title: Class I antiarrhythmics inhibit Na+ absorption and Cl- secretion in rabbit descending colon epithelium.
abstract: To clarify the mechanism of the diarrhea associated with the clinical use of antiarrhythmic drugs we assessed the effects of these agents on transepithelial Na+ absorption and Cl- secretion, on basolateral K+ conductance, and on the properties of single basolateral K+ channels of rabbit colon epithelium. Quinidine and propafenone, both at 10 microM, inhibited Na+ absorption by 27 and 38% respectively, compared with 50% with 5 mM Ba2+. The other tested class I antiarrhythmics disopyramide, mexiletine, lidocaine, and flecainide decreased Na+ current by 9-13%. Procainamide and the class III antiarrhythmics N-acetylprocainamide, sotalol, ibutilide, and amiodarone were no or were very weak inhibitors of Na+ absorption. Cl- secretion, stimulated with the adenosine analogue NECA (5'-N-ethylcarboxamide-adenosine), was reduced by 54% with quinidine and by 29% with propafenone compared with 100% with Ba2+. Mexiletine, lidocaine, and flecainide inhibited Cl- secretion by 10-23%, whereas the class III antiarrhythmics were no or were weak inhibitors. Those antiarrhythmics that inhibited Na+ and Cl- transport also reduced basolateral K+ conductance, determined in amphotericin B permeabilized epithelia. The activity of the high-conductance, Ca2+-activated, voltage-dependent K+ (BK(Ca)) channel, which is primarily responsible for basolateral K+ recycling during Na+ absorption, was inhibited by 10-30 microM quinidine or propafenone in the form of a rapidly dissociating block. Mexiletine and flecainide inhibited the single channel conductance at higher concentrations; disopyramide, lidocaine, and procainamide were ineffective. In conclusion, the present evidence suggests that the diarrhea caused by class I antiarrhythmic drugs such as quinidine and propafenone is a result of a reduction in basolateral K+ conductance and inhibition of BK(Ca) channels, thereby impeding transepithelial Na+ and water absorption.
authors: Besondere Einrichtung für medizinische Aus- und Weiterbildung, Medizinische Universität Wien, Spitalgasse 23, 1090 Vienna, Austria. herbert.plass@meduniwien.ac.at
authors: Herbert
authors: H
authors: Plass
authors: Markus
authors: M
authors: Charisius
authors: Wolfgang
authors: W
authors: Wyskovsky
authors: Florian
authors: F
authors: Amor
authors: Klaus
authors: K
authors: Turnheim
authors: Hubert
authors: H
authors: Wiener
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism*; D044683:Colon, Descending / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004553:Electric Conductivity; D005260:Female; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects / Q000502:physiology; D011405:Propafenone / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*
chemical_list: D000889:Anti-Arrhythmia Agents; D002712:Chlorides; D024681:Potassium Channels, Calcium-Activated; D011405:Propafenone; D012964:Sodium; D011802:Quinidine; D011188:Potassium