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

Abstract

SUMMARY We used standard microelectrode techniques to record delayed afterdepolarizations (DAD) induced by ouabain (2 x 1 0 7 M) in isolated canine Purkinje fibers (PF) and studied the response of DAD to the fast Na* channel blocker, tetrodotoxin (TTX, 1 mg/liter); the slow channel blocker, verapamil (verap, 1 mg/liter); the putative Ca 2+ blocker, AHR-2666 (AHR, 45 mg/liter); and lidocaine (lido, 4 mg/liter), which increases steady state outward current and decreases background inward current. PF were driven at cycle lengths of 1000-200 msec. Ouabain superfusion for 30 minutes induced DAD with amplitudes of 17.0 ± 1.5 (mean ± SE) mV at a cycle length of 200 msec. 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 * .

Automaticity, triggered activity, and responses to adrenergic stimulation in cat subendocardial Purkinje fibers after healing of myocardial infarction.

“…'7 The measurements of the amplitude and coupling interval of delayed afterdepolarizations were made in a manner similar to that described by Rosen and Danilo. 18 The amplitude was measured from the most negative level recorded during repolarization to the peak positive level reached by the delayed afterdepolarization. The coupling interval was measured from the upstroke of the last driven action potential to the peak positive level of the delayed afterdepolarization.…”

Premature escape beats. A model for triggered activity in the intact heart?

“…Based on the response of PEBs to electrical stimulation, we postulate that PEBs are based on triggered activity resulting from delayed afterdepolarizations. This hypothesis was tested in 82 experiments by 1) stimulation under control conditions and in combination with 2) subtoxic and toxic amounts of ouabain 20-50 jig/kg, 3) lidocaine 3 mg/kg, and 4) doxorubicin [16][17][18][19][20][21][22][23][24] mg/M2. The stimulation protocol, which was repeated at random five to 10 times, consisted of 10 and 50 stimuli using interstimulus intervals of 200, 400, 600, and 800 msec.…”

Premature escape beats induced by overdrive pacing in canine Purkinje fibers. Evidence for the role of normal automaticity as an underlying cellular mechanism.

“…Previous studies had shown that lidocaine at therapeutic concentrations suppresses normal automaticity and delayed afterdepolarizations. 22,23 The effects of the drug matrix on mechanisms for normal and abnormal impulse initiation have been studied extensively, as have its effects on conduction.9-12,18,23,26 However, knowledge of its actions on cell coupling, on passive membrane properties, and on threshold for excitability are incomplete. Needless to say, such information would be valuable in furthering our understanding of the actions of the drugs in the matrix.…”

“…The Purkinje fibers were impaled with 3 M KCIfilled glass microelectrodes having tip resistances of [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] Mfl. Attempts were made to impale the site of earliest impulse initiation, at which the slope of phase 4 and phase 0 merged smoothly in the typical configuration of a pacemaker fiber.…”