Interval-dependent effects of small antiarrhythmic drugs on excitability of guinea-pig myocardium

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

“…Such fast onset kinetics are consistent with the finding that amiodarone binds strongly and selectively to inactivated sodium chan-800 1000 1200 nels (Mason et al, 1984). Courtney, 1980a;Campbell, 1983b) and for the Ta drugs quinidine, disopyramide and procainamide (Tre = 2.3-12.2 s; Courtney, 1980a;Grant et al, 1982;Campbell, 1983a (Courtney, 1980a,b,c;Campbell, 1983b) (Varro et al, 1985). They are able to prolong action potential duration (Class III effect) and they have Class I effects with fast onset and offset kinetics so they respond rapidly to step increases in heart rate with an increased degree of depression of V. Thus in therapeutic concentrations, they have minimal influence on V.., and hence conduction at normal heart rates (Finerman et al, 1982;Zipes et al, 1984) but are able to respond to a premature beat or tachycardia with a rapid decrease in V,, (Campbell, 1983a).…”

“…While the ability to produce resting depression of V correlates well with lipophilicity for relatively low molecular weight drugs (Sada & Ban, 1981), this relationship does not hold for antiarrhythmic drugs with molecular weights above about 350 (Campbell, 1983b). For these compounds it has been suggested that their physical size somehow limits access to the resting sodium channel (Courtney, 1980a).…”

“…It is well-established that the ability of Class I antiarrhythmic agents to block the fast inward sodium channel and hence depress m of cardiac action potentials is enhanced at faster driving rates (Hondeghem & Katzung, 1980;Campbell, 1982;1983c;Courtney, 1980a). Several models of drug interaction with the sodium channel have been proposed to explain this behaviour (Hondeghem & Katzung, 1977;1980;1984;Courtney, 1980b,c;Grant et al, 1984).…”

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

“…Stimulation frequency-dependent (Estes et al, 1987;Nieminen et al, 1987) and 4.7 to 7.7 for oral administration (Farnham, 1987;Estes et al, 1987), pirmenol seems to show the ability to prolong action potentials. The characteristics of the use-dependent inhibition of V,,.x induced by pirmenol are similar to those of slow kinetic drugs, such as disopyramide which was shown to have a recovery time constant of 12.0 to 37.8s (Campbell, 1983a;Varro et al, 1985), rather than of fast kinetic drugs, according to the classification proposed by Courtney (1980a). 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 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.…”