Bradykinin stimulates airway epithelial Cl- secretion via two second messenger pathways.
In canine airway epithelial cells, bradykinin increases intracellular concentrations of D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], cytosolic calcium concentration ([Ca2+]c), and adenosine 3',5'-cyclic monophosphate (cAMP). To determine the role of these second messengers in bradykinin-stimulated Cl- secretion, we studied the secretory response to this peptide using canine tracheal monolayers mounted in Ussing chambers. Bradykinin stimulated Cl- secretion [measured as short-circuit current (Isc)] when added to submucosal or mucosal surfaces; however, secretory responses differed substantially. Submucosal addition of bradykinin induced a biphasic increase in secretion; mucosal addition induced a monophasic increase in secretion. Both responses were mediated by B2 receptors. We show that activation of bradykinin receptors can stimulate Cl- secretion in two ways. 1) Bradykinin added to either surface stimulates prostaglandin synthesis and release at the basolateral surface. This leads to activation of prostaglandin E2-sensitive receptors on the basolateral surface that are coupled to cAMP production and an increase in apical membrane Cl- conductance. 2) In addition, bradykinin added to the submucosal surface increases Ins(1,4,5)P3 and [Ca2+]c levels, which enhance basolateral K+ conductance and the electrical driving force for apical Cl- exit. Whereas secretion requires activation of apical Cl- channels, the data show that Cl- secretion can also be modulated by activation of basolateral K+ channels. These data indicate that bradykinin-induced transepithelial Cl- secretion is mediated by two independent, second messenger pathways. These results provide the first evidence for expression of both pathways in a polar fashion in an epithelial monolayer.
Howard Hughes Medical Institute, Department of Pediatrics, University of Iowa College of Medicine, Iowa City 52242.
J J
JJ
Smith
J D
JD
McCann
M J
MJ
Welsh
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D018999:Charybdotoxin; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D004285:Dogs; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D007213:Indomethacin / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D009092:Mucous Membrane / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011796:Quinacrine / Q000494:pharmacology; D012604:Scorpion Venoms / Q000494:pharmacology; D015290:Second Messenger Systems / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000502:physiology*; D014966:Xanthenes / Q000494:pharmacology; D044004:Xanthones
D002712:Chlorides; D011448:Prostaglandin Antagonists; D012604:Scorpion Venoms; D013873:Thionucleotides; D014966:Xanthenes; D044004:Xanthones; D018999:Charybdotoxin; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D000001:Calcimycin; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D011796:Quinacrine; D007545:Isoproterenol; D001920:Bradykinin; D015056:1-Methyl-3-isobutylxanthine; D007213:Indomethacin