Antiarrhythmic drug action. Blockade of the inward sodium current.

1The cellular electrophysiological effects of amiodarone and its metabolite desethylamiodarone (DEA) were studied in guinea-pig ventricular myocardium by use of standard microelectrode techniques. 2 Both compounds produced significant increases in action potential duration (Class III antiarrhythmic effect) and decreases in maximum rate of depolarization (Class I effect), at clinically relevant concentrations. 3 The Class I effects were rate-dependent, with small (0-16%) falls in maximum depolarization rate in the absence of stimulation ('resting block') and progressively larger effects at decreasing interstimulus intervals (range 1200-300 ms). 4 The kinetics of onset and offset of the Class I effect in response to a step change in driving rate were quite fast for both drugs (comparable to those reported for Class lb agents). 5 It is concluded that this unique combination of Class III action plus Class I effects with fast onset and offset kinetics may help explain the great efficacy of amiodarone in antiarrhythmic therapy.

Section: Rate-dependent Blockmentioning

confidence: 94%

Resting, and rate‐dependent depression of of guinea‐pig ventricular action potentials by amiodarone and desethylamiodarone

Pallandi

Campbell

1987

“…This class of antiarrhythmic agent usually depresses V.., of the action potential upstroke (related to the fast inward sodium current) in a manner modulated by the level of membrane potential and the rate ofstimulation (Johnson & McKinnon, 1957;Chen & Gettes, 1976). The combination of these two factors is explained by the 'modulated receptor' (Hille, 1977;Hondeghem & Katzung, 1977; and the 'guarded receptor' (Grant et al, 1984) hypotheses. Although not marked, labetalol showed a higher affinity for activated than inactivated channel states, since its inhibitory effects on V.. of Purkinje fibres were dependent on the frequency of stimulation and on the membrane potential.…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological effects of labetalol on canine atrial, cardiac Purkinje fibres and ventricular muscle

Mill

Neto

1987

1 Using conventional microelectrode techniques for the intracellular recordings of the membrane potential, the effects of labetalol were studied on cardiac Purkinje, atrial and ventricular muscle fibres of the dog. 2 Labetalol (1-101M) reduced, in a concentration-dependent manner, the action potential amplitude (APA) and the maximum rate of rise of the action potential (V. ) in Purkinje fibres.3 The action potential duration (APD) was decreased in Purkinje fibres but significantly increased in ventricular fibres after small concentrations of labetalol (1-3 jIM). The atrial fibres were not very sensitive to labetalol. 4 Depolarization of the cardiac Purkinje fibres by increasing the external potassium concentration (8-12mM), potentiated the labetalol effects on APA and V,",. but blocked its effects on the APD. 5 The effects of labetalol on V,,, of Purkinje fibres were dependent on the frequency of stimulation.

“…Previous studies indicate that the onset rate of the use-dependent block correlates directly with molecular weight, (Courtney, 1979;1980a,b) and increases with increasing drug concentration (Courtney, 1980a;Gintant et al, 1983;Grant et al, 1984). The studies of 2 ms I I--Onset recovery of Vmax from the block show a strong correlation between molecular weight and recovery times (Courtney, 1980a,b;Grant et al, 1984). The relationship between the usedependent kinetics and pKa (the dissociation constant), or the log P (the log of the n-octanol: partition coefficient) has also been investigated (Courtney, 1979;1980a,b;Grant et al, 1984).…”

Section: Recoveryfrom the Use-dependent Effect Ofpirmenolmentioning

confidence: 99%

“…The studies of 2 ms I I--Onset recovery of Vmax from the block show a strong correlation between molecular weight and recovery times (Courtney, 1980a,b;Grant et al, 1984). The relationship between the usedependent kinetics and pKa (the dissociation constant), or the log P (the log of the n-octanol: partition coefficient) has also been investigated (Courtney, 1979;1980a,b;Grant et al, 1984). Pirmenol (338.5) has a very similar molecular weight to disopyramide (339) and a somewhat larger molecular weight than quinidine (324).…”

Section: Recoveryfrom the Use-dependent Effect Ofpirmenolmentioning

confidence: 99%

“…The use-dependent block of Vemx was measured by a procedure similar to that previously described (Courtney, 1980a;Kohlhardt, 1982;Campbell, 1983a,b;Kohlhardt et al, 1983;Grant et al, 1984). The preparation was stimulated at rates of 0.2, 1, 2 and 3Hz for 30-60 s. These trains of stimuli were applied after a rest period of 90s, which was sufficient for recovery from the use-dependent decrease in V,,..x and conduction velocity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Use‐dependent effects of pirmenol on and conduction in guinea‐pig ventricular myocardium

Hasegawa

Hirai

Noguchi

et al. 1990

1 The use-dependent effects of pirmenol, a new antiarrhythmic drug, on the maximal rate of rise (V,) of the action potential, conduction velocity, and their corresponding recovery kinetics were studied in isolated papillary muscles of guinea-pig. Standard microelectrode techniques were used to monitor the conduction and action potential characteristics of the muscles. 2 Pirmenol decreased V,,,x and the overshoot of action potentials in a dose-dependent fashion. Also, doses of pirmenol greater than 1 mm abolished the generation of action potentials. Low concentrations of pirmenol (3 and 1OpM) prolonged the action potential duration, while concentrations greater than 0.1 mm shortened it markedly.3 The resting block of V,,.x in the presence of 10 and 30M pirmenol was 9.48 + 3.12 and 20.36 + 3.61%, and that of conduction velocity 2.87 + 1.52 and 6.58 + 2.09%, respectively. 4 The degree of use-dependent block induced by 10 and 30M pirmenol during 0.2, 1, 2 and 3Hz stimulations was dose-and rate-dependent. 5 In the presence of 30Mm pirmenol, mean values of time constants for the onset of the use-dependent inhibition of V,,,x and conduction velocity during a 2Hz stimulation were 1.32 + 0.15 and 1.28 + 0.09s, respectively. The recovery time constants averaged 15.83 + 2.14 (for V,,.x) and 27.80 + 8.74 (for conduction velocity) s in the presence of 30 gM pirmenol.6 These results showed that the characteristics of the use-dependent inhibition of V,,mx and conduction velocity induced by pirmenol are similar to those of slow kinetic drugs such as disopyramide rather than of fast ones.