Effects of tetrodotoxin, lidocaine, verapamil, and AHR-2666 on Ouabain-induced delayed afterdepolarizations in canine Purkinje fibers.

Abstract

Standard microelectrode techniques were used to record delayed afterdepolarizations (DAD) induced by ouabain (2 .times. 10-7 M) in isolated canine Purkinje fibers (PF) and studied the response of DAD to the fast Na+ channel blocker, tetrodotoxin (TTX, 1 mg/l); the slow channel blocker, verapamil (verap, 1 mg/l); the putative Ca2+ blocker, AHR-2666 [1-(N-methylcarbamoyl)-3-(m-chlorphenoxy)-pyrrolidine] (AHR, 45 mg/l); and lidocaine (lido, 4 mg/l), which increases steady state outward current and decreases background inward current. PF were driven at cycle lengths of 1000-200 ms. Ouabain superfusion for 30 min induced DAD with amplitudes of 17.0 .+-. 1.5 (mean .+-. SE) mV at a cycle length of 200 ms. TTX, verap, AHR and lido all depressed DAD amplitude (P < 0.05). To intercompare the effects of the drugs, graphs were constructed relating DAD amplitude to basic cycle length, and the relative magnitude of effects of the drugs on DAD amplitude at all cycle lengths was tested using a nested analysis of variance. The effects of verap and AHR were equivalent, and both decreased DAD amplitude more at short (to 37% of ouabain control) than at long (to 76%) cycle lengths (P < 0.05). Lido had a different effect and decreased DAD nearly equivalently at short (to 64%) and long (to 75%) cycle lengths. The actions of TTX were intermediate between, and significantly different from, those of the other drugs (P < 0.05). AHR and verap appear to act similarly, by modifying the current responsible for DAD, whereas lido appears to act by a different mechanism, perhaps by increasing steady state outward current. The actions of TTX may be a result of its effect on the transient inward current or on a background current carried by Na+.