphates; D011943:Receptors, Adrenergic, beta; D007294:Inositol; D010869:Pindolol; D000242:Cyclic AMP; D011494:Protein Kinases; D000262:Adenylyl Cyclases; D004072:Digitonin; D007545:Isoproterenol