Class I antiarrhythmics inhibit Na+ absorption and Cl- secretion in rabbit descending colon epithelium

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.