Lubiprostone stimulates secretion from tracheal submucosal glands of sheep, pigs, and humans.
Lubiprostone, a putative ClC-2 chloride channel opener, has been investigated for its effects on airway epithelia (tracheas). Lubiprostone is shown to increase submucosal gland secretion in pigs, sheep, and humans and to increase short-circuit current (SCC) in the surface epithelium of pigs and sheep. Use of appropriate blocking agents and ion-substitution experiments shows anion secretion is the driving force for fluid formation in both glands and surface epithelium. From SCC concentration-response relations, it is shown that for apical lubiprostone K(d) = 10.5 nM with a Hill slope of 1.08, suggesting a single type of binding site and, from the speed of the response, close to the apical surface, confirmed the rapid blockade by Cd ions. Responses to lubiprostone were reversible and repeatable, responses being significantly larger with ventral compared with dorsal epithelium. Submucosal gland secretion rates following basolateral lubiprostone were, respectively, 0.2, 0.5, and 0.8 nl gl(-1) min(-1) in humans, sheep, and pigs. These rates dwarf any contribution surface secretion adds to the accumulation of surface liquid under the influence of lubiprostone. Lubiprostone stimulated gland secretion in two out of four human cystic fibrosis (CF) tissues and in two of three disease controls, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis (COPD/IPF), but in neither type of tissue was the increase significant. Lubiprostone was able to increase gland secretion rates in normal human tissue in the continuing presence of a high forskolin concentration. Lubiprostone had no spasmogenic activity on trachealis muscle, making it a potential agent for increasing airway secretion that may have therapeutic utility.
Joo
N S
NS
Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, UK.
Wine
J J
JJ
Cuthbert
A W
AW
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000838:Anions / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D018118:Chloride Channels / Q000378:metabolism; D003550:Cystic Fibrosis / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D005088:Exocrine Glands / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D000068238:Lubiprostone; D009092:Mucous Membrane / Q000187:drug effects* / Q000378:metabolism*; D009119:Muscle Contraction / Q000187:drug effects; D012756:Sheep; D034421:Sus scrofa; D014132:Trachea / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*
D000838:Anions; D018118:Chloride Channels; D000068238:Lubiprostone; D002217:Carbachol; D000527:Alprostadil