title: Importance of basolateral K+ conductance in maintaining Cl- secretion in murine nasal and colonic epithelia.
abstract: 1. Epithelia lining the nasal passages and descending colon of wild-type and cystic fibrosis (CF) mice were examined by the short-circuit current technique. Additionally, intracellular Ca2+ ion determinations were made in nasal epithelial cells. Forskolin produced anion secretory currents in wild-type and CF nasal epithelia. It produced similar effects in wild-type colonic epithelia, but not in colonic epithelia from CF mice. 2. After electrogenic Na+ transport was blocked with amiloride and electrogenic Cl- secretion was stimulated with forskolin, the ability of K+ channel blockers to inhibit the forskolin-induced Cl- current was determined. The order of efficiency for nasal epithelium was: Ba2+ > clofilium >>> TEA = azimilide >>> trans-6-cyano-4-(N-ethylsulphonyl-N-methylamino)-3-hydroxy-2, 2-dimethyl-chromane (293B) = charybdotoxin, whereas for the colonic epithelium the order was: Ba2+ = 293B >>> azimilide = TEA >>> clofilium = charybdotoxin. 3. 1-Ethyl-2-benzimdazolinone (1-EBIO) was able to generate large Cl--secretory currents in colonic epithelia which were partially sensitive to charybdotoxin, with the remaining current being inhibited by 293B. In nasal epithelia 1-EBIO produced only a small transient effect on current. 4. Forskolin released intracellular Ca2+ in nasal epithelial cells; this activity was attenuated when more powerful Ca2+-releasing agents were applied first. 5. It is concluded that an action on basolateral cAMP-sensitive K+ channels is an important determinant of the maintained responses to forskolin in nasal and colonic epithelia, in addition to the effects on the cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane. In CF nasal epithelia the activation of calcium-activated chloride channels (CACs) substitutes for the effect on CFTR. On the basis of the different orders of potency of the blocking agents and the differential response to 1-EBIO it is concluded that the cAMP-sensitive K+ channels are different in the airways and the gut.
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QJ, UK.
authors.forename: L J
authors.initials: LJ
authors.lastname: MacVinish
authors.forename: M E
authors.initials: ME
authors.lastname: Hickman
authors.forename: D A
authors.initials: DA
authors.lastname: Mufti
authors.forename: H J
authors.initials: HJ
authors.lastname: Durrington
authors.forename: A W
authors.initials: AW
authors.lastname: Cuthbert
mesh_terms: D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000378:metabolism*; D004553:Electric Conductivity; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D051379:Mice; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism*; D009994:Osmolar Concentration; D011188:Potassium / Q000502:physiology*; D026902:Potassium Channel Blockers
chemical_list: D001562:Benzimidazoles; D002120:Calcium Channel Agonists; D002712:Chlorides; D026902:Potassium Channel Blockers; D005576:Colforsin; D000584:Amiloride; C102635:1-ethyl-2-benzimidazolinone; D011188:Potassium; D002118:Calcium